From leptin to other adipokines in health and disease: Facts and expectations at the beginning of the 21st century Matthias Bl¨uher, Christos S. Mantzoros PII: DOI: Reference:
S0026-0495(14)00310-2 doi: 10.1016/j.metabol.2014.10.016 YMETA 53111
To appear in:
Metabolism
Please cite this article as: Bl¨ uher Matthias, Mantzoros Christos S., From leptin to other adipokines in health and disease: Facts and expectations at the beginning of the 21st century, Metabolism (2014), doi: 10.1016/j.metabol.2014.10.016
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Invited Review
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From leptin to other adipokines in health and disease:
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Facts and expectations at the beginning of the 21st century
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Matthias Blüher, Christos S. Mantzoros
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Department of Medicine, University of Leipzig, Leipzig, Germany Department of Endocrinology, Metabolism and Diabetes, VA Boston Medical Health Center, Boston, MA, USA
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Key words: Adipokines; obesity; type 2 diabetes, leptin, adiponectin, AdipoRon, DPP4,
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FGF21, TNFα, IL-1β, nampt/visfatin, BMP7
Corresponding author: Matthias Blüher, MD University of Leipzig Department of Medicine Liebigstr. 20 D-04103 Leipzig Tel. (+49) 341-9715984 Fax (+49) 341-9722439 E-mail: [email protected]
ACCEPTED MANUSCRIPT Abstract This year marks the 20th anniversary of the discovery of leptin, which has
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tremendously stimulated translational obesity research. The discovery of leptin has led to
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realizations that have established adipose tissue as an endocrine organ, secreting bioactive molecules including hormones now termed adipokines. Through adipokines, the adipose
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tissue influences the regulation of several important physiological functions including but not limited to appetite, satiety, energy expenditure, activity, insulin sensitivity and secretion,
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glucose and lipid metabolism, fat distribution, endothelial function, hemostasis, blood pressure, neuroendocrine regulation, and function of the immune system. Adipokines have a great potential for clinical use as potential therapeutics for obesity, obesity related metabolic, cardiovascular and other diseases. After 20 years of intense research efforts, recombinant
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leptin and the leptin analog metreleptin are already available for the treatment of congenital
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leptin deficiency and lipodystrophy. Other adipokines are also emerging as promising candidates for urgently needed novel pharmacological treatment strategies not only in obesity
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but also other disease states associated with and influenced by adipose tissue size and activity.
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In addition, prediction of reduced type 2 diabetes risk by high circulating adiponectin concentrations suggests that adipokines have the potential to be used as biomarkers for individual treatment success and disease progression, to monitor clinical responses and to identify non-responders to anti-obesity interventions. With the growing number of adipokines there is an increasing need to define their function, molecular targets and translational potential for the treatment of obesity and other diseases. In this review we present research data on adipose tissue secreted hormones, the discovery of which followed the discovery of leptin 20 years ago pointing to future research directions to unravel mechanisms of action for adipokines.
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ACCEPTED MANUSCRIPT List of abbreviations ADA, American Diabetes Association
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BMI, body mass index
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CrP, C-reactive protein CT, computed tomography
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DBP, diastolic blood pressure
HbA1c, Hemoglobin A1c HDL, High Density Lipoprotein
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GIR, glucose infusion rate
HDL-C, High Density Lipoprotein-cholesterol
HOMA-IR, Homeostasis Model Assessment - Insulin-Resistance
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hsCrP, high sensitive C-reactive protein
IL-6, interleukin-6
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IGT, impaired glucose tolerance
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LDL, Low Density Lipoprotein
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LDL-C, Low Density Lipoprotein-cholesterol MCP-1, monocyte chemoattractant protein-1 mRNA, messenger ribonucleic acid NGT, normal glucose tolerance OGTT, oral glucose tolerance test SC, subcutaneous SBP, systolic blood pressure T2D, type 2 diabetes TNFα, tumor necrosis factor-α
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ACCEPTED MANUSCRIPT 1. Introduction In 2014, the research community “celebrates” the 20th anniversary of the discovery of leptin
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[1]. Even preceding this important discovery, adipose tissue had been identified as an
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endocrine organ and adipsin/complement factor D was the first “adipokine” described [2, 3]. Adipsin circulating levels decline in animal models of diabetes and obesity [3]. Obesity and
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adverse (visceral) fat distribution increase the risk for metabolic (type 2 diabetes, hepatosteatosis, dyslipidemia), cardiovascular (hypertension, coronary artery disease, stroke),
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malignant, orthopaedic and psychological diseases [4, 5]. Except for bariatric surgery, current anti-obesity treatment strategies based on decreasing energy intake and increasing physical activity are frequently not successful most likely because pathogenetic factors cannot be targeted, which affect energy intake, metabolism and expenditure [6-8]. Therefore, both the
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treatment of obesity and the prevention of obesity related diseases may require novel
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pharmacotherapies targeting root causes of a sustained positive energy balance and the adverse signals from adipose tissue contributing to metabolic and cardiovascular diseases [9].
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Over the past two decades following the discovery of leptin which directed much needed
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attention to the study of adipose tissue, it has been acknowledged that several adipokines regulate important biological processes in target organs including the brain, liver, skeletal muscle, vasculature, heart, immune system and pancreatic β-cells (Figure 1) and may therefore link obesity to its metabolic and cardiovascular comorbidities [5, 9-12]. Under conditions of adipose tissue dysfunction, which is frequently found to accompany obesity, secretion of adipokines is dysregulated [5, 10]. Altered adipokine secretion may contribute to impaired regulation of appetite and satiety, fat distribution, insulin secretion and sensitivity, energy expenditure, endothelial function, inflammation, blood pressure, and hemostasis [4, 912]. Therefore, adipokines may offer exciting new opportunities for the future pharmacotherapy of obesity and obesity related diseases [12]. Translational research approaches [9, 13] are particularly important to identify novel pharmacotherapies for diseases 4
ACCEPTED MANUSCRIPT in which an incomplete understanding of the molecular mechanisms leads to a lack of etiology based treatment strategies. Obesity and other disease states associated with
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excess/lack or dysfunction of adipose tissue certainly belongs to these diseases.
2. From leptin to more than 600 adipokines
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Different cell types of adipose tissue (adipocytes, immune cells, fibroblasts, endothelial cells and others) release fatty acids, other lipids and metabolites and adipokines [9, 14-16].
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Stimulated by the discovery of leptin and the notion that adipose tissue is an endocrine organ, more than six hundred adipokines have been described so far [17] and search for novel adipokines still represents a hot topic in obesity research. Adipokines have been proposed to play specific roles in immune response (e.g. adipsin/complement factor D, acylation-
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stimulating protein, serum amyloid A3, interleukins) and inflammation (e.g. IL-1β, IL-6, IL-8,
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IL-10, CrP, monocyte chemoattractant protein-1, osteopontin, progranulin, chemerin), glucose metabolism (e.g. leptin, adiponectin, dipeptidyl peptidase-4, fibroblast growth factor 21,
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resistin, vaspin), insulin sensitivity (e.g. leptin, adiponectin, chemerin), hypertension (e.g.
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angiotensinogen), cell adhesion (e.g. PAI-1), vascular growth and function (e.g. VEGF), atherosclerosis development (e.g. cathepsins, apelin), adipogenesis and bone morphogenesis (e.g. BMP-7), growth (e.g. IGF-1, TGFβ, fibronectin), lipid metabolism (e.g. CD36), regulation of appetite and satiety (e.g. leptin, vaspin), eating disorders such as anorexia nervosa (e.g. leptin, adiponectin, resistin) and other biological processes [9-11]. However, for the majority of recently identified adipokines, physiologic regulation, functions, molecular action and targets need to be defined to develop future pharmacological therapeutics [14-16]. The lack of understanding adipokine related mechanisms still represents an important road block in translational adipokine research. The path of leptin from its discovery to the clinical application for patients with congenital leptin deficiency [18] and lipodystrophy [19-21] may
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ACCEPTED MANUSCRIPT serve as the first example for successful translational adipokine research. Other adipokines
Clinical importance of adipokines and translational adipokine research
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3.
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may follow leptin as potential novel therapeutics or treatment targets.
Translational adipokine research may lead to clinically important applications of adipokines
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either as biomarkers or as substrates/targets for pharmacological management of obesity and
3.1.
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prevention of obesity related disorders in the future (Figure 2).
Adipokines as predictors of mortality and obesity related diseases
Adipokines are involved in the regulation of metabolism, insulin sensitivity, inflammation and serum concentrations of distinct adipokines are associated with obesity, metabolic and
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cardiovascular diseases [4, 10, 14-16]. It has been therefore hypothesized that adipokine
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serum concentrations may serve as predictors of mortality, obesity related diseases or the individual disease outcomes [4, 10]. Indeed, in a prospective cohort study of 981 outpatients
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with stable coronary artery disease, low leptin serum concentrations at baseline were
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independently of gender, obesity and traditional cardiovascular risk factors associated with a 37% increased risk for cardiovascular events and mortality [22]. In a larger prospective study including 5,672 participants, circulating leptin was not associated with the risk of cardiovascular disease (CVD), but with type 2 diabetes risk in men [23]. In women with diabetes, circulating leptin levels were also not associated with cardiovascular morbidity and mortality [24]. A recent meta-analysis using data from 14,063 CVD patients from 15 prospective cohort and 1 nested case control studies, revealed that increased baseline plasma adiponectin levels are significantly associated with elevated risk of all-cause and cardiovascular mortality [25]. Moreover, data from the Cardiovascular Health Study have shown that higher plasma adiponectin concentrations are associated with new-onset heart failure, left ventricular systolic 6
ACCEPTED MANUSCRIPT dysfunction and left atrial enlargement in adults ≥65 years [26]. Noteworthy, in another meta-analysis, no associations between adiponectin and CV events have been observed [27]
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and in the EPIC Norfolk Prospective Population Study, low adiponectin concentrations have
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been associated with an increased CVD risk [28]. Adiponectin has also been proposed as a biomarker for stroke [29, 30]. Despite the general consideration of adiponectin as a protective
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molecule, increased concentrations of adiponectin in patients with type 1 diabetes were independently associated with all-cause and cardiovascular mortality [31]. The role of
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adiponectin in determining CVD health, especially in relation to heart failure [32] was recently summarized in the journal [33-35].
On the other hand, a protective role of higher adiponectin serum concentrations
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against the development of type 2 diabetes has been suggested [36-38]. Spranger and colleagues found in 27,548 participants of a prospective, nested case-control study within the
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population-based EPIC (European Prospective Investigation into Cancer and Nutrition) Potsdam cohort that high concentrations of adiponectin were associated with a substantially
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reduced relative risk to develop of type 2 diabetes in apparently healthy individuals [36]. This
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relationship was stable even after adjusting for age, gender, waist-to-hip ratio, body-mass index, smoking, exercise, alcohol consumption, education, and HbA1c [36]. In addition to type 2 diabetes and CVD, adipokine measurements maybe useful tools for the prediction of other not as commonly with obesity associated diseases including malignancies [39-41]. For instance, high adiponectin serum concentrations predispose men to a lower risk of developing high-grade prostate cancer and a lower risk of subsequently dying from it [42]. High non-HMW adiponectin as well as IL-6 and CrP serum concentrations have been found to be independently associated with increased risk for hepatocellular carcinoma [43]. We have shown, however, that although HMW adiponectin may slightly improve clinical prediction of metabolic variables [44] the added benefit is only incremental and probably not corresponding to the extra cost and burden conferred by the measurement of 7
ACCEPTED MANUSCRIPT HMW adiponectin over just measuring total adiponectin. More recent studies have raised the possibility that other measurements, such as the high serum C1q-adiponectin/total adiponectin
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may be novel promising biomarkers of risk [45] but detailed comparative evaluations against
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more traditional markers are lacking.
In addition to circulating adiponectin [46, 47] several papers have also indicated that
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adiponectin gene variants as well as variants of the adiponectin receptor are also strongly related to risk for metabolic diseases [48, 49]. Taken together, associations of adipokine
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serum concentrations with obesity related diseases (type 2 diabetes, CVD) and mortality have been frequently reported. However, it is not clear whether these sometimes contradictory associations are due to a mechanistic link between altered adipokine levels and an increased disease risk or simply reflect uncontrolled confounding. Further studies are required to
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identify potential mechanisms underlying the association between differences in adipokine
Adipokines – potential role as biomarkers
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3.2.
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serum concentrations and individual disease risks or outcomes.
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At least theoretically, adipokines have the potential to serve as biomarkers for the functional status of adipose tissue [5, 10] (Figure 2). Altered adipokine serum concentrations maybe related to hypertrophy of adipocytes, infiltration of AT with immune cells and processes within AT including hypoxia [50], autophagy [51], apoptosis [52], and different types of stresses [53]. In this context, we could recently show that using a specific circulating adipokine pattern with higher adiponectin, but lower RBP4, chemerin, progranulin, and fetuin-A serum concentrations an insulin sensitive obese subphenotype could be distinguished from an insulin resistant otherwise metabolically healthy obese subphenotype [54]. These adipokine changes were associated with an adverse (visceral) fat distribution, hypertrophic adipocytes and AT inflammation [54]. Moreover, several adipokines (e.g. omentin, RBP4, Nampt) have been suggested as biomarkers for visceral fat mass [5, 10]. In the future, 8
ACCEPTED MANUSCRIPT adipokines could become relevant biomarkers for the prediction of individual weight dynamics in response to lifestyle or bariatric surgery interventions, as markers of food
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preferences or diet adherence (Figure 2). So far, adipokines have not been proven to predict
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obesity related metabolic diseases better than classical parameters to define the metabolic syndrome [55]. Recently, we identified distinct adipokine clusters related to fat mass and
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inflammation (ANGPTL3, chemerin, clusterin, DLL1, GPX3, Nampt, resistin), insulin sensitivity, glucose and lipid metabolism (adiponectin, ANGPTL6, progranulin, RBP4, BMP7,
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DLK1, SFRP5, vaspin, glypican4, CTRP3 and 5, omentin) [55]. Interestingly, an adipokine panel consisting of ANGPTL6, DLK1, Nampt and progranulin was independently correlated to T2D in obese individuals, but with a lower sensitivity and specificity than established
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parameters of glucose metabolism [55].
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3.2.1 Adipokine dynamics and weight loss Weight loss interventions frequently induce a rapid decline in body weight followed by a
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weight stabilization and/or regain phase with significant intra-individual variation. There is
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still an unmet need to predict individual outcomes from weight loss interventions with the aim to define the individual who will benefit the most from such weight loss interventions. Measurement of baseline adipokine serum concentrations or changes of adipokines in the initial rapid weight loss phase could provide such information. Recently, we analyzed the dynamics of adipokines among 322 participants in the 2-year Dietary Intervention Randomized Controlled Trial (DIRECT) of low-fat, Mediterranean or low-carbohydrate diets for weight loss [56]. In the DIRECT a weight loss phase of ~ 6 months was followed by either weight stabilization or partial to full weight regain despite continued dieting [56]. In the context of this dietary intervention study, we found that adipokine serum concentrations independently of gender, diabetes diagnosis, or diet group either follow the weight loss pattern (leptin, chemerin, MCP-1, RBP4) or the continued healthy diet (adiponectin, fetuin-A, 9
ACCEPTED MANUSCRIPT progranulin, vaspin) [57]. However, we were unable to link a specific adipokine (or its early change) serum concentration to specific dietary components, food preference or diet
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adherence [57]. On the other hand, weight regain in the DIRECT was significantly and
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independently associated with genetic variations in the leptin gene (P = 0.006 for both rs4731426 and rs2071045) [58]. The inclusion of the leptin genotype to the phenotypic
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multivariate model increased its predictive value for weight regain by 34% [58]. Moreover, the importance of adipokines as biomarkers is further supported by data from the DIOGENES
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study, which demonstrated that high baseline RBP4 serum concentrations (together with low total testosterone and low SHBG) significantly predicts weight regain after weight loss [59].
3.2.2 Adipokines as predictors of adverse fat distribution
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Visceral fat distribution is clearly a stronger predictor for obesity related metabolic and
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cardiovascular diseases as whole body fat mass or BMI [4, 60, 61]. However, quantification of total visceral fat mass requires sophisticated and expensive imaging techniques. Both
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magnetic resonance imaging (MRI) and computerized tomography (CT) have been widely
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used for total visceral fat assessment. The exposure to ionizing radiation makes CT a largely inappropriate technique for prospective studies. MRI, on the other hand, is safer but typically involves longer acquisition times and higher costs [62]. Serum concentrations of adipokines including fetuin-A, chemerin, RBP-4, omentin, vaspin, progranulin, Nampt and others have been suggested to predict visceral fat mass [5, 10]. However, associations between circulating adipokines and visceral fat mass are not always robust across different cohorts and therefore no generally accepted adipokine marker of visceral fat mass exists. In addition, it is not clear, whether adipokines cause or reflect visceral fat accumulation. The discovery of Nampt, also named visfatin, is one example for how difficult the search for circulating markers of visceral fat mass may be. Nampt/visfatin has been defined as an adipokine exclusively secreted from visceral fat with insulin-mimetic 10
ACCEPTED MANUSCRIPT effects [63], however, subsequent human studies revealed that other tissues and adipose tissue depots may also express Nampt/visfatin [64]. Noteworthy, with aging and hypercaloric
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feeding, impaired NAMPT-mediated NAD+ biosynthesis may contribute to T2D development
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[65]. For another adipokine, RBP4, different studies found either strong positive correlations between circulating RBP4 and visceral fat distribution [54, 66, 67] or no associations [68, 69].
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Such contradictory findings may at least in part be explained by the fact that in addition to adipose tissue other tissues such as the liver may determine circulating levels. For the
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adipokines chemerin [70, 71], progranulin [72] and omentin [73], associations between increased visceral fat mass and higher serum concentrations may be influenced by AT immune cell infiltration and AT dysfunction [5]. Noteworthy, so far there are no genome wide association studies using visceral or subcutaneous AT distribution as traits. Such studies may
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unravel adipokines, which are directly involved in the regulation of fat distribution.
3.2.3 Altered circulating adipokines reflect adipose tissue dysfunction
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Storage of excessive calories as triglycerides and release of fatty acids during fasting and
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prolonged food deprivation may represent the main functions of AT [74]. In addition, AT is an important organ for thermoregulation, mechanical organ protection and endocrine signalling. With increasing body weight upon excessive energy intake, AT dysfunction may develop and seems to determine the individual risk to develop metabolic and cardiovascular comorbidities [4, 10, 74]. The inability to store excess calories in subcutaneous fat depots may represent a critical node in the development of subsequent ectopic fat deposition in visceral depots, the liver and other cell types [74]. Typical symptoms of AT dysfunction are therefore: 1) visceral (ectopic) fat accumulation, 2) changes in the cellular and intracellular matrix composition of adipose tissue, 3) increased number of immune cells within AT, 4) adipocyte hypertrophy, 5) increased autophagy and apoptosis, 6) AT extracellular matrix changes (AT fibrosis), 7) alterations in AT mRNA and protein expression patterns [74]. An 11
ACCEPTED MANUSCRIPT adipokine pattern with low circulating adiponectin and high serum concentrations of chemerin, progranulin, RBP4, fetuin-A, CrP, glypican-4, DPP-4 and others may reflect AT
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dysfunction [54, 75, 76]. Importantly, further studies are required to identify robust predictors
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of AT function.
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3.2.4 Adipokines and neurodegenerative diseases
Obesity has been associated with changes in brain structure, cognitive deficits, dementia and
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Alzheimer׳s disease (AD) [77]. The association between obesity, structural changes in the brain and neurodegenerative diseases could be mediated by pleiotropic effects of adipokines, particularly those adipokines which may cross the blood brain barrier including leptin, adiponectin, plasminogen activator inhibitor-1 (PAI-1), IL-6, TNF-α and angiotensingen [77].
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Indeed, circulating leptin levels correlate with the development of AD, leptin has previously
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been shown to attenuate tau hyperphosphorylation in neuronal cells and to be modulated by amyloid-β [78, 79]. Recent data further suggest that leptin resistance in the hippocampus may
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play a role in the characteristic changes associated with AD [79]. Moreover, leptin treatment
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has been proposed as a potential clinical application for AD [80]. In a mouse model for AD with an overexpression of the amyloid-β protein precursor, chronic administration of leptin results in a significant improvement in the cognitive performance [80]. Noteworthy, weight loss often precedes the onset of dementia and AD and the level of circulating leptin is inversely proportional to the severity of cognitive decline [80]. However, the concept that leptin treatment may improve the natural course of AD needs to be proven in clinical studies. Another example for the association between changes in adipokine patterns and neurodegenerative disorders is adiponectin [77]. Decreased adiponectin serum concentrations are associated with mild cognitive impairment and AD, but do not predict cognitive decline in elderly individuals [81]. In contrast to that notion, in dementia-free women participating in the Framingham Heart Study, increased plasma adiponectin levels have been detected as 12
ACCEPTED MANUSCRIPT independent risk factor for the development of both all-cause dementia and AD [82]. In patients with probable AD, lower leptin and higher circulating adiponectin serum
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concentrations are positively correlated with the severity of dementia [83]. However, other
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studies did not find associations between adiponectin and neurodegenerative disorders [84-85]. In addition to associations between leptin and adiponectin with neurodegenerative diseases, it
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has been recently shown that resistin may protect against endogenous amyoloid β neuronal cytotoxicity in a mouse model of AD, raising the possibility of novel AD therapies using
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resistin [86]. However, further mechanistic studies are required to unravel the role of adipokines on structural changes in the brain, cognitive deficits, dementia, and AD.
3.3
Specific adipokines in health and disease: Are adipokines a novel therapeutic tool
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to treat obesity and obesity-related diseases?
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Changes in circulating adipokines and adipokine expression in AT have been linked to metabolic diseases (type 2 diabetes, fatty liver disease), cardiovascular diseases, malignancies
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and compromised reproductive health [12]. Therefore, translational research efforts have been
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put into the path from the discovery of adipokines to their clinical use in the treatment of such diseases. There are important obstacles in the successful translation of biomedical research into clinical implementation of new adipokine-based therapeutic concepts, which have been extensively discussed elsewhere [9]. Some adipokines, including leptin [18, 19], adiponectin [87] and FGF21 [88] have been systematically developed into drug applications. For other adipokines including DPP-4 [89] and BMP-7 [90], clinical application preceded their recognition as adipokines. The translational potential of adipokines research is not restricted to metabolic or cardiovascular diseases – indication fields such as infertility, lipodystrophy, fractures or musculo-skeletal diseases are either in clinical development, have been tested in clinical phase I trials or clinical pilot studies already [9].
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ACCEPTED MANUSCRIPT To fully develop an adipokine until its clinical applications are proven may take ~15 years. Even if we celebrate this year the 20th anniversary of the discovery of leptin, the long
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development process makes it obvious that for more recently identified adipokines clinical
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applications can not be expected in the next few years. For many adipokines, we still have an incomplete knowledge about the mechanism of action and the major interaction partners (e.g.
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receptors).
In addition, since many adipokines are upregulated in disease states, it may be useful to
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develop an inhibitor for such adipokines. For TNFα [91, 92] or IL-1β [93] – which could also be considered as adipokines - inhibition of action have been already tested for different indications. Moreover, a chemerin (ChemR23) antagonist CCX832 has been shown to protect against chemerin-related arterial contraction, thus linking higher chemerin concentrations in
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obesity to impaired vascular function [94]. There are several additional adipokines in the
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3.3.1 Leptin
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“pipeline” from drug discovery to clinical testing [9].
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Leptin has been considered as the prototype for all adipocyte secreted hormones [12]. Leptin levels are pulsatile [95] and are associated with fat mass/BMI as well as circulating inflammatory markers [95-98]. Leptin in low leptin states plays an important role in satiety, appetite [99, 100], food intake, reproductive function and puberty [101-106] activity and energy expenditure regulation [107]. Originally, leptin was viewed as a potential anti-obesity therapeutic agent and was originally developed mainly with the aim to reduce body fat mass in obesity [18, 108-111]. In mice [108] and humans [109] with genetically inherited leptin deficiency, leptin has been proven as an effective weight loss drug. In contrast to leptin substitution treatment, in human obese patients [110, 111] with obesity as well as in high caloric diet induced obesity in mice [112], leptin had only little effects on weight loss [113, 114]. Even high doses of leptin and once weekly treatment with pegylated leptin did not 14
ACCEPTED MANUSCRIPT improve weight loss effects, but increased the risk for side effects of recombinant leptin therapy of obesity [111]. Despite these hurdles in the human application of leptin as an anti-
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obesity drug, there are still research efforts to improve leptin analogues for their clinical use.
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For example several site-specifically enhanced leptin analogues have been designed to increase the potency and lead to a more sustained action leptin, which provided enhanced
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weight loss in diet induced obesity mice [115].Administration of leptin to human obese individuals does not significantly affect appetite and body weight [21]. It has been suggested
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that the lack of leptin efficacy in human obesity is due to the development of central leptin resistance or tolerance in parallel with increased circulating leptin levels upon and before obesity development [21]. Leptin signaling pathways, the abnormality of which may eventually lead to the development of leptin resistance, have only recently started to be
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studied in humans [116-121]. In the search for agents that may restore leptin sensitivity,
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amylin (pramlintide) has been shown to induce weight loss in obese rodent models and humans when given together with leptin [122]. The leptin analogue metreleptin combined
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with pramlintide has been advanced to a clinical proof of concept study, which demonstrated
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a significant weight-lowering effect in a 24-week study in human obesity [123]. Unfortunately, a recent randomized clinical trial using pramlintide/metreleptin as anti-obesity therapeutic had to be stopped due to adverse events such as antibody generation and skin reactions [9, 118].
3.3.2 Clinical applications of leptin and other adipokines Recombinant leptin is now available for compassionate use for patients with congenital leptin deficiency [19]. Metreleptin also has been already approved for the treatment of lipodystrophy in Japan and in the US and is under consideration at European regulatory agencies for approval [20]. The FDA Advisory Committee voted in favor of metreleptin for the treatment of diabetes and/or hypertriglyceridemia, in patients with rare forms of 15
ACCEPTED MANUSCRIPT congenital lipodystrophy [20]. An additional potential future indication for metreleptin treatment has been recently emerged from clinical studies in five patients with Rabson-
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Mendenhall syndrome (RMS), which is caused by mutations in the insulin receptor [124]. In
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these patients, metreleptin treatment for 12 months was associated with a 1.7% reduction in HbA1c and reduced body weight suggesting metreleptin is a promising treatment option for
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rare RMS patients [124]. We have recently reviewed the role of leptin in lipodystrophy elsewhere [125] and herein [126]. Moreover, the effects of metreleptin administration in
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replacement doses were investigated in a randomized, double-blinded, placebo-controlled trial in women with hypothalamic amenorrhea and acquired chronic hypoleptinemia induced by negative energy balance [101, 121, 127-131]. This study could demonstrate that metreleptin restores both CD4(+) T-cell counts and their in vitro proliferative responses in these women
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suggesting metreleptin as an effective therapy for selective CD4(+) T-cell immune
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reconstitution in hypoleptinemic states such as tuberculosis and HIV infection in which CD4(+) T cells are reduced [121]. In contrast, patients with HIV-associated dyslipidemic
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lipodystrophy did not significantly improve their leptin kinetics in response to metreleptin
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replacement treatment over 2-4 months [132] although metreleptin was successful in both open label and randomized placebo controlled trials in patients with HIV-associated lipodystrophy [133-135]. Proof of concept studies demonstrated that a safe leptin analogue has a potential clinical application in the treatment of hypothalamic amenorrhea and related infertility [101, 121, 127-131]. Moreover, serum leptin concentrations in women with anorexia nervosa are lower and show reduced diurnal variation than those of normal-weight controls as a result of decreased body weight and fat mass [reviewed in 127]. In addition to these leptin alterations, anorexia nervosa is characterized by significant changes of hormones (e.g. IGF-1, cortisol, ghrelin, PYY) including adipokines (e.g. adiponectin, resistin). Importantly, dietary therapy of anorexia nervosa leads to increased circulating leptin which correlates with increasing gonadotropins, indicating that increasing leptin in response to 16
ACCEPTED MANUSCRIPT weight gain could activate the hypothalamic-pituitary-gonadal axis [127]. Because the nutritional therapy for women with anorexia nervosa takes time, maintaining recovered
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weight maybe difficult and long-term effectiveness of this method remains to be proven,
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treatment of eating disorders such as anorexia nervosa with safe leptin analogues and careful dose titration could be an additional clinical application of leptin in the future [127-129].
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However, so far recombinant leptin has not yet been successfully introduced for the treatment of this eating disorder.
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To date, leptin is the best example for a successful translational adipokine research, which already successfully advanced to clinical application. In the future, more clinical applications of adipokine-based treatment strategies are under consideration or tested in randomized clinical proof of concept trials for the treatment of impaired glucose metabolism (e.g.
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adiponectin, FGF21, BMP7), insulin resistance (e.g. adiponectin, FGF21), dyslipidemia (e.g.
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leptin, FGF21), chronic systemic inflammation (e.g. anti IL-1 antibodies), eating disorders
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such as anorexia nervosa (e.g. leptin), bone fracture healing (e.g. BMP7) and others (Figure 2).
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3.3.3 Adiponectin
Adiponectin belongs to the highest expressed proteins in adipocytes and represents ~0.01% of total plasma protein [136]. Discovered shortly after leptin in 1995 [137-139], adiponectin gained wide interest due to its insulin sensitizing, anti-inflammatory and anti-apoptotic actions on a number of different cell types [14, 140]. In the past almost 20 years and in more than 11,000 references in the international literature, several aspects of adiponectin´s actions have been discovered, which make adiponectin-based therapies a promising approach for both treatment of obesity itself as well as for obesity-related disorders [14, 136]. Importantly, the basic principles of adiponectin physiology have been maintained remarkably well across the different species [140]. Adiponectin emerged as a suitable biomarker, because it is easily detectable in blood, stable upon collection and relatively inert to the method of collection and 17
ACCEPTED MANUSCRIPT diurnal changes [14, 137]. Circulating adiponectin levels inversely correlate with multiple metabolic disorders including obesity and related diseases [136, 137, 140]. Moreover, in large
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scale longitudinal studies circulating adiponectin has been identified as a marker for all-cause
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mortality, heart failure, coronary artery disease and type 2 diabetes [26-28, 31, 36]. In addition to beneficial peripheral effects on insulin sensitivity, adiponectin acts in the brain to
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increase energy expenditure and may thereby promote weight loss [140]. Administration of recombinant adiponectin results in improved insulin sensitivity (predominantly in the liver),
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increased insulin secretion [141], reduction of body weight and improved glycemia [reviewed in [136, 140]. In some studies, which can not confirm these adiponectin treatment data, ineffective recombinant adiponectin preparations may underlie the lack of efficacy [142]. Last year, a potential breakthrough in the adiponectin field has been reported by Okada-Iwabu and
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coworkers, who synthesized an orally active, synthetic small-molecule adiponectin receptor
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agonist [87, 143]. The molecule which has been given the name AdipoRon significantly improves insulin sensitivity and glucose tolerance in mice, thereby extending lifespan of
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db/db mice on a high-fat diet [87, 143]. The observation that agonists of the adiponectin
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receptor may have beneficial effects on increasing longevity in a mouse model of obesity provides strong evidence for the hypothesis that higher circulating adiponectin levels are associated with prolonged life expectancy under conditions of shortened life span due to obesity-related diseases [143-145]. In this context, increased adiponectin levels are associated with extended longevity in mice [145-148]. Transgenic mice expressing high levels of human adiponectin have increased longevity [146] and various mouse models of extended longevity including fat-specific insulin receptor knockout mice [147], mice with defects in growth hormone production [148], and calorie-restricted mice [149] have increased adiponectin. Moreover, female centenarians have significantly higher adiponectin plasma concentrations compared to BMI-matched women at other ages [150]. Together with evidence from longitudinal human studies that lower circulating adiponectin is related to increased all-cause 18
ACCEPTED MANUSCRIPT mortality [31] these data support the concept that adiponectin has a potential beneficial role in extending life span [145].
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These promising recent advances in the adiponectin further establish adiponectin itself or
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adiponectin receptor agonists as candidates for the further development as pharmacotherapy for diseases associated with obesity and insulin resistance, including not only diabetes and
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cardiovascular disease but also possibly obesity associated malignancies [14, 39, 49, 151-180].
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3.3.4 FGF21
Fibroblast growth factor 21 (FGF21) is a hepato-adipokine that has been shown to stimulate glucose uptake into adipocytes in an additive manner to insulin [88, 181]. The initial breakthrough in uncovering the function of FGF21 came as a result of a phenotypic screen
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carried out at Lilly Research Laboratories in early 2000 [182]. In patients with obesity and
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T2D, circulating FGF21 levels are significantly increased [183]. The obesity and diabetes research community considers FGF21 as promising molecule for the treatment of metabolic
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diseases, because this molecule may increase thermogenesis, energy expenditure, fat
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utilization and has significant glucose and lipid lowering effects [88]. In animal studies, recombinant FGF21 reduces hyperglycemia and produces additional beneficial metabolic effects [88]. In a truly translational research effort, many of the animal data have been reproduced in a randomized, placebo-controlled, double-blind trial on the effects of a FGF21 variant (LY2405319) in patients with obesity and type 2 diabetes [88]. LY2405319 administration caused body weight reduction, as well as significant improvements in fasting insulin, LDL-cholesterol, HDL-cholesterol, triglycerides and apolipoprotein profile [88]. In contrast to FGF21 overexpression studies in transgenic mice in which FGF21 not only protected animals from diet-induced obesity, but also lowered blood glucose [181], LY2405319 did not significantly improve glucose concentrations [88].
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ACCEPTED MANUSCRIPT Despite several lines of evidence about the positive metabolic actions of FGF21, safety concerns associated with targeting the FGF21 pathway have also emerged [182]. The
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translational adipokine research related to FGF21 may serve as an example how basic
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research may unravel data to guide drug discovery, but may also lead to unexpected findings. FGF21 was initially discovered using in vitro assays as a potential insulin mimetic, emerged
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as a potential agent in animals which improved more than only hyperglycemia, and ended up providing several metabolic benefits yet failed to deliver sustained glucose lowering in
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humans [182]. Taken together, FGF21 serves as a prime example that novel and potentially better medicines also derived from translational adipokine research are within the reach [182].
3.3.5 DPP-4
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Compared to leptin, adiponectin and FGF21, the drug discovery path went a totally different
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way for the clinical importance of the molecule dipeptidyl peptidase-4 (DPP-4). In an attempt to develop incretin-based therapies for type 2 diabetes, DPP-4 emerged as the most prominent
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indirect target, because DPP-4 rapidly degrades incretins including GLP-1 [89]. DPP-4
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inhibitors lower increased plasma glucose by increasing the concentration, half life time and action of incretins thereby stimulating glucose-induced insulin secretion and suppressing glucagon production [89]. Although research has focused on the role of DPP-4 in the degradation of GLP-1, recent data suggest that DPP-4 also exerts direct effects, as it is able to induce insulin resistance in adipocytes and skeletal muscle cells in concentrations that can be found in the circulation of overweight and obese subjects [184]. Only very recently, it has been appreciated that adipose tissue maybe an important source of circulating DPP-4 and DPP-4 may be considered an adipokine [184]. Importantly, obese individuals particularly those with impaired insulin sensitivity [54] have a significantly increased adipose tissue DPP-4 secretion compared to lean controls [76]. From such studies, it has been concluded that increased DPP-4 production in AT could contribute to obesity and 20
ACCEPTED MANUSCRIPT insulin resistance [9]. However, there are open questions about the net contribution of AT derived DPP-4 to changes in endogenous GLP-1 levels and whether DPP-4 inhibitors may
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disproportionately affect AT produced DPP-4 from that of other sources.
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It has been shown that DPP-4 serum concentration and adipose tissue DPP-4 expression correlate with hypertrophy of adipocytes and AT dysfunction [76, 184]. Therefore,
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DPP-4 might not only reflect adipose tissue function, but it may also have local effects within adipose tissue and systemic effects. Increased DPP-4 activity and serum concentrations in
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obesity may serve as a model how altered adipokine secretion may be successfully used as therapeutic target in the treatment of obesity related diseases. However, further work is needed to elucidate the functional role of DPP-4 within adipose tissue and to define whether higher DPP-4 expression and serum concentration may contribute to higher efficacy of DPP-4
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inhibitors in patients with type 2 diabetes [9].
3.3.6 TNFα and IL-1β
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Both TNFα and IL-1β are highly expressed in and secreted from adipose [185, 186] and may
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therefore qualify for the term adipokine. Both cytokines are attractive targets for antiinflammatory therapies with beneficial effects on insulin sensitivity and glucose metabolism [9]. In a rat model of obesity, neutralization of TNFα leads to an increase in peripheral glucose uptake in response to insulin [187]. Genetic ablation of the TNFα gene in mice results in improved insulin sensitivity in different obesity models suggesting that blocking TNFα action may improve insulin sensitivity and its related traits [188]. Treatment with TNFα antibodies resulted in inhibited inflammatory activity, improved fatty liver disease [189], protection against diet induced obesity and insulin resistance [190] in several animal models. However, these beneficial metabolic effects using anti-TNF treatment could not be proven to be successful in obese Zucker rats [191] or recent clinical studies [192]. On the other hand, there are studies reporting improvements in insulin sensitivity or hyperglycemia in insulin 21
ACCEPTED MANUSCRIPT resistant individuals during prolonged treatment with TNFα targeting strategies infliximab [91] or etanercept [92].
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IL-1β is another potential drug target, because it may contribute to β-cell destruction and
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apoptosis associated with the pathogenesis of both type 1 and type 2 diabetes [93]. In the first clinical double-blind, parallel-group proof of concept study, Larsen and coworkers
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demonstrated that blocking IL-1 using the recombinant human IL-1-receptor antagonist anakinra significantly lowers plasma glucose, improves β-cell function and reduced markers
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of systemic inflammation [93]. These data support the concept that targeting proinflammatory adipokines/cytokines may be an approach to improve metabolic diseases.
3.3.7 BMP-7
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Bone morphogenetic proteins (BMPs) are developmental factors that belong to the
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transforming growth factor (TGF) β superfamily and regulate several processes of organogenesis and patterning during embryonic development [193-196]. Moreover, BMPs
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may act as a molecular switch in regulating white versus brown adipogenesis [195, 196].
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Recently, several members of the BMP family of ligands and receptors have been found to associate with obesity-related traits in humans [61, 197, 198]. Therefore, targeting BMPs has emerged as a novel therapeutic concept to treat obesity and its related diseases by inducing increased energy expenditure and browning of white adipose tissue [193, 194]. As an example, BMP7 has gained attention after the notion that BMP-7 stimulates brown adipogenesis, reduces food intake, increases energy expenditure resulting in reduced weight gain [195, 196]. For BMP7 translational adipokine research is facilitated by the fact that human recombinant BMP7 is already available [90]. Under the brand name OP1, recombinant BMP7 is locally applied to aid in the fusion of vertebral bodies in the treatment of non-union after tibia fractures [90]. From the clinical use, it is known that local recombinant BMP7 application does not have local or systemic toxic effects or other 22
ACCEPTED MANUSCRIPT adverse events [90]. So far, BMP7 has not been tested in the treatment of obesity or metabolic
Conclusions
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4.
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diseases.
Several important advances in our understanding of the function of the adipose tissue and
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important changes in the way we approach and treat several disease states have occurred over the twenty years since the discovery of leptin. Adipokines contribute to the regulation of
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appetite, satiety, energy expenditure and physical activity. Targeting or using adipokine-based mechanisms to treat obesity and diseases which are caused by a positive energy balance is therefore a promising strategy, and has driven translational adipokine research during the past 20 years. Moreover, we have also realized during the same period of time that several
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adipokines, including but not limited to adiponectin, leptin, etc. serve as messages linking
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adipose tissue with specific organs and conveying information that may alter human
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issue [14].
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physiology and pathophysiology as outlined in part in this renew and elsewhere in this special
Thus, all these newly discovered adipokines are not only promising new potential biomarkers and therapeutic agents; we have already started realizing tangible benefits. In the energy deficiency part of the energy homeostasis spectrum, congenital leptin deficiency and generalized lipodystrophy are now indications for therapy with leptin. Proof of concept studies have demonstrated that a safe leptin analogue could be a reasonable, physiology based, approach for the treatment of hypothalamic amenorrhea and related infertility and possibly, in well controlled doses, for some cases of anorexia nervosa. In the treatment of obesity, lifestyle changes, psychological interventions or pharmaco-therapies have provided only very limited sustained beneficial effects. In the long-term, weight loss surgery are much more effective compared to the non-surgical intervention, but the bare an increased perioperative 23
ACCEPTED MANUSCRIPT mortality risk. In particular, pharmacological anti-obesity therapies rarely lead to leanness or a complete remission of obesity-associated diseases.
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At the 20th anniversary of the discovery of leptin, translational research has already led
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to clinical application of the leptin analogue metreleptin as a pharmacotherapy in individuals with congenital leptin deficiency and lipodystrophies [199]. More adipokine-based treatment
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strategies using for example adiponectin, FGF21 or BMP7 may follow leptin in the path of drug discovery. In summary, adipokines may open exciting new diagnostic and treatment
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opportunities for diseases with unmet clinical needs.
Conflict of interest
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Dr. Mantzoros is a consultant for Astra Zeneca. Dr. Blüher does not have any conflict of
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interest related to this manuscript.
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ACCEPTED MANUSCRIPT Figure legends Figure 1. Adipokines regulate important physiologic processes. Secreted factors from
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adipose tissue (representative histologic slide of human subcutaneous adipose tissue,
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hematoxylin and eosin staining; magnification: 20X) play an important role in the regulation of appetite and satiety, energy expenditure, insulin sensitivity and insulin secretion,
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inflammation, blood pressure, hemostasis, endothelial function and others.
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Figure 2. Translational adipokine research. Adipokines have the potential to be used in clinical practice as markers (predictors) for obesity related diseases, mortality, individual disease outcomes or as substrates/targets for pharmacological management of obesity and prevention of obesity related disorders. For several adipokines there is evidence for the
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prediction of obesity complications, but also a need for future development and validation.
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Some adipokines have been already used in clinical studies for different indications, whereas
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for more recently discovered adipokines only data from animal experiments are available.
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ACCEPTED MANUSCRIPT Table 1. Examples of adipokines and main function(s).
Adipokine
Target action Regulation of satiety, appetite, food intake,
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Leptin
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activity and energy expenditure, fertility, atherogenesis and growth induction Antidiabetic, anti-atherogenic and anti-
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Adiponectin
inflammatory
Chemoattractant protein, regulation of
Chemerin
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adipogenesis
Pro-inflammatory
TNFα
Pro-inflammatory
IL-1β
Stimulates glucose uptake into adipocytes,
FGF21
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increases thermogenesis, energy expenditure,
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Retinol binding protein-4 (RBP4)
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Vaspin
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Visfatin/PBEF/Nampt
fat utilization, lowers glucose and triglycerides Related to insulin resistance, visceral fat distribution Decreases food intake, improves hyperglycemia Nampt-mediated systemic NAD biosynthesis is critical for β cell function
Monocyte chemotactic protein-1
Chemoattractant protein, promotes adipose
(MCP-1)
tissue inflammation
Progranulin
Promotes adipose tissue inflammation
DPP-4
Degrades GIP and GLP-1 Inhibitors in clinical use for type 2 diabetes
BMP-7
Stimulates brown adipogenesis, reduces food intake, increases energy expenditure
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[192] Wascher TC, Lindeman JH, Sourij H, Kooistra T, Pacini G, Roden M. Chronic TNFalpha neutralization does not improve insulin resistance or endothelial function in "healthy" men with metabolic syndrome. Mol Med 2011;17:189-93. [193] Schulz TJ, Huang P, Huang TL, Xue R, McDougall LE, Townsend KL, et al. Brown-fat paucity due to impaired BMP signalling induces compensatory browning of white fat. Nature 2013;495:379-83. [194] Schulz TJ, Tseng YH. Emerging role of bone morphogenetic proteins in adipogenesis and energy metabolism. Cytokine Growth Factor Rev 2009;20:523-31. [195] Tseng YH, Kokkotou E, Schulz TJ, Huang TL, Winnay JN, Taniguchi CM, et al. New role of bone morphogenetic protein 7 in brown adipogenesis and energy expenditure. Nature 2008;454:1000-4. 47
ACCEPTED MANUSCRIPT [196] Townsend KL, Suzuki R, Huang TL, Jing E, Schulz TJ, Lee K, et al. Bone morphogenetic protein 7 (BMP7) reverses obesity and regulates appetite through a central
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mTOR pathway. FASEB J 2012;26:2187-96.
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[197] Böttcher Y, Unbehauen H, Klöting N, Ruschke K, Körner A, Schleinitz D, et al. Adipose tissue expression and genetic variants of the bone morphogenetic protein receptor 1A
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gene (BMPR1A) are associated with human obesity. Diabetes 2009;58:2119-28. [198] Schleinitz D, Klöting N, Böttcher Y, Wolf S, Dietrich K, Tönjes A, et al. Genetic and
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evolutionary analyses of the human bone morphogenetic protein receptor 2 (BMPR2) in the pathophysiology of obesity. PLoS One 2011;6:e16155.
[199] Dalamaga M, Chou SH, Shields K, Papageorgiou P, Polyzos SA, Mantzoros CS. Leptin at the intersection of neuroendocrinology and metabolism: current evidence and therapeutic
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S0026-0495(14)00310-2 doi: 10.1016/j.metabol.2014.10.016 YMETA 53111
To appear in:
Metabolism
Please cite this article as: Bl¨ uher Matthias, Mantzoros Christos S., From leptin to other adipokines in health and disease: Facts and expectations at the beginning of the 21st century, Metabolism (2014), doi: 10.1016/j.metabol.2014.10.016
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Invited Review
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From leptin to other adipokines in health and disease:
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Facts and expectations at the beginning of the 21st century
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Matthias Blüher, Christos S. Mantzoros
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Department of Medicine, University of Leipzig, Leipzig, Germany Department of Endocrinology, Metabolism and Diabetes, VA Boston Medical Health Center, Boston, MA, USA
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Key words: Adipokines; obesity; type 2 diabetes, leptin, adiponectin, AdipoRon, DPP4,
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FGF21, TNFα, IL-1β, nampt/visfatin, BMP7
Corresponding author: Matthias Blüher, MD University of Leipzig Department of Medicine Liebigstr. 20 D-04103 Leipzig Tel. (+49) 341-9715984 Fax (+49) 341-9722439 E-mail: [email protected]
ACCEPTED MANUSCRIPT Abstract This year marks the 20th anniversary of the discovery of leptin, which has
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tremendously stimulated translational obesity research. The discovery of leptin has led to
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realizations that have established adipose tissue as an endocrine organ, secreting bioactive molecules including hormones now termed adipokines. Through adipokines, the adipose
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tissue influences the regulation of several important physiological functions including but not limited to appetite, satiety, energy expenditure, activity, insulin sensitivity and secretion,
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glucose and lipid metabolism, fat distribution, endothelial function, hemostasis, blood pressure, neuroendocrine regulation, and function of the immune system. Adipokines have a great potential for clinical use as potential therapeutics for obesity, obesity related metabolic, cardiovascular and other diseases. After 20 years of intense research efforts, recombinant
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leptin and the leptin analog metreleptin are already available for the treatment of congenital
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leptin deficiency and lipodystrophy. Other adipokines are also emerging as promising candidates for urgently needed novel pharmacological treatment strategies not only in obesity
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but also other disease states associated with and influenced by adipose tissue size and activity.
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In addition, prediction of reduced type 2 diabetes risk by high circulating adiponectin concentrations suggests that adipokines have the potential to be used as biomarkers for individual treatment success and disease progression, to monitor clinical responses and to identify non-responders to anti-obesity interventions. With the growing number of adipokines there is an increasing need to define their function, molecular targets and translational potential for the treatment of obesity and other diseases. In this review we present research data on adipose tissue secreted hormones, the discovery of which followed the discovery of leptin 20 years ago pointing to future research directions to unravel mechanisms of action for adipokines.
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ACCEPTED MANUSCRIPT List of abbreviations ADA, American Diabetes Association
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BMI, body mass index
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CrP, C-reactive protein CT, computed tomography
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DBP, diastolic blood pressure
HbA1c, Hemoglobin A1c HDL, High Density Lipoprotein
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GIR, glucose infusion rate
HDL-C, High Density Lipoprotein-cholesterol
HOMA-IR, Homeostasis Model Assessment - Insulin-Resistance
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hsCrP, high sensitive C-reactive protein
IL-6, interleukin-6
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IGT, impaired glucose tolerance
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LDL, Low Density Lipoprotein
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LDL-C, Low Density Lipoprotein-cholesterol MCP-1, monocyte chemoattractant protein-1 mRNA, messenger ribonucleic acid NGT, normal glucose tolerance OGTT, oral glucose tolerance test SC, subcutaneous SBP, systolic blood pressure T2D, type 2 diabetes TNFα, tumor necrosis factor-α
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ACCEPTED MANUSCRIPT 1. Introduction In 2014, the research community “celebrates” the 20th anniversary of the discovery of leptin
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[1]. Even preceding this important discovery, adipose tissue had been identified as an
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endocrine organ and adipsin/complement factor D was the first “adipokine” described [2, 3]. Adipsin circulating levels decline in animal models of diabetes and obesity [3]. Obesity and
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adverse (visceral) fat distribution increase the risk for metabolic (type 2 diabetes, hepatosteatosis, dyslipidemia), cardiovascular (hypertension, coronary artery disease, stroke),
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malignant, orthopaedic and psychological diseases [4, 5]. Except for bariatric surgery, current anti-obesity treatment strategies based on decreasing energy intake and increasing physical activity are frequently not successful most likely because pathogenetic factors cannot be targeted, which affect energy intake, metabolism and expenditure [6-8]. Therefore, both the
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treatment of obesity and the prevention of obesity related diseases may require novel
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pharmacotherapies targeting root causes of a sustained positive energy balance and the adverse signals from adipose tissue contributing to metabolic and cardiovascular diseases [9].
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Over the past two decades following the discovery of leptin which directed much needed
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attention to the study of adipose tissue, it has been acknowledged that several adipokines regulate important biological processes in target organs including the brain, liver, skeletal muscle, vasculature, heart, immune system and pancreatic β-cells (Figure 1) and may therefore link obesity to its metabolic and cardiovascular comorbidities [5, 9-12]. Under conditions of adipose tissue dysfunction, which is frequently found to accompany obesity, secretion of adipokines is dysregulated [5, 10]. Altered adipokine secretion may contribute to impaired regulation of appetite and satiety, fat distribution, insulin secretion and sensitivity, energy expenditure, endothelial function, inflammation, blood pressure, and hemostasis [4, 912]. Therefore, adipokines may offer exciting new opportunities for the future pharmacotherapy of obesity and obesity related diseases [12]. Translational research approaches [9, 13] are particularly important to identify novel pharmacotherapies for diseases 4
ACCEPTED MANUSCRIPT in which an incomplete understanding of the molecular mechanisms leads to a lack of etiology based treatment strategies. Obesity and other disease states associated with
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excess/lack or dysfunction of adipose tissue certainly belongs to these diseases.
2. From leptin to more than 600 adipokines
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Different cell types of adipose tissue (adipocytes, immune cells, fibroblasts, endothelial cells and others) release fatty acids, other lipids and metabolites and adipokines [9, 14-16].
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Stimulated by the discovery of leptin and the notion that adipose tissue is an endocrine organ, more than six hundred adipokines have been described so far [17] and search for novel adipokines still represents a hot topic in obesity research. Adipokines have been proposed to play specific roles in immune response (e.g. adipsin/complement factor D, acylation-
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stimulating protein, serum amyloid A3, interleukins) and inflammation (e.g. IL-1β, IL-6, IL-8,
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IL-10, CrP, monocyte chemoattractant protein-1, osteopontin, progranulin, chemerin), glucose metabolism (e.g. leptin, adiponectin, dipeptidyl peptidase-4, fibroblast growth factor 21,
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resistin, vaspin), insulin sensitivity (e.g. leptin, adiponectin, chemerin), hypertension (e.g.
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angiotensinogen), cell adhesion (e.g. PAI-1), vascular growth and function (e.g. VEGF), atherosclerosis development (e.g. cathepsins, apelin), adipogenesis and bone morphogenesis (e.g. BMP-7), growth (e.g. IGF-1, TGFβ, fibronectin), lipid metabolism (e.g. CD36), regulation of appetite and satiety (e.g. leptin, vaspin), eating disorders such as anorexia nervosa (e.g. leptin, adiponectin, resistin) and other biological processes [9-11]. However, for the majority of recently identified adipokines, physiologic regulation, functions, molecular action and targets need to be defined to develop future pharmacological therapeutics [14-16]. The lack of understanding adipokine related mechanisms still represents an important road block in translational adipokine research. The path of leptin from its discovery to the clinical application for patients with congenital leptin deficiency [18] and lipodystrophy [19-21] may
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Clinical importance of adipokines and translational adipokine research
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3.
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may follow leptin as potential novel therapeutics or treatment targets.
Translational adipokine research may lead to clinically important applications of adipokines
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either as biomarkers or as substrates/targets for pharmacological management of obesity and
3.1.
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prevention of obesity related disorders in the future (Figure 2).
Adipokines as predictors of mortality and obesity related diseases
Adipokines are involved in the regulation of metabolism, insulin sensitivity, inflammation and serum concentrations of distinct adipokines are associated with obesity, metabolic and
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cardiovascular diseases [4, 10, 14-16]. It has been therefore hypothesized that adipokine
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serum concentrations may serve as predictors of mortality, obesity related diseases or the individual disease outcomes [4, 10]. Indeed, in a prospective cohort study of 981 outpatients
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with stable coronary artery disease, low leptin serum concentrations at baseline were
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independently of gender, obesity and traditional cardiovascular risk factors associated with a 37% increased risk for cardiovascular events and mortality [22]. In a larger prospective study including 5,672 participants, circulating leptin was not associated with the risk of cardiovascular disease (CVD), but with type 2 diabetes risk in men [23]. In women with diabetes, circulating leptin levels were also not associated with cardiovascular morbidity and mortality [24]. A recent meta-analysis using data from 14,063 CVD patients from 15 prospective cohort and 1 nested case control studies, revealed that increased baseline plasma adiponectin levels are significantly associated with elevated risk of all-cause and cardiovascular mortality [25]. Moreover, data from the Cardiovascular Health Study have shown that higher plasma adiponectin concentrations are associated with new-onset heart failure, left ventricular systolic 6
ACCEPTED MANUSCRIPT dysfunction and left atrial enlargement in adults ≥65 years [26]. Noteworthy, in another meta-analysis, no associations between adiponectin and CV events have been observed [27]
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and in the EPIC Norfolk Prospective Population Study, low adiponectin concentrations have
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been associated with an increased CVD risk [28]. Adiponectin has also been proposed as a biomarker for stroke [29, 30]. Despite the general consideration of adiponectin as a protective
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molecule, increased concentrations of adiponectin in patients with type 1 diabetes were independently associated with all-cause and cardiovascular mortality [31]. The role of
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adiponectin in determining CVD health, especially in relation to heart failure [32] was recently summarized in the journal [33-35].
On the other hand, a protective role of higher adiponectin serum concentrations
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against the development of type 2 diabetes has been suggested [36-38]. Spranger and colleagues found in 27,548 participants of a prospective, nested case-control study within the
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population-based EPIC (European Prospective Investigation into Cancer and Nutrition) Potsdam cohort that high concentrations of adiponectin were associated with a substantially
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reduced relative risk to develop of type 2 diabetes in apparently healthy individuals [36]. This
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relationship was stable even after adjusting for age, gender, waist-to-hip ratio, body-mass index, smoking, exercise, alcohol consumption, education, and HbA1c [36]. In addition to type 2 diabetes and CVD, adipokine measurements maybe useful tools for the prediction of other not as commonly with obesity associated diseases including malignancies [39-41]. For instance, high adiponectin serum concentrations predispose men to a lower risk of developing high-grade prostate cancer and a lower risk of subsequently dying from it [42]. High non-HMW adiponectin as well as IL-6 and CrP serum concentrations have been found to be independently associated with increased risk for hepatocellular carcinoma [43]. We have shown, however, that although HMW adiponectin may slightly improve clinical prediction of metabolic variables [44] the added benefit is only incremental and probably not corresponding to the extra cost and burden conferred by the measurement of 7
ACCEPTED MANUSCRIPT HMW adiponectin over just measuring total adiponectin. More recent studies have raised the possibility that other measurements, such as the high serum C1q-adiponectin/total adiponectin
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may be novel promising biomarkers of risk [45] but detailed comparative evaluations against
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more traditional markers are lacking.
In addition to circulating adiponectin [46, 47] several papers have also indicated that
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adiponectin gene variants as well as variants of the adiponectin receptor are also strongly related to risk for metabolic diseases [48, 49]. Taken together, associations of adipokine
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serum concentrations with obesity related diseases (type 2 diabetes, CVD) and mortality have been frequently reported. However, it is not clear whether these sometimes contradictory associations are due to a mechanistic link between altered adipokine levels and an increased disease risk or simply reflect uncontrolled confounding. Further studies are required to
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identify potential mechanisms underlying the association between differences in adipokine
Adipokines – potential role as biomarkers
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3.2.
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serum concentrations and individual disease risks or outcomes.
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At least theoretically, adipokines have the potential to serve as biomarkers for the functional status of adipose tissue [5, 10] (Figure 2). Altered adipokine serum concentrations maybe related to hypertrophy of adipocytes, infiltration of AT with immune cells and processes within AT including hypoxia [50], autophagy [51], apoptosis [52], and different types of stresses [53]. In this context, we could recently show that using a specific circulating adipokine pattern with higher adiponectin, but lower RBP4, chemerin, progranulin, and fetuin-A serum concentrations an insulin sensitive obese subphenotype could be distinguished from an insulin resistant otherwise metabolically healthy obese subphenotype [54]. These adipokine changes were associated with an adverse (visceral) fat distribution, hypertrophic adipocytes and AT inflammation [54]. Moreover, several adipokines (e.g. omentin, RBP4, Nampt) have been suggested as biomarkers for visceral fat mass [5, 10]. In the future, 8
ACCEPTED MANUSCRIPT adipokines could become relevant biomarkers for the prediction of individual weight dynamics in response to lifestyle or bariatric surgery interventions, as markers of food
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preferences or diet adherence (Figure 2). So far, adipokines have not been proven to predict
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obesity related metabolic diseases better than classical parameters to define the metabolic syndrome [55]. Recently, we identified distinct adipokine clusters related to fat mass and
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inflammation (ANGPTL3, chemerin, clusterin, DLL1, GPX3, Nampt, resistin), insulin sensitivity, glucose and lipid metabolism (adiponectin, ANGPTL6, progranulin, RBP4, BMP7,
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DLK1, SFRP5, vaspin, glypican4, CTRP3 and 5, omentin) [55]. Interestingly, an adipokine panel consisting of ANGPTL6, DLK1, Nampt and progranulin was independently correlated to T2D in obese individuals, but with a lower sensitivity and specificity than established
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parameters of glucose metabolism [55].
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3.2.1 Adipokine dynamics and weight loss Weight loss interventions frequently induce a rapid decline in body weight followed by a
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weight stabilization and/or regain phase with significant intra-individual variation. There is
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still an unmet need to predict individual outcomes from weight loss interventions with the aim to define the individual who will benefit the most from such weight loss interventions. Measurement of baseline adipokine serum concentrations or changes of adipokines in the initial rapid weight loss phase could provide such information. Recently, we analyzed the dynamics of adipokines among 322 participants in the 2-year Dietary Intervention Randomized Controlled Trial (DIRECT) of low-fat, Mediterranean or low-carbohydrate diets for weight loss [56]. In the DIRECT a weight loss phase of ~ 6 months was followed by either weight stabilization or partial to full weight regain despite continued dieting [56]. In the context of this dietary intervention study, we found that adipokine serum concentrations independently of gender, diabetes diagnosis, or diet group either follow the weight loss pattern (leptin, chemerin, MCP-1, RBP4) or the continued healthy diet (adiponectin, fetuin-A, 9
ACCEPTED MANUSCRIPT progranulin, vaspin) [57]. However, we were unable to link a specific adipokine (or its early change) serum concentration to specific dietary components, food preference or diet
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adherence [57]. On the other hand, weight regain in the DIRECT was significantly and
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independently associated with genetic variations in the leptin gene (P = 0.006 for both rs4731426 and rs2071045) [58]. The inclusion of the leptin genotype to the phenotypic
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multivariate model increased its predictive value for weight regain by 34% [58]. Moreover, the importance of adipokines as biomarkers is further supported by data from the DIOGENES
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study, which demonstrated that high baseline RBP4 serum concentrations (together with low total testosterone and low SHBG) significantly predicts weight regain after weight loss [59].
3.2.2 Adipokines as predictors of adverse fat distribution
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Visceral fat distribution is clearly a stronger predictor for obesity related metabolic and
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cardiovascular diseases as whole body fat mass or BMI [4, 60, 61]. However, quantification of total visceral fat mass requires sophisticated and expensive imaging techniques. Both
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magnetic resonance imaging (MRI) and computerized tomography (CT) have been widely
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used for total visceral fat assessment. The exposure to ionizing radiation makes CT a largely inappropriate technique for prospective studies. MRI, on the other hand, is safer but typically involves longer acquisition times and higher costs [62]. Serum concentrations of adipokines including fetuin-A, chemerin, RBP-4, omentin, vaspin, progranulin, Nampt and others have been suggested to predict visceral fat mass [5, 10]. However, associations between circulating adipokines and visceral fat mass are not always robust across different cohorts and therefore no generally accepted adipokine marker of visceral fat mass exists. In addition, it is not clear, whether adipokines cause or reflect visceral fat accumulation. The discovery of Nampt, also named visfatin, is one example for how difficult the search for circulating markers of visceral fat mass may be. Nampt/visfatin has been defined as an adipokine exclusively secreted from visceral fat with insulin-mimetic 10
ACCEPTED MANUSCRIPT effects [63], however, subsequent human studies revealed that other tissues and adipose tissue depots may also express Nampt/visfatin [64]. Noteworthy, with aging and hypercaloric
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feeding, impaired NAMPT-mediated NAD+ biosynthesis may contribute to T2D development
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[65]. For another adipokine, RBP4, different studies found either strong positive correlations between circulating RBP4 and visceral fat distribution [54, 66, 67] or no associations [68, 69].
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Such contradictory findings may at least in part be explained by the fact that in addition to adipose tissue other tissues such as the liver may determine circulating levels. For the
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adipokines chemerin [70, 71], progranulin [72] and omentin [73], associations between increased visceral fat mass and higher serum concentrations may be influenced by AT immune cell infiltration and AT dysfunction [5]. Noteworthy, so far there are no genome wide association studies using visceral or subcutaneous AT distribution as traits. Such studies may
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unravel adipokines, which are directly involved in the regulation of fat distribution.
3.2.3 Altered circulating adipokines reflect adipose tissue dysfunction
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Storage of excessive calories as triglycerides and release of fatty acids during fasting and
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prolonged food deprivation may represent the main functions of AT [74]. In addition, AT is an important organ for thermoregulation, mechanical organ protection and endocrine signalling. With increasing body weight upon excessive energy intake, AT dysfunction may develop and seems to determine the individual risk to develop metabolic and cardiovascular comorbidities [4, 10, 74]. The inability to store excess calories in subcutaneous fat depots may represent a critical node in the development of subsequent ectopic fat deposition in visceral depots, the liver and other cell types [74]. Typical symptoms of AT dysfunction are therefore: 1) visceral (ectopic) fat accumulation, 2) changes in the cellular and intracellular matrix composition of adipose tissue, 3) increased number of immune cells within AT, 4) adipocyte hypertrophy, 5) increased autophagy and apoptosis, 6) AT extracellular matrix changes (AT fibrosis), 7) alterations in AT mRNA and protein expression patterns [74]. An 11
ACCEPTED MANUSCRIPT adipokine pattern with low circulating adiponectin and high serum concentrations of chemerin, progranulin, RBP4, fetuin-A, CrP, glypican-4, DPP-4 and others may reflect AT
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dysfunction [54, 75, 76]. Importantly, further studies are required to identify robust predictors
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of AT function.
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3.2.4 Adipokines and neurodegenerative diseases
Obesity has been associated with changes in brain structure, cognitive deficits, dementia and
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Alzheimer׳s disease (AD) [77]. The association between obesity, structural changes in the brain and neurodegenerative diseases could be mediated by pleiotropic effects of adipokines, particularly those adipokines which may cross the blood brain barrier including leptin, adiponectin, plasminogen activator inhibitor-1 (PAI-1), IL-6, TNF-α and angiotensingen [77].
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Indeed, circulating leptin levels correlate with the development of AD, leptin has previously
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been shown to attenuate tau hyperphosphorylation in neuronal cells and to be modulated by amyloid-β [78, 79]. Recent data further suggest that leptin resistance in the hippocampus may
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play a role in the characteristic changes associated with AD [79]. Moreover, leptin treatment
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has been proposed as a potential clinical application for AD [80]. In a mouse model for AD with an overexpression of the amyloid-β protein precursor, chronic administration of leptin results in a significant improvement in the cognitive performance [80]. Noteworthy, weight loss often precedes the onset of dementia and AD and the level of circulating leptin is inversely proportional to the severity of cognitive decline [80]. However, the concept that leptin treatment may improve the natural course of AD needs to be proven in clinical studies. Another example for the association between changes in adipokine patterns and neurodegenerative disorders is adiponectin [77]. Decreased adiponectin serum concentrations are associated with mild cognitive impairment and AD, but do not predict cognitive decline in elderly individuals [81]. In contrast to that notion, in dementia-free women participating in the Framingham Heart Study, increased plasma adiponectin levels have been detected as 12
ACCEPTED MANUSCRIPT independent risk factor for the development of both all-cause dementia and AD [82]. In patients with probable AD, lower leptin and higher circulating adiponectin serum
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concentrations are positively correlated with the severity of dementia [83]. However, other
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studies did not find associations between adiponectin and neurodegenerative disorders [84-85]. In addition to associations between leptin and adiponectin with neurodegenerative diseases, it
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has been recently shown that resistin may protect against endogenous amyoloid β neuronal cytotoxicity in a mouse model of AD, raising the possibility of novel AD therapies using
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resistin [86]. However, further mechanistic studies are required to unravel the role of adipokines on structural changes in the brain, cognitive deficits, dementia, and AD.
3.3
Specific adipokines in health and disease: Are adipokines a novel therapeutic tool
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to treat obesity and obesity-related diseases?
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Changes in circulating adipokines and adipokine expression in AT have been linked to metabolic diseases (type 2 diabetes, fatty liver disease), cardiovascular diseases, malignancies
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and compromised reproductive health [12]. Therefore, translational research efforts have been
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put into the path from the discovery of adipokines to their clinical use in the treatment of such diseases. There are important obstacles in the successful translation of biomedical research into clinical implementation of new adipokine-based therapeutic concepts, which have been extensively discussed elsewhere [9]. Some adipokines, including leptin [18, 19], adiponectin [87] and FGF21 [88] have been systematically developed into drug applications. For other adipokines including DPP-4 [89] and BMP-7 [90], clinical application preceded their recognition as adipokines. The translational potential of adipokines research is not restricted to metabolic or cardiovascular diseases – indication fields such as infertility, lipodystrophy, fractures or musculo-skeletal diseases are either in clinical development, have been tested in clinical phase I trials or clinical pilot studies already [9].
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ACCEPTED MANUSCRIPT To fully develop an adipokine until its clinical applications are proven may take ~15 years. Even if we celebrate this year the 20th anniversary of the discovery of leptin, the long
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development process makes it obvious that for more recently identified adipokines clinical
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applications can not be expected in the next few years. For many adipokines, we still have an incomplete knowledge about the mechanism of action and the major interaction partners (e.g.
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receptors).
In addition, since many adipokines are upregulated in disease states, it may be useful to
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develop an inhibitor for such adipokines. For TNFα [91, 92] or IL-1β [93] – which could also be considered as adipokines - inhibition of action have been already tested for different indications. Moreover, a chemerin (ChemR23) antagonist CCX832 has been shown to protect against chemerin-related arterial contraction, thus linking higher chemerin concentrations in
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obesity to impaired vascular function [94]. There are several additional adipokines in the
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3.3.1 Leptin
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“pipeline” from drug discovery to clinical testing [9].
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Leptin has been considered as the prototype for all adipocyte secreted hormones [12]. Leptin levels are pulsatile [95] and are associated with fat mass/BMI as well as circulating inflammatory markers [95-98]. Leptin in low leptin states plays an important role in satiety, appetite [99, 100], food intake, reproductive function and puberty [101-106] activity and energy expenditure regulation [107]. Originally, leptin was viewed as a potential anti-obesity therapeutic agent and was originally developed mainly with the aim to reduce body fat mass in obesity [18, 108-111]. In mice [108] and humans [109] with genetically inherited leptin deficiency, leptin has been proven as an effective weight loss drug. In contrast to leptin substitution treatment, in human obese patients [110, 111] with obesity as well as in high caloric diet induced obesity in mice [112], leptin had only little effects on weight loss [113, 114]. Even high doses of leptin and once weekly treatment with pegylated leptin did not 14
ACCEPTED MANUSCRIPT improve weight loss effects, but increased the risk for side effects of recombinant leptin therapy of obesity [111]. Despite these hurdles in the human application of leptin as an anti-
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obesity drug, there are still research efforts to improve leptin analogues for their clinical use.
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For example several site-specifically enhanced leptin analogues have been designed to increase the potency and lead to a more sustained action leptin, which provided enhanced
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weight loss in diet induced obesity mice [115].Administration of leptin to human obese individuals does not significantly affect appetite and body weight [21]. It has been suggested
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that the lack of leptin efficacy in human obesity is due to the development of central leptin resistance or tolerance in parallel with increased circulating leptin levels upon and before obesity development [21]. Leptin signaling pathways, the abnormality of which may eventually lead to the development of leptin resistance, have only recently started to be
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studied in humans [116-121]. In the search for agents that may restore leptin sensitivity,
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amylin (pramlintide) has been shown to induce weight loss in obese rodent models and humans when given together with leptin [122]. The leptin analogue metreleptin combined
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with pramlintide has been advanced to a clinical proof of concept study, which demonstrated
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a significant weight-lowering effect in a 24-week study in human obesity [123]. Unfortunately, a recent randomized clinical trial using pramlintide/metreleptin as anti-obesity therapeutic had to be stopped due to adverse events such as antibody generation and skin reactions [9, 118].
3.3.2 Clinical applications of leptin and other adipokines Recombinant leptin is now available for compassionate use for patients with congenital leptin deficiency [19]. Metreleptin also has been already approved for the treatment of lipodystrophy in Japan and in the US and is under consideration at European regulatory agencies for approval [20]. The FDA Advisory Committee voted in favor of metreleptin for the treatment of diabetes and/or hypertriglyceridemia, in patients with rare forms of 15
ACCEPTED MANUSCRIPT congenital lipodystrophy [20]. An additional potential future indication for metreleptin treatment has been recently emerged from clinical studies in five patients with Rabson-
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Mendenhall syndrome (RMS), which is caused by mutations in the insulin receptor [124]. In
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these patients, metreleptin treatment for 12 months was associated with a 1.7% reduction in HbA1c and reduced body weight suggesting metreleptin is a promising treatment option for
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rare RMS patients [124]. We have recently reviewed the role of leptin in lipodystrophy elsewhere [125] and herein [126]. Moreover, the effects of metreleptin administration in
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replacement doses were investigated in a randomized, double-blinded, placebo-controlled trial in women with hypothalamic amenorrhea and acquired chronic hypoleptinemia induced by negative energy balance [101, 121, 127-131]. This study could demonstrate that metreleptin restores both CD4(+) T-cell counts and their in vitro proliferative responses in these women
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suggesting metreleptin as an effective therapy for selective CD4(+) T-cell immune
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reconstitution in hypoleptinemic states such as tuberculosis and HIV infection in which CD4(+) T cells are reduced [121]. In contrast, patients with HIV-associated dyslipidemic
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lipodystrophy did not significantly improve their leptin kinetics in response to metreleptin
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replacement treatment over 2-4 months [132] although metreleptin was successful in both open label and randomized placebo controlled trials in patients with HIV-associated lipodystrophy [133-135]. Proof of concept studies demonstrated that a safe leptin analogue has a potential clinical application in the treatment of hypothalamic amenorrhea and related infertility [101, 121, 127-131]. Moreover, serum leptin concentrations in women with anorexia nervosa are lower and show reduced diurnal variation than those of normal-weight controls as a result of decreased body weight and fat mass [reviewed in 127]. In addition to these leptin alterations, anorexia nervosa is characterized by significant changes of hormones (e.g. IGF-1, cortisol, ghrelin, PYY) including adipokines (e.g. adiponectin, resistin). Importantly, dietary therapy of anorexia nervosa leads to increased circulating leptin which correlates with increasing gonadotropins, indicating that increasing leptin in response to 16
ACCEPTED MANUSCRIPT weight gain could activate the hypothalamic-pituitary-gonadal axis [127]. Because the nutritional therapy for women with anorexia nervosa takes time, maintaining recovered
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weight maybe difficult and long-term effectiveness of this method remains to be proven,
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treatment of eating disorders such as anorexia nervosa with safe leptin analogues and careful dose titration could be an additional clinical application of leptin in the future [127-129].
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However, so far recombinant leptin has not yet been successfully introduced for the treatment of this eating disorder.
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To date, leptin is the best example for a successful translational adipokine research, which already successfully advanced to clinical application. In the future, more clinical applications of adipokine-based treatment strategies are under consideration or tested in randomized clinical proof of concept trials for the treatment of impaired glucose metabolism (e.g.
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adiponectin, FGF21, BMP7), insulin resistance (e.g. adiponectin, FGF21), dyslipidemia (e.g.
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leptin, FGF21), chronic systemic inflammation (e.g. anti IL-1 antibodies), eating disorders
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such as anorexia nervosa (e.g. leptin), bone fracture healing (e.g. BMP7) and others (Figure 2).
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3.3.3 Adiponectin
Adiponectin belongs to the highest expressed proteins in adipocytes and represents ~0.01% of total plasma protein [136]. Discovered shortly after leptin in 1995 [137-139], adiponectin gained wide interest due to its insulin sensitizing, anti-inflammatory and anti-apoptotic actions on a number of different cell types [14, 140]. In the past almost 20 years and in more than 11,000 references in the international literature, several aspects of adiponectin´s actions have been discovered, which make adiponectin-based therapies a promising approach for both treatment of obesity itself as well as for obesity-related disorders [14, 136]. Importantly, the basic principles of adiponectin physiology have been maintained remarkably well across the different species [140]. Adiponectin emerged as a suitable biomarker, because it is easily detectable in blood, stable upon collection and relatively inert to the method of collection and 17
ACCEPTED MANUSCRIPT diurnal changes [14, 137]. Circulating adiponectin levels inversely correlate with multiple metabolic disorders including obesity and related diseases [136, 137, 140]. Moreover, in large
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scale longitudinal studies circulating adiponectin has been identified as a marker for all-cause
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mortality, heart failure, coronary artery disease and type 2 diabetes [26-28, 31, 36]. In addition to beneficial peripheral effects on insulin sensitivity, adiponectin acts in the brain to
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increase energy expenditure and may thereby promote weight loss [140]. Administration of recombinant adiponectin results in improved insulin sensitivity (predominantly in the liver),
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increased insulin secretion [141], reduction of body weight and improved glycemia [reviewed in [136, 140]. In some studies, which can not confirm these adiponectin treatment data, ineffective recombinant adiponectin preparations may underlie the lack of efficacy [142]. Last year, a potential breakthrough in the adiponectin field has been reported by Okada-Iwabu and
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coworkers, who synthesized an orally active, synthetic small-molecule adiponectin receptor
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agonist [87, 143]. The molecule which has been given the name AdipoRon significantly improves insulin sensitivity and glucose tolerance in mice, thereby extending lifespan of
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db/db mice on a high-fat diet [87, 143]. The observation that agonists of the adiponectin
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receptor may have beneficial effects on increasing longevity in a mouse model of obesity provides strong evidence for the hypothesis that higher circulating adiponectin levels are associated with prolonged life expectancy under conditions of shortened life span due to obesity-related diseases [143-145]. In this context, increased adiponectin levels are associated with extended longevity in mice [145-148]. Transgenic mice expressing high levels of human adiponectin have increased longevity [146] and various mouse models of extended longevity including fat-specific insulin receptor knockout mice [147], mice with defects in growth hormone production [148], and calorie-restricted mice [149] have increased adiponectin. Moreover, female centenarians have significantly higher adiponectin plasma concentrations compared to BMI-matched women at other ages [150]. Together with evidence from longitudinal human studies that lower circulating adiponectin is related to increased all-cause 18
ACCEPTED MANUSCRIPT mortality [31] these data support the concept that adiponectin has a potential beneficial role in extending life span [145].
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These promising recent advances in the adiponectin further establish adiponectin itself or
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adiponectin receptor agonists as candidates for the further development as pharmacotherapy for diseases associated with obesity and insulin resistance, including not only diabetes and
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cardiovascular disease but also possibly obesity associated malignancies [14, 39, 49, 151-180].
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3.3.4 FGF21
Fibroblast growth factor 21 (FGF21) is a hepato-adipokine that has been shown to stimulate glucose uptake into adipocytes in an additive manner to insulin [88, 181]. The initial breakthrough in uncovering the function of FGF21 came as a result of a phenotypic screen
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carried out at Lilly Research Laboratories in early 2000 [182]. In patients with obesity and
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T2D, circulating FGF21 levels are significantly increased [183]. The obesity and diabetes research community considers FGF21 as promising molecule for the treatment of metabolic
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diseases, because this molecule may increase thermogenesis, energy expenditure, fat
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utilization and has significant glucose and lipid lowering effects [88]. In animal studies, recombinant FGF21 reduces hyperglycemia and produces additional beneficial metabolic effects [88]. In a truly translational research effort, many of the animal data have been reproduced in a randomized, placebo-controlled, double-blind trial on the effects of a FGF21 variant (LY2405319) in patients with obesity and type 2 diabetes [88]. LY2405319 administration caused body weight reduction, as well as significant improvements in fasting insulin, LDL-cholesterol, HDL-cholesterol, triglycerides and apolipoprotein profile [88]. In contrast to FGF21 overexpression studies in transgenic mice in which FGF21 not only protected animals from diet-induced obesity, but also lowered blood glucose [181], LY2405319 did not significantly improve glucose concentrations [88].
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ACCEPTED MANUSCRIPT Despite several lines of evidence about the positive metabolic actions of FGF21, safety concerns associated with targeting the FGF21 pathway have also emerged [182]. The
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translational adipokine research related to FGF21 may serve as an example how basic
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research may unravel data to guide drug discovery, but may also lead to unexpected findings. FGF21 was initially discovered using in vitro assays as a potential insulin mimetic, emerged
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as a potential agent in animals which improved more than only hyperglycemia, and ended up providing several metabolic benefits yet failed to deliver sustained glucose lowering in
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humans [182]. Taken together, FGF21 serves as a prime example that novel and potentially better medicines also derived from translational adipokine research are within the reach [182].
3.3.5 DPP-4
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Compared to leptin, adiponectin and FGF21, the drug discovery path went a totally different
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way for the clinical importance of the molecule dipeptidyl peptidase-4 (DPP-4). In an attempt to develop incretin-based therapies for type 2 diabetes, DPP-4 emerged as the most prominent
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indirect target, because DPP-4 rapidly degrades incretins including GLP-1 [89]. DPP-4
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inhibitors lower increased plasma glucose by increasing the concentration, half life time and action of incretins thereby stimulating glucose-induced insulin secretion and suppressing glucagon production [89]. Although research has focused on the role of DPP-4 in the degradation of GLP-1, recent data suggest that DPP-4 also exerts direct effects, as it is able to induce insulin resistance in adipocytes and skeletal muscle cells in concentrations that can be found in the circulation of overweight and obese subjects [184]. Only very recently, it has been appreciated that adipose tissue maybe an important source of circulating DPP-4 and DPP-4 may be considered an adipokine [184]. Importantly, obese individuals particularly those with impaired insulin sensitivity [54] have a significantly increased adipose tissue DPP-4 secretion compared to lean controls [76]. From such studies, it has been concluded that increased DPP-4 production in AT could contribute to obesity and 20
ACCEPTED MANUSCRIPT insulin resistance [9]. However, there are open questions about the net contribution of AT derived DPP-4 to changes in endogenous GLP-1 levels and whether DPP-4 inhibitors may
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disproportionately affect AT produced DPP-4 from that of other sources.
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It has been shown that DPP-4 serum concentration and adipose tissue DPP-4 expression correlate with hypertrophy of adipocytes and AT dysfunction [76, 184]. Therefore,
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DPP-4 might not only reflect adipose tissue function, but it may also have local effects within adipose tissue and systemic effects. Increased DPP-4 activity and serum concentrations in
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obesity may serve as a model how altered adipokine secretion may be successfully used as therapeutic target in the treatment of obesity related diseases. However, further work is needed to elucidate the functional role of DPP-4 within adipose tissue and to define whether higher DPP-4 expression and serum concentration may contribute to higher efficacy of DPP-4
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inhibitors in patients with type 2 diabetes [9].
3.3.6 TNFα and IL-1β
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Both TNFα and IL-1β are highly expressed in and secreted from adipose [185, 186] and may
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therefore qualify for the term adipokine. Both cytokines are attractive targets for antiinflammatory therapies with beneficial effects on insulin sensitivity and glucose metabolism [9]. In a rat model of obesity, neutralization of TNFα leads to an increase in peripheral glucose uptake in response to insulin [187]. Genetic ablation of the TNFα gene in mice results in improved insulin sensitivity in different obesity models suggesting that blocking TNFα action may improve insulin sensitivity and its related traits [188]. Treatment with TNFα antibodies resulted in inhibited inflammatory activity, improved fatty liver disease [189], protection against diet induced obesity and insulin resistance [190] in several animal models. However, these beneficial metabolic effects using anti-TNF treatment could not be proven to be successful in obese Zucker rats [191] or recent clinical studies [192]. On the other hand, there are studies reporting improvements in insulin sensitivity or hyperglycemia in insulin 21
ACCEPTED MANUSCRIPT resistant individuals during prolonged treatment with TNFα targeting strategies infliximab [91] or etanercept [92].
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IL-1β is another potential drug target, because it may contribute to β-cell destruction and
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apoptosis associated with the pathogenesis of both type 1 and type 2 diabetes [93]. In the first clinical double-blind, parallel-group proof of concept study, Larsen and coworkers
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demonstrated that blocking IL-1 using the recombinant human IL-1-receptor antagonist anakinra significantly lowers plasma glucose, improves β-cell function and reduced markers
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of systemic inflammation [93]. These data support the concept that targeting proinflammatory adipokines/cytokines may be an approach to improve metabolic diseases.
3.3.7 BMP-7
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Bone morphogenetic proteins (BMPs) are developmental factors that belong to the
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transforming growth factor (TGF) β superfamily and regulate several processes of organogenesis and patterning during embryonic development [193-196]. Moreover, BMPs
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may act as a molecular switch in regulating white versus brown adipogenesis [195, 196].
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Recently, several members of the BMP family of ligands and receptors have been found to associate with obesity-related traits in humans [61, 197, 198]. Therefore, targeting BMPs has emerged as a novel therapeutic concept to treat obesity and its related diseases by inducing increased energy expenditure and browning of white adipose tissue [193, 194]. As an example, BMP7 has gained attention after the notion that BMP-7 stimulates brown adipogenesis, reduces food intake, increases energy expenditure resulting in reduced weight gain [195, 196]. For BMP7 translational adipokine research is facilitated by the fact that human recombinant BMP7 is already available [90]. Under the brand name OP1, recombinant BMP7 is locally applied to aid in the fusion of vertebral bodies in the treatment of non-union after tibia fractures [90]. From the clinical use, it is known that local recombinant BMP7 application does not have local or systemic toxic effects or other 22
ACCEPTED MANUSCRIPT adverse events [90]. So far, BMP7 has not been tested in the treatment of obesity or metabolic
Conclusions
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4.
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diseases.
Several important advances in our understanding of the function of the adipose tissue and
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important changes in the way we approach and treat several disease states have occurred over the twenty years since the discovery of leptin. Adipokines contribute to the regulation of
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appetite, satiety, energy expenditure and physical activity. Targeting or using adipokine-based mechanisms to treat obesity and diseases which are caused by a positive energy balance is therefore a promising strategy, and has driven translational adipokine research during the past 20 years. Moreover, we have also realized during the same period of time that several
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adipokines, including but not limited to adiponectin, leptin, etc. serve as messages linking
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adipose tissue with specific organs and conveying information that may alter human
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issue [14].
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physiology and pathophysiology as outlined in part in this renew and elsewhere in this special
Thus, all these newly discovered adipokines are not only promising new potential biomarkers and therapeutic agents; we have already started realizing tangible benefits. In the energy deficiency part of the energy homeostasis spectrum, congenital leptin deficiency and generalized lipodystrophy are now indications for therapy with leptin. Proof of concept studies have demonstrated that a safe leptin analogue could be a reasonable, physiology based, approach for the treatment of hypothalamic amenorrhea and related infertility and possibly, in well controlled doses, for some cases of anorexia nervosa. In the treatment of obesity, lifestyle changes, psychological interventions or pharmaco-therapies have provided only very limited sustained beneficial effects. In the long-term, weight loss surgery are much more effective compared to the non-surgical intervention, but the bare an increased perioperative 23
ACCEPTED MANUSCRIPT mortality risk. In particular, pharmacological anti-obesity therapies rarely lead to leanness or a complete remission of obesity-associated diseases.
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At the 20th anniversary of the discovery of leptin, translational research has already led
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to clinical application of the leptin analogue metreleptin as a pharmacotherapy in individuals with congenital leptin deficiency and lipodystrophies [199]. More adipokine-based treatment
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strategies using for example adiponectin, FGF21 or BMP7 may follow leptin in the path of drug discovery. In summary, adipokines may open exciting new diagnostic and treatment
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opportunities for diseases with unmet clinical needs.
Conflict of interest
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Dr. Mantzoros is a consultant for Astra Zeneca. Dr. Blüher does not have any conflict of
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interest related to this manuscript.
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ACCEPTED MANUSCRIPT Figure legends Figure 1. Adipokines regulate important physiologic processes. Secreted factors from
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adipose tissue (representative histologic slide of human subcutaneous adipose tissue,
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hematoxylin and eosin staining; magnification: 20X) play an important role in the regulation of appetite and satiety, energy expenditure, insulin sensitivity and insulin secretion,
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inflammation, blood pressure, hemostasis, endothelial function and others.
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Figure 2. Translational adipokine research. Adipokines have the potential to be used in clinical practice as markers (predictors) for obesity related diseases, mortality, individual disease outcomes or as substrates/targets for pharmacological management of obesity and prevention of obesity related disorders. For several adipokines there is evidence for the
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prediction of obesity complications, but also a need for future development and validation.
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Some adipokines have been already used in clinical studies for different indications, whereas
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for more recently discovered adipokines only data from animal experiments are available.
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ACCEPTED MANUSCRIPT Table 1. Examples of adipokines and main function(s).
Adipokine
Target action Regulation of satiety, appetite, food intake,
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Leptin
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activity and energy expenditure, fertility, atherogenesis and growth induction Antidiabetic, anti-atherogenic and anti-
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Adiponectin
inflammatory
Chemoattractant protein, regulation of
Chemerin
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adipogenesis
Pro-inflammatory
TNFα
Pro-inflammatory
IL-1β
Stimulates glucose uptake into adipocytes,
FGF21
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increases thermogenesis, energy expenditure,
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Retinol binding protein-4 (RBP4)
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Vaspin
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Visfatin/PBEF/Nampt
fat utilization, lowers glucose and triglycerides Related to insulin resistance, visceral fat distribution Decreases food intake, improves hyperglycemia Nampt-mediated systemic NAD biosynthesis is critical for β cell function
Monocyte chemotactic protein-1
Chemoattractant protein, promotes adipose
(MCP-1)
tissue inflammation
Progranulin
Promotes adipose tissue inflammation
DPP-4
Degrades GIP and GLP-1 Inhibitors in clinical use for type 2 diabetes
BMP-7
Stimulates brown adipogenesis, reduces food intake, increases energy expenditure
26
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