Lipid signaling in adipose tissue: Connecting inflammation & metabolism.

BBAMCB-57702; No. of pages: 16; 4C: 3, 4, 9 Biochimica et Biophysica Acta xxx (2014) xxx–xxx

Contents lists available at ScienceDirect

Biochimica et Biophysica Acta journal homepage: www.elsevier.com/locate/bbalip

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Mojgan Masoodi a,⁎, Ondrej Kuda b, Martin Rossmeisl b, Pavel Flachs b, Jan Kopecky b,⁎⁎

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Article history: Received 24 July 2014 Received in revised form 25 September 2014 Accepted 28 September 2014 Available online xxxx

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Keywords: Healthy adipocyte Futile substrate cycle Macrophage Lipid mediator Omega-3 Calorie restriction

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Nestlé Institute of Health Sciences SA, EPFL Innovation Park, bâtiment H, 1015 Lausanne, Switzerland Department of Adipose Tissue Biology, Institute of Physiology Academy of Sciences of the Czech Republic, v.v.i., Prague, Czech Republic

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Obesity-associated low-grade inflammation of white adipose tissue (WAT) contributes to development of insulin resistance and other disorders. Accumulation of immune cells, especially macrophages, and macrophage polarization from M2 to M1 state, affect intrinsic WAT signaling, namely anti-inflammatory and proinflammatory cytokines, fatty acids (FA), and lipid mediators derived from both n− 6 and n− 3 long-chain PUFA such as (i) arachidonic acid (AA)-derived eicosanoids and endocannabinoids, and (ii) specialized pro-resolving lipid mediators including resolvins derived from both eicosapentaenoic (EPA) and docosahexaenoic acid (DHA), lipoxins (AA metabolites), protectins and maresins (DHA metabolites). In this respect, potential differences in modulating adipocyte metabolism by various lipid mediators formed by inflammatory M1 macrophages typical of obese state, and non-inflammatory M2 macrophages typical of lean state remain to be established. Studies in mice suggest that (i) transient accumulation of M2 macrophages could be essential for the control of tissue FA levels during activation of lipolysis, (ii) a currently unidentified M2 macrophage-borne signaling molecule(s) could inhibit lipolysis and re-esterification of lipolyzed FA back to triacylglycerols (TAG/FA cycle), and (iii) the egress of M2 macrophages from rebuilt WAT and removal of the negative feedback regulation could allow for a full unmasking of metabolic activities of adipocytes. Thus, M2 macrophages could support remodeling of WAT to a tissue containing metabolically flexible adipocytes endowed with a high capacity of both TAG/FA cycling and oxidative phosphorylation. This situation could be exemplified by a combined intervention using mild calorie restriction and dietary supplementation with EPA/DHA, which enhances the 7formation of “healthy” adipocytes. © 2014 Published by Elsevier B.V.

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Lipid signaling in adipose tissue: Connecting inflammation & metabolism☆

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Abbreviations: 14-HDoHE, 14-hydroxydocosahexaenoic acid; 17-HDoHE, 17-hydroxydocosahexaenoic acid; 15d-PGJ2, 15-deoxy-Δ12, 14-prostaglandin J2; 2-AG, 2arachidonoylglycerol; AA, arachidonic acid; ACC, acetyl-CoA carboxylase; AEA, anandamide (arachidonoylethanolamide); AMPK, AMP-activated protein kinase; AQP7, aquaporin 7; ATGL, desnutrin/adipose triglyceride lipase; ATMs, adipose tissue macrophages; BAT, brown adipose tissue; β-AR, β-adrenergic receptor; CB1 or CB2, cannabinoid receptors type 1 or 2; CCL2, monocyte chemotactic protein-1 (also called MCP1); CLS, crown-like structures; COX, cyclooxygenases; CPT-1, carnitine palmitoyltransferase 1; DAG, diacylglycerol; DAGK, diacylglycerol kinase; DGAT1, acyl-CoA:diacylglycerol acyltransferase; DGL, diacylglycerol lipase; DHA, docosahexaenoic acid; DHEA, docosahexaenoylethanolamide; ECS, endocannabinoid system; EP, receptor for PGE2; EP3, prostaglandin E receptor 3; EPA, eicosapentaenoic acid; EPEA, eicosapentaenoylethanolamide; FA, fatty acids; FAAH, fatty acid amide hydrolase; FAS, fatty acid synthase; FAT/ CD36, FA translocase CD36; FP, receptor for PGF2α; GLUT4, glucose transporter type 4; GPR120, G protein-coupled receptor 120; HF, high-fat; HSL, hormone-sensitive lipase; HX, hepoxilin; ChREBP, carbohydrate response-element binding protein; IP, receptor for PGI2; IR, insulin resistance; IRS-1, insulin receptor substrate-1; LA, linoleic acid; LOX, lipoxygenase; LPL, lipoprotein lipase; LT, leukotriene; MGL, monoglyceride lipase; NAPE-PLD, N-acyl phosphatidylethanolamine-specific phospholipase D; NAT, N-acyl transferase; NE, neutrophil elastase; NFkB, proinflammatory transcription factor NFκB; NP, natriuretic peptides; NPRA, natriuretic peptide receptor A; OEA, oleoylethanolamide; omega-3 PL, oils containing omega-3 PUFA as phospholipids; omega-3PUFA,long-chainn-3 PUFA;omega-3 TAG,oilscontainingomega-3 PUFA astriacylglycerols; OXPHOS, oxidative phosphorylation;p38 MAPK, p38α mitogen-activatedprotein kinase; P450, cytochrome P450; PA, phosphatidic acid; PC, phosphatidylcholine; PD, protectin; PDH, pyruvate dehydrogenase; PDK4, pyruvate dehydrogenase 4; PE, phosphatidylethanolamine; PEPCK, phosphoenolpyruvate carboxykinase; PG, prostaglandin; PGC-1β, the PPARγ coactivator PGC-1β; PGE2, prostaglandin E2; PGF2, prostaglandin F2α; PIP, prostaglandin I2 receptor; PIP2, phosphatidylinositol biphosphate; PKA, protein kinase A; PKB, protein kinase B; PKG, protein kinase G; PLC, phospholipase C; PPAR, peroxisome proliferator-activated receptor; PRRs, pattern-recognition receptors; RBP4, retinol-binding protein 4; RvD1, resolvin D1; SREBP-1c, sterol regulatory element-binding protein 1c; SVF, stromal vascular fraction from adipose tissue; TAG, triacylglycerols; TAG/FA cycle, futile substrate cycle based on lipolysis of intracellular triacylglycerols and re-esterification of fatty acids; TRPV1, transient receptor potential vaniloid type-1; TX, thromboxane; WAT, white adipose tissue ☆ This article is part of a Special Issue entitled Oxygenated metabolism of PUFA: analysis and biological relevance. ⁎ Corresponding author. Tel.: +41 216326156. ⁎⁎ Correspondence to: J. Kopecky, Department of Adipose Tissue Biology, Institute of Physiology of the Academy of Sciences of the Czech Republic, v.v.i., Videnska 1083, 14220 Prague 4, Czech Republic. Tel.: +420 241062554; fax: +420 241062599. E-mail addresses: [email protected] (M. Masoodi), [email protected] (J. Kopecky).

http://dx.doi.org/10.1016/j.bbalip.2014.09.023 1388-1981/© 2014 Published by Elsevier B.V.

Please cite this article as: M. Masoodi, et al., Lipid signaling in adipose tissue: Connecting inflammation & metabolism, Biochim. Biophys. Acta (2014), http://dx.doi.org/10.1016/j.bbalip.2014.09.023

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M. Masoodi et al. / Biochimica et Biophysica Acta xxx (2014) xxx–xxx

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Adipose tissue is distributed throughout the body in several discrete depots located mainly in the subcutaneous region (subcutaneous fat) or in the thorax and abdominal cavities (visceral fat). Areas composed mainly of white adipocytes are considered WAT, whereas areas mainly composed of brown adipocytes are considered BAT [1]. Different cell morphologies correspond to different functions, as white adipocytes are filled with one lipid droplet (unilocullar adipocytes) and equipped with a small cytosolic compartment, while brown adipocytes are multilocullar and rich in large mitochondria. In addition to the classical WAT and BAT adipocytes, a distinct type of thermogenic inducible adipocytes, so called brite/beige adipocytes also exist [2–4]. A plausible concept of adipose tissue organ as a continuum of both WAT and BAT has been coined by Cinti and colleagues [5,6]. WAT, as the most plastic organ among the metabolically relevant tissues, can represent 5–60% of total body weight [7,8]. Fat mass reflects energy balance, however, adipocyte number is very static in adult humans and independent of body weight fluctuations, even in response to massive weight loss. This indicates that the number of adipocytes is set during childhood and adolescence [8], while only approximately 10% of fat cells are renewed annually in adult humans [9]. Accumulation of visceral fat, which characterizes upper-body obesity, is known to correlate with metabolic syndrome [10]. This is typical for men, who, unlike women, accumulate fat centrally in both subcutaneous and visceral depots [11], but do not show high rates of subcutaneous fat accumulation unless morbidly obese [8].

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2.1. Secretory functions of adipose tissue

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WAT generates a number of signals, which include cytokines, hormones, growth factors, complement factors and matrix proteins that not only affect the neighboring cells but also target other peripheral tissues as well as the brain. Thus, WAT-derived signals could influence various processes including food intake, energy expenditure, metabolism, immunity and blood pressure. Two major adipokines (adipocytokines) are leptin and adiponectin, although there are probably hundreds of other adipokines and cytokines produced in WAT with some of them exerting only autocrine and paracrine, but not systemic effects (reviewed in [12,13]). The involvement of several adipokines and WAT-borne cytokines in control of (WAT) inflammation as well as insulin sensitivity are mentioned in the text below. In this context, it is especially retinol-binding protein 4 (RBP4), a retinol transporter secreted from adipocytes, which is of relevant importance [14], as its secretion is increased in obesity while it also activates innate

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Intrinsic metabolism of WAT (Fig. 1) is of key importance for the whole organism with respect to storage of energy in triacylglycerols (TAG) during the postprandial state, as well as the mobilization of energy reserves during fasting or exercise and control of circulating FA levels (reviewed in [17]). Lipolysis of TAG from intracellular lipid droplets (see below) in adipocytes is under complex hormonal control and it is mediated by several co-operating enzymes (reviewed in [18, 19]; see Fig. 1 and Section 2.3). These include: (i) desnutrin/adipose triglyceride lipase (ATGL), an enzyme that catalyzes the initial step in TAG hydrolysis and the rate-limiting hydrolysis of TAG [20], (ii) hormone-sensitive lipase (HSL), which catalyzes the hydrolysis of TAG into diacylglycerols, and then into monoacylglycerols, and finally (iii) monoglyceride lipase (MGL). Besides its metabolic role, MGL also has an important function in the degradation of endocannabinoids ([19, 21]; see Section 4.3 and Fig. 2). Lipolysis is associated with in situ re-esterification of a part of lipolyzed FA back into TAG (TAG/FA cycle; [22–25]), in which acyl-CoA:diacylglycerol acyltransferase 1 (DGAT1) is specially involved, while DGAT2 is linked to endogenous FA synthesis and esterification [26]. Re-esterification requires glyceroneogenesis, i.e. a process in which pyruvate serves as the major precursor for glycerol 3-phosphate formation via phosphoenolpyruvate carboxykinase (PEPCK; [17,27]). The TAG/FA substrate cycling in WAT enables fine tuning of opposite metabolic fluxes, it is essential for buffering of plasma FA levels and marks “healthy” adipocytes (reviewed in [17]; see Section 5). Stimulation of this mechanism by peroxisome proliferatoractivated receptor-γ (PPARγ; product of the Pparg gene; also known as Nr1c3; see Section 2.3) agonists could contribute to the insulinsensitizing effects of these compounds (reviewed in [17]). Energy required for this futile substrate cycle [28] could be covered either by β-oxidation of FA in mitochondria, or by glycolysis/glucose oxidation, and also via energy equivalents produced during de novo FA synthesis [17]. It has been described only recently (reviewed in [19,29]) that the cycle of FA re-esterification and hydrolysis is also required for the formation of the lipolytic products, namely FA and diacylglycerols, acting as regulatory ligands of nuclear receptors (FA acting directly, and diacyl glycerols as their further metabolites); in fact FA must be always activated by the passage through TAG/FA cycle to act as lipid mediators. Thus, in analogy to the situation in cardiac muscle, where ATGL-derived molecule(s) is/are essential for the induction PPARα target-genes (see Section 2.3) and mitochondrial function [30], this mechanism could be also important for the induction of mitochondrial oxidative capacity in WAT. All the enzymes involved in lipolysis, including some of their regulatory proteins such as perilipin, as well as DGAT1, which is involved in FA re-esterification (see above) are located on lipid droplets (also referred to as adiposomes) in adipocytes. These organelles are delimited by a single phospholipid membrane that separates TAG and other lipids inside droplets from the aqueous phase and forms a matrix for all the lipid droplet-associated proteins. Lipid droplets interact with other cell organelles such as peroxisomes, mitochondria and endoplasmic reticulum (reviewed in [19,26,31]). The interaction with endoplasmic reticulum is essential for the formation of TAG, in which DGAT2 localized to both endoplasmic reticulum and lipid droplets is involved [31]. WAT is also an important site of de novo FA synthesis (de novo lipogenesis), namely in rodents, but also in humans, where up to 40% of whole-body de novo FA synthesis from glucose may take place in WAT [32]. Importantly, glucose transporter type 4 (GLUT4)-mediated

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Obesity, i.e. excessive accumulation of white adipose tissue (WAT), is associated with severe metabolic diseases (metabolic syndrome) and represents one of the key problems of health care systems in affluent societies. Obesity is accompanied by chronic low-grade inflammation of WAT, which, in turn may affect adipocyte metabolism. Consequently, obesity-associated changes in WAT are consistent with an emerging concept that immune and metabolic systems are interconnected. This review focuses on: (i) WAT rather than thermogenic brown adipose tissue (BAT), since it is becoming increasingly apparent that besides energy expenditure in BAT, WAT metabolism may also have important systemic consequences on both the control of circulating fatty acids (FA) levels and insulin sensitivity; (ii) the roles of various lipid molecules in WAT, which are involved in autocrine (intracellular) and paracrine (intercellular) signaling, regulating metabolism of fat cells and reflecting inflammatory status of the tissue; and (iii) mutual interactions between various cell types contained in WAT, specially adipocytes and macrophages, as one of the keys to the integrated control of inflammatory status and metabolism in this tissue.

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immunity and inflammatory responses in WAT (ref. [15]; see 104 Section 3.1). In contrast to WAT, the secretory functions of BAT are 105 poorly characterized [16]. 106

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uptake of glucose into adipocytes, and FA synthesis associated with it, are linked to whole body insulin sensitivity. It has been hypothesized that some de novo formed lipid(s) in adipocytes could support insulin signaling in other tissues (reviewed in [33,34]). A novel (β) isoform of carbohydrate responsive-element binding protein (ChREBPβ, also referred to as MLX interacting protein-like) serves as the major determinant of FA synthesis in WAT and represents a predictor of insulin sensitivity (ref. [34]; see below). Similarly as in most other cells, mitochondria represent the main site of oxygen consumption and ATP production also in white adipocytes. The mitochondrial content of mature white adipocytes is several-fold higher than in preadipocytes and depends on the anatomical location of fat depot (reviewed in [17]). Mitochondria play a critical regulatory role in major metabolic pathways, i.e. de novo FA synthesis, glyceroneogenesis, lipolysis and FA re-esterification in adipocytes (ref. [17]; see above). Obesity and insulin resistance (IR) are associated with a low capacity of both mitochondrial oxidative phosphorylation [17,35,36] and de novo FA synthesis [37] in WAT.

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Fig. 1. Pathways involved in regulation of adipocyte metabolism. As explained in the main text (see Sections 2.2 and 2.3.), the central node of adipocyte metabolism is lipolysis of triacylglycerols (TAG) and re-esterification of fatty acids (FA) in cytoplasmic lipid droplets (i.e. TAG/FA cycle). The associated metabolic pathways are de novo lipogenesis, glyceroneogenesis via phosphoenolpyruvate carboxykinase (PEPCK), and β-oxidation of FA in mitochondria. The induction of TAG/FA (FA liberated from TAG during lipolysis may be released from adipocyte and taken back by FA translocase CD36; FAT/CD36) requires ATP, leading to lowering of cellular energy status and activation of AMP-activated protein kinase (AMPK), which could stimulate uptake FA by increasing intravascular lipoprotein lipase (LPL) activity and by modulating intracellular TAG lipolysis and re-esterification of FA via a complex mechanism (reviewed in [17]). AMPK activity is decreased by protein kinase B (PKB) and at the early stages of adrenergic stimulation, also by protein kinase A (PKA). AMPK phosphorylates acetyl-CoA carboxylase (ACC), which leads to a decrease in de novo lipogenesis activity and to decrease in cellular malonyl-CoA levels. Malonyl Co-A is an inhibitor of carnitine palmitoyltransferase 1 (CPT-1) activity, the rate-limiting step in β-oxidation. Prolonged activation of AMPK could also decrease glucose oxidation by increasing peroxisome proliferator-activated receptor-γ (PPARγ)/ PPARγ coactivator/1 (PGC-1) transcriptional activity and subsequent induction of pyruvate dehydrogenase 4 (PDK4). Phosphorylation/inhibition of pyruvate dehydrogenase (PDH) by PDK4 enables pyruvate to be used for glyceroneogenesis [203]. Both, PKA and protein kinase G (PKG) induce lipolysis by direct phosphorylation of hormone-sensitive lipase (HSL) and through phosphorylation of perilipin 1 on lipid droplets and they also activate desnutrin/adipose triglyceride lipase (ATGL). PKA and PKG can phosphorylate/activate p38α mitogen-activated protein kinase (p38 MAPK; ref. [204]). Thus, in response to β-agonist or natriuretic peptides (NP), which bind to β-adrenergic receptor (β-AR) and natriuretic peptide receptor A (NPRA), respectively, p38 MAPK phosphorylates the transcriptional regulators ATF2 and PGC-1α, leading to the induction of expression of PPARα and PPARγ target genes (pink box and black box on the bottom). PKA- but not PKG-mediated lipolysis is inhibited by insulin [33]. Endogenous PPARs ligands are depicted in rectangular callouts on the right. Carbohydrate responsive-element binding protein (ChREBP; also called MLX interacting protein-like) is a transcription factor activated by glucose; its target genes are involved in the pathways of glucose and lipid metabolism. ChREBP is inactivated by both PKA and AMPK. In WAT, glucose-mediated activation of canonical ChREBPα isoform induces expression of ChREBPβ, as an important step in the induction of lipogenesis and increase in insulin sensitivity via adipocyte-derived signaling molecules [34]. 2-AG, 2-arachidonoylglycerol; AA, arachidonic acid; AEA, arachidonoylethanolamide; AQP7, aquaporin 7; COX, cyclooxygenase; CB1, cannabinoid receptor type 1; EP3, prostaglandin E receptor 3; FAS, fatty acid synthase; GPR120, G protein-coupled receptor 120; GLUT-*, glucose transporter; InsR, insulin receptor; LOX, lipoxygenase; MGL, monoacylglycerol lipase; PC, pyruvate carboxylase; PIR, prostaglandin I2 receptor; OEA, oleoylethanolamide; PG*, prostaglandin; SREBP1, sterol regulatory element-binding protein 1; TRPV1, transient receptor potential vaniloid type-1.

Even a small shift in the balance of activities in the major metabolic pathways contributing to TAG/FA cycle, i.e. lipolysis and FA re-esterification, as well as in the associated metabolic fluxes (see above) could affect adiposity. Notably, activity of the TAG/FA cycle also plays a crucial role in transformation of WAT to BAT [6]. The TAG/FA cycle in WAT could be responsible for about 2–3% of resting metabolic rate in obese humans [17]. Total WAT contribution to resting metabolic rate in lean human subjects is approximately 5% and it doubles in obesity [23].

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2.3. Intracellular pathways engaged in the regulation of adipocyte 195 metabolism 196 The key molecular players that participate in regulation of adipocyte metabolism are shown in Fig. 1. Regarding the topic of this review, i.e. the interactions between the components of metabolism and the immune system, nuclear receptors from the family of PPARs play the key role. These receptors serve as ligand-dependent transcription


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R1-acyl: -20:4 n-6 -20:5 n-3 -22:6 n-3 9-HEPE -18:1 n-9 -16:0

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factors that control expression of metabolic genes, as well as mitochondrial biogenesis, and they also exert anti-inflammatory effects (reviewed in [38]). Thus PPARs bind as heterodimers with retinoid X receptor to specific regulatory sequences of the target genes, also in the interactions with several regulatory proteins and other transcription factors. Various endogenous lipids have been identified as their activating ligands, including FA, oxylipins, endocannabinoids and phospholipids (see Fig. 1; reviewed in [38]; see Section 4.1). PPARs family members show some tissue-specific differences in their expression, PPARα and PPARγ being abundant predominantly in the liver and adipose tissue, respectively, and PPARβ/δ in many tissues. These differences reflect the preferential involvement of both PPARα and PPARβ/δ in lipid catabolism, and the key regulatory role of PPARγ in adipocyte differentiation as well as in lipogenesis in these cells, respectively (reviewed in [39,40]). In WAT, the PPARγ2 isoform is predominantly expressed [41], located upstream from two major transcription factors controlling the activity of metabolic genes, i.e. sterol regulatory element-binding protein 1c (SREBP-1c) and ChREBP (reviewed in [33]; see Fig. 1). Transcriptional PPARγ coactivator PGC-1β plays a major role in the control of mitochondrial biogenesis in WAT [42]. The anti-inflammatory effects of PPARγ activation in WAT are mediated by multiple mechanisms, including physical interaction of PPARγ with the pro-inflammatory transcription factor NFκB (reviewed in [38]), as well as the prevention of CDK5-mediated phosphorylation of PPARγ at serine 273, which could elicit antidiabetic action [43,44]. The anti-inflammatory role of PPARγ is tightly linked to systemic insulin sensitivity, as documented by the effects of anti-diabetic drugs acting as specific PPARγ agonists, namely thiazolidinediones. Indeed, WAT-specific upregulation of PPARγ confers strong antidiabetic effects [45].

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Fig. 2. Overview of lipid mediators in WAT. Production of lipid mediators begins on the plasma membrane, where phospholipids (violet) are cleaved by phospholipase A2 to yield free arachidonic, eicosapentaenoic or docosahexaenoic acids, which are subsequently metabolized into either eicosanoids (orange, yellow, green) or docosanoids (blue) by a variety of enzymes. Endocannabinoids (red) come either from membrane phospholipids via N-acyl-phosphatidylethanolamine intermediate or from 1,2-diacylglycerol, product of PIP2, PA or TAG metabolism, in case of 2-AG. 2-AG, 2-arachidonoyl glycerol; AA, arachidonic acid; AEA, arachidonoylethanolamide; ATGL, adipose triglyceride lipase; COX, cyclooxygenase; DAG, diacylglycerol; DAGK, diacylglycerol kinase; DGL, diacylglycerol lipase; DHEA, docosahexaenoylethanolamide; −EA, −ethanolamide; EPEA, eicosapentaenoylethanolamide; FAAH, fatty acid amide hydrolase; HSL, hormone-sensitive lipase; HX*, hepoxilin; LOX, lipoxygenase; LT*, leukotriene; MGL, monoacylglycerol lipase; n.e., non-enzymatic oxidation; NAPE-PLD, N-acyl phosphatidylethanolamine-specific phospholipase D; NAT, N-acyl transferase; OEA, oleoylethanolamide; P450, cytochrome P450; PA, phosphatidic acid; PC, phosphatidylcholine; PE, phosphatidylethanolamine; PEA, palmitoylethanolamide; PG*, prostaglandin; PIP2, phosphatidylinositol biphosphate; PLC, phospholipase C; TX*, thromboxane. For nomenclature of lipid mediators see LIPIDMAPS.org.

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Although obesity is one of the major risk factors for type 2 diabetes, not all obese subjects become diabetic. Obesity-associated low-grade inflammation is now recognized as an important cause of obesityinduced IR [46,47], also in accordance with the general notion that immune and metabolic systems are interconnected [38,48,49]. The inflammatory process, including activation of the innate immune system (macrophages, monocytes, neutrophils), is triggered by WAT expansion and hypoxia. However, molecular mechanism that underlies this process is not fully understood. Adipose tissue macrophages (ATMs) recognize pathogen-associated molecular patterns through expression of pattern-recognition receptors (PRRs) such as Toll-like and Nod-like receptors [50]. Saturated FA or their metabolites have been suggested to induce inflammation by activating Toll-like receptor 4 [51], resulting in downstream activation of several serine kinases such as IkB kinase and JNK [52,53]. In concert with the action of proinflammatory cytokines (see Section 3.1; refs [53,54]), these signaling events converge to enhance the activities of NFκB, and p38α mitogen-activated protein kinase (p38 MAPK) pathways, leading to the release of further inflammatory mediators and impairment of insulin signaling via serine phosphorylation of insulin receptor substrate-1 (IRS-1; reviewed in [55]). Activation of Toll-like receptor 4 by saturated FA, as well as by independently acting pro-inflammatory cytokines, can lead to upregulation of the ceramide biosynthesis pathway. The correlation between increased ceramide levels in plasma and IR has been demonstrated. Ceramides decrease insulin sensitivity and glucose transport via activation of protein kinase B (PKB; also known as Akt) dephosphorylation by

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P

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3.1. Macrophages — major players mediating inflammation in adipose tissue WAT in lean subjects contains so called “alternatively activated” ATMs (i.e. M2 form ATMs) that produce anti-inflammatory cytokines such as IL-4, IL-10 and IL-13, which are marked by the expression of arginase-1 and several other genes. These ATMs promote WAT remodeling and clearance of apoptotic cells (efferocytosis), and support systemic insulin sensitivity (reviewed in [38,70,71]). In obesity, ATMs contribute significantly to increased production of inflammatory markers (see below) that play pivotal roles in the induction of systemic IR, glucose intolerance, and type 2 diabetes, while adiponectin secretion is decreased [72,73]. Accordingly, obesity is accompanied by macrophage polarization from the M2 form to the proinflammatory (classically activated) M1 form of ATMs [74,75]. M1 macrophages secrete proinflammatory cytokines such as TNF-α, IL-6, IL-1β and IL-12 and express lectin Lgals3 (also called as Mac-2), which mediates macrophage phagocytic and inflammatory responses. ATMs can comprise up to 40% of the cells in obese WAT, while their numbers correlates with the degree of obesity [76,77] and represent the strongest predictor of type 2 diabetes development in obese patients [78]. Macrophages may infiltrate WAT in response to chemokines, such as monocyte chemotactic protein-1 (CCL2; also called MCP1), which in contrast to its name is predominantly released from adipocytes as part of a scavenger function in response to hypoxia and adipocyte necrosis. Targeted deletion of the CCL2 gene reduced macrophage accumulation and inflammation in WAT, as well as IR associated with obesity [79]. In addition, over-expression of CCL2 gene in WAT induces macrophage recruitment and IR [79,80]. Increased content of ATMs in WAT during obesity-associated inflammation reflects both post-mitotic differentiation of bone-marrow-derived monocytes infiltrating the tissue [76], as well as local proliferation of macrophages [81,82]. The monocyte recruitment from blood stream is linked to WAT infiltration by M1 ATMs, whereas proliferation of M2 ATMs occurs on site ([81,82]; see below). Macrophages aggregate around dead adipocytes and form syncytia, often referred to as “crown-like structures” (CLS), while scavenging residual adipocyte lipids and ultimately forming multi-nucleate giant cells; thus adipocyte necrotic death could represent the primary stimulus driving ATM accumulation [83]. Although M2 and M1 forms are currently the two defined statuses of macrophages based on in vitro stimulation, macrophage polarization is

323 324 325 326 327 328 329 330 331 332 333 334 335 336 337 338 339 340 341 342 343 344 345 346 347 348

D

274 275

3.2. Involvement of various cells of immune system in macrophage 349 polarization 350

E

272 273

more dynamic in vivo and changes upon their local environment. RBP4 is the key endogenous protein in WAT (see Section 2.1), which is engaged in the control of ATM polarization. It activates both resident ATMs to induce their M1 form, as well as dendritic cells, leading to WAT inflammation and systemic IR [15]. The polarization switching is also influenced by dietary lipid composition. The dietary FA (see above) and FA-derived lipid mediators can influence cell signaling between adipocytes and macrophages in WAT and play an important role in the generation of the adipokine profile. For example in HF diet-induced obese mice, ATMs are polarized toward proinflammatory M1 form whereas treating obese mice with long-chain n− 3 PUFA (omega-3 PUFA) could drive the polarization toward M2 ATMs [71]. Omega-3 PUFA exhibit their anti-inflammatory effects via signaling through G protein-coupled receptor 120 (GPR120), resulting in improved insulin sensitivity in obese mice [71,84]. In contrast, its dysfunctions leads to obesity [85], documenting once again the tight link between the immune system and metabolism. In addition, docosahexaenoic acid (C22:6n−3, DHA)-derived lipid mediators such as resolvin D1 (RvD1) have been reported to decrease ATM accumulation, shifting macrophage polarization toward M2 form and improving insulin sensitivity in obese mice [86,87]. Moreover, production of (ATMs-derived) inflammatory mediators is highly dependent on the type of WAT depot (see [88] and Section 4.3). M2 ATMs exert high activity of mitochondrial oxidative phosphorylation, in agreement with their lasting role in tissue remodeling, while M1 ATMs rely on anaerobic glycolysis ([89]; see Section 5).

T

270 271

C

268 269

E

266 267

R

265

R

263 264

N C O

261 262

protein phosphatase 2a [56,57]. Of note in this regard, pleiotropic beneficial effects of adiponectin are initiated by stimulation of ceramidase activity and enhancement of ceramide catabolism [58]. Ceramides are also capable of activating the NLRP3 inflammasome, a transient complex of proteins responsible for activation of inflammatory processes [59–61]. Nalp3 (NLR family, pyrin domain containing protein 3, encoded by the NLRP3 gene), adaptor molecule ASC and caspase-1, components of the inflammasome, are preferentially expressed in ATMs. The NLRP3 inflammasome has been recently identified as an important contributor to obesity-induced inflammation and IR [55,62] and its activation is mediated by sensing mitochondrial dysfunction through the direct binding of Nalp3 to the mitochondrial lipid cardiolipin ([63]; see also Section 6). Recent studies have reported reduction in weight gain, fat mass and IR in Nlrp3−/−, Casp1−/− and Asc−/− mice with high-fat (HF) diet-induced obesity [60,64,65], demonstrating the important role of inflammasome in regulating insulin signaling. Although proinflammatory mediators play an important role in the initiation of the inflammatory response, chronic low-grade inflammation is also a result of inappropriate resolution capacity and uncontrolled inflammatory response. That resolution of inflammation is an active process regulated by the so-called “specialized pro-resolving lipid mediators” has been discovered by the Serhan's laboratory (reviewed in [66–69]; see Section 4.1).

U

259 260

5

ATM recruitment to WAT and their activation state are influenced by other immune cells in the tissue such as T cells and B cells (i.e. subpopulations of lymphocytes), eosinophils and mast cells. T cells play an important role in obesity-induced inflammation, at least in part, via influencing macrophage infiltration and polarization. Several subsets of T cells are present, like T helper cells, which can be classified into two groups (Th1 and Th2) based on their inflammatory properties (in analogy with ATMs); although both populations express CD4+, Th1 cells produce proinflammatory mediators while Th2 cells produce antiinflammatory mediators. Regulatory T cells secrete anti-inflammatory mediators and induce macrophage polarization toward M2. In the obese state, the number of proinflammatory T cells, CD4+ Th1 and CD8+ effector T cells increase, while anti-inflammatory Th2 cells are reduced in adipose tissue [90–92]. CD8+ T cells have essential roles in the initiation and maintenance of WAT inflammation, recruitment and differentiation of ATMs and systemic IR. The infiltration of WAT by these cells is an early event during the development of HF diet-induced obesity [91]. Regarding granulocytes in WAT, eosinophils decrease in their number during obesity-induced inflammation. Eosinophils are the major IL-4 expressing cells in WAT and contribute to polarization of ATMs toward M2 through an IL-4/IL-13-dependent process (refs. [93–95]; see Section 5). Neutrophils are involved in the initiation of the inflammatory response by contributing to ATMs recruitment and their number increases in obese state. Neutrophils secrete proteases such as neutrophil elastase (NE). Serum NE activity was elevated in dietary-obese mice [96], while the deletion of NE in these mice resulted in reduced inflammation and the content of neutrophils/macrophages in WAT [97]. Serum NE activity was also increased in human obese subjects and was correlated with leptin resistance [96]. The number of mast cells also increased in WAT of obese humans and mice. In addition, it was demonstrated that genetically-induced deficiency of mast cells resulted in reduced body weight gain and the levels of inflammatory cytokines while improving glucose homeostasis [98]. Mast cells could contribute to adipocyte differentiation by producing prostaglandins and directly promoting adipogenesis via production of 15-deoxy-


351 352 353 354 355 356 357 358 359 360 361 362 363 364 365 366 367 368 369 370 371 372 373 374 375 376 377 378 379 380 381 382 383 384 385 386

6 Table 1 White adipose tissue-borne lipid mediators.

t1:19 t1:20 t1:21 t1:22 t1:23 t1:24 t1:25 t1:26 t1:27 t1:28 t1:29 t1:30 t1:31

t1:36 t1:37 t1:38 t1:39 t1:40 t1:41 t1:42

t1:43 t1:44 t1:45 t1:46

Modulation of adipogenesis

[205]

H

Subcutaneous

Endo

Stimulation of leptin release

[105,101]

Modulation of adipogenesis Modulation of lipolysis

[108] [104]

M

Epididymal

Endo Endo, Exo Endo

Modulation of lipolysis

[100]

H, R M

Subcutaneous Intraabdominal

Endo Endo, Exo

Modulation of lipolysis Shift the differentiation of mesenchymal progenitors toward a brown adipocyte phenotype, induction of UCP1 in WAT

[103,206] [207,208]

M,R,H R

Perivascular

Exo Endo

Adipocyte differentiation Source of vasoactive prostaglandins

[209] [144]

M

Subcutaneous

Endo

Modulation of lipolysis

[210]

Epididymal Subcutaneous

Exo Exo Endo Endo Endo Exo

Increase of glucose transport Inhibition of adipogenesis Inhibition of adipogenesis Modulation of adipogenesis and MCP-1 expression Modulation of adipogenesis Production of Macrophage inhibitory cytokine-1

[109] [211,212] [213] [114] [110] [214]

M

Epididymal

Exo Exo Endo Exo Exo Endo

[215] [216] [111] [217] [116] [159]

M

Epididymal

H, M

Subcutaneous, Endo epididymal Epididymal Endo

Decrease of leptin production Stimulation of adipogenesis Stimulation of adipogenesis Stimulation of adipocyte differentiation Stimulation of adipogenesis Induction of lipid catabolism, anti-inflammatory Stimulation of MCP-1, IL-6, and TNF-α secretion Chemoattractant for macrophages in obesity Lipolysis may stimulate production of CysLTs Upregulation of IL-6, TNF-α, MCP-1

[123]

Induction of ER stress

[219]

Adipose tissue inflammation in obese humans

[119]

Exo Exo

Induction of inflammation and IR Modulation of adipocyte differentiation, decrease of TNF-α, MCP-1, and increase of adiponectin levels

[122,121] [220]

Exo

Stimulation of PPARγ, induction of adipogenesis

[221]

[87]

M H

M R

Perigonadal

M H

M

Exo

Exo

Epididymal

Endo, Exo Subcutaneous, Endo omental

Visceral

M

O

R

F

Endo

R

t1:35

O

t1:34

C

t1:33

LOX pathway

N

t1:32

Subcutaneous

R O

t1:18

H

P

t1:9 t1:10 t1:11 t1:12 t1:13 t1:14 t1:15 t1:16 t1:17

Reference

D

t1:7 t1:8

Adipocytes, SVF Adipose tissue, adipocytes 3T3-L1 PGE2, PGI2 Adipocytes, SVF Adipocytes, SVF, 3T3-L1 Adipocytes Adipose tissue, adipocytes, 3T3-L1 SVF, Ob1771 PGE2,PGI2, TXA2 Adipose tissue PGD2-related Adipose tissue PGF2a 3T3-L1 3T3-L1 Ob1771 d15-PGJ2 & PGJ2 3T3-L1 series Adipocytes Adipocytes, 3T3-L1 3T3-L1 NIH-3T3 3T3-L1 C3H10T1/2 d15-PGJ2, 8-HETE 3T3-L1 d15-PGJ2, PD1/ Adipose PDX tissue LTB4 Adipocytes, SVF LTB4, CysLTs Adipocytes, 3T3-L1 LTC4, CysLTs Adipocytes, SVF 12-HETE, 5-HETE, Adipocytes, LTB4 SVF, 3T3-L1 12/15-LOX related, Adipocytes, 3T3-L1 12-HETE, 12HpETE Adipose tissue, adipocytes, SVF 3T3-L1 EET, DHET Adipose tissue, adipocytes 3T3-F442A 5-HEPE, 8-HEPE, 9-HEPE, 12-HEPE and 18-HEPE RvD1, RvD2 Adipocytes, SVF, macrophage

Source Reported action of mediator

E

t1:5 t1:6

PGE2

Species Tissue

T

COX pathway

Model

C

t1:4

Lipid mediator

E

t1:3

R

t1:1 t1:2


Adipose tissue, SVF

M

Epididymal

Exo

t1:49 t1:50

Adipose tissue, adipocytes Adipose tissue Adipose tissue Adipose tissue

H, M

Epididymal

Exo

H

Subcutaneous

Endo

M

Epididymal

Exo

M

Epididymal

Endo

Prevention of obesity-linked inflammation and IR

t1:54 t1:55

U

t1:47 t1:48

Downregulation of IL-6, MCP-1, and TNF-α, ROS; upregulation of IL-10, CD206, arginase 1, resistin-like molecule a, and chitinase-3 like protein, stimulation of nonphlogistic phagocytosis; shift M1 N M2 macrophage phenotype Increase of adiponectin production and insulin sensitivity; decrease of IL-6 production and macrophage infiltration; shift M1 N M2 macrophage phenotype Increase of adiponectin level; decrease of leptin, TNF-α, MCP-1, IL-6, and IL-1b levels Enhancement of resolution capacity in fat depot Increase of adiponectin levels and insulin sensitivity

t1:51 t1:52 t1:53

RvD1, RvD2, PD1, LXA4, RvE1 etc. PD1, RvD1, 17HDoHE, PD1, 17-HDoHE, 18-HEPE

M

Epididymal

Endo, Exo


[120] [218]

[122]

[86]

[124]

[126] [222] [223]


7

Table 1 (continued) Model

Species Tissue

Reported action Source of mediator

Reference

Epididymal

Endo

Induction of lipid catabolism, anti-inflammatory

[159]

M

Perinodal

Exo

Resolution of inflammation

[224]

t1:58 t1:59 t1:60

omega 3 and omega 6 oxylipins LXA4

Endo

Modulation of inflammatory status in adipose tissue

[225]

Perigonadal

Exo

Decrease of IL-6 and increase of IL-10 expression; increase of insulin sensitivity, anti-inflammatory

[226]

t1:61

HXA3, HXB3

Adipose tissue Adipose tissue/ leukocytes Adipose tissue Adipose tissue, adipocytes, SVF 3T3-L1

M

t1:57

PD1/PDX, d15PGJ2 PD1, RvE1, LXA4

Stimulation of adipogenesis

[117]

Epididymal

Endo, Exo Exo Endo

Visceral

Endo

Decrease of inflammation

Epididymal

Endo

Decrease of inflammation

[138]

Endo, Exo Endo

Reduction of IL-6 by DHEA levels

[193]

Reduction of endocannabinoid tonus by Krill

[192]

Exo

Increased AMPK-α phosphorylation and carnitine palmitoyltransferase 1 transcription in adipose tissue, suggesting an increase in ATP-producing catabolic pathway; PEA also polarized adipose tissue macrophages to M2 lean phenotype Impairment of glucose tolerance and inhibition of insulin stimulated glucose uptake Stimulation of lipolysis Enhancement of β-adrenergic-mediated Thermogenesis; switch from white to brown adipocyte phenotype Inhibition of adipogenesis

t1:67 t1:68

Adipose tissue Adipose tissue

M

t1:69

AEA, 2-AG, PEA, OEA PEA

t1:70

OEA

Adipocytes

R

t1:71 t1:72 t1:73

PGF2a-EA

Inguinal, epididymal

R

Adipocytes R Adipose R tissue 3T3-L1, H, M preadipocytes

Epididymal

Endo

Epididymal Epididymal

Exo Exo

O

R O

AEA, 2-AG, EPEA, DHEA DHEA, EPEA

Increase of glucose transport activity Induction of IR

P

t1:66

3T3-L1 3T3-L1, M adipose tissue Adipose R tissue Adipose M tissue 3T3-L1

D

AA, LOX products Endocannabinoids AEA, 2-AG and related compounds AEA, 2-AG

M

E

t1:62 t1:63 t1:64 t1:65

M

Exo

T

t1:56

F

Lipid mediator

[118] [135] [191]

[136]

[227] [228] [229] [137]

Adipocytes, collagenase-liberated adipocytes from adipose tissue; SVF, stromal vascular fraction from adipose tissue (containing immune cells); H, human; M, mouse; R, rat; endo, endogenous source of the mediator (produced by the tissue itself); Endo, endogenous mediator; Exo, exogenous application of the mediator (artificial stimulation); IR, insulin resistance.

387 388

Δ12,14-prostaglandin J2 (15d-PGJ2; see Section 4.1) or indirectly through the regulation of adiponectin [99].

389

4. Lipid signaling in adipose tissue

390 391

397

Besides the cytokines, a large family of endogenous lipid mediators contributes to the immune and metabolic state of WAT. Thus, while traditional eicosanoids/prostanoids as well as endocannabinoids are involved in the control of metabolism and inflammation, omega-3 PUFA-derived mediators exert mostly anti-inflammatory effects. Moreover, other lipids active in cell signaling, such as sphingolipids (ceramides, sphingosine-1-phosphate), phospholipids (lysophosphatidic acid, platelet-activating factor) or steroids, can affect WAT metabolism.

398

4.1. Eicosanoids and specialized pro-resolving lipid mediators

399

Eicosanoids, produced via cyclooxygenases, lipoxygenases, and cytochrome P450 pathways, are potent local mediators of signal transduction and modulate the inflammatory response as well as metabolism of WAT. Although immune cells are the main producers of eicosanoids, adipocytes can also synthesize the main prostanoids and leukotrienes and express eicosanoid receptors. Thus, members of both adipocyte and immune cell lineages are able to communicate using lipid mediators as membrane or nuclear receptor ligands (see also Section 2.3 and Fig. 1). Selected lipid mediators produced in WAT are summarized in Table 1 and Fig. 2. Prostanoids are important for differentiation of adipocytes and regulation of lipolysis in an autocrine and paracrine manner.

395 396

400 401 402 403 404 405 406 407 408 409 410

E

R

R

N C O

394

U

392 393

C

t1:74 t1:75

They are produced by the action of cyclooxygenases (prostaglandin-endoperoxide synthases; COX) 1 and 2, which is a dominant pathway in generating eicosanoids in WAT. The best characterized prostanoid is prostaglandin E2 (PGE2). Endogenous PGE2 produced within WAT was shown to regulate lipolysis [100–103], where it works as an antilipolytic agent [104], although its effect is minor as compared to noradrenergic-mediated stimulation of lipolysis (see Fig. 1). It is still unknown which cell types contribute the most to the prostanoid pool in WAT, but in the human tissue, PGE2 is produced by adipocytes and other cell types [101,105,106]. Together with prostaglandin F2α (PGF2α), PGE2 also inhibits adipogenesis, which was documented in 3T3-L1 adipocytes [107,108]. PGF2α may enhance glucose transport in 3T3-L1 adipocytes by stimulating GLUT1 expression [109]. Cyclopentenone prostaglandins (prostaglandin J2 series, including PGJ2, Δ12-PGJ2 and 15d-PGJ2) act as ligands of PPARγ, the master regulator of adipogenesis. 15d-PGJ2 was shown to be important for differentiation and maturation of adipocytes [110–112], where it interferes in inducible synthesis of PGE2 and PGF2α [113], and in the production of adipokines linked to inflammation [114]. Adipose tissue expresses both PPARα and PPARγ isoforms (see Section 2.3 and Fig. 1), and although not yet demonstrated in WAT yet, various eicosanoids (e.g. 8,9-EET, 11,12-EET, LTB4, 9-HODE, 13-HODE etc.) have been found to activate PPARs in other tissues and cells (reviewed in [115]). Yu et al. tested activation of PPAR family members by eicosanoids; prostanoids, including prostaglandins PGA1 and 2, PGD1 and 2, and PGJ2-series [116], had an effect in 3T3-L1 cells. Of note, 8(S)-HETE and hepoxilins, lipoxygenase products and activators of PPARα and PPARγ, respectively, were able to induce


411 412 413 414 415 416 417 418 419 420 421 422 423 424 425 426 427 428 429 430 431 432 433 434 435 436 437 438

464 465 466 467 468 469 470 471 472 473

478 479 480 481 482 483 484 485 486 487 488 489 490 491 492 493 494 495 496 497 498 499 500 501 502

C

462 463

E

460 461

R

458 459

R

456 457

O

454 455

C

452 453

N

450 451

U

448 449

4.3. Lipid mediator-related enzymes and receptors in adipose tissue

511

WAT is able to express several enzymes metabolizing PUFA into active lipid mediators. Prostanoid biosynthesis is driven by COX and both of its isoforms, COX-1, the constitutive form, and COX-2, the inducible form, have been identified in this tissue [108,140]. Production of PGE2 is controlled by microsomal prostaglandin E2 synthase-1 and − 2, or by its cytosolic homologues [141]. Production of PGD2 and subsequent J-series is controlled by PGD synthase of which two types have been identified including lipocalintype PGD synthase and hematopoietic PGD synthase [142,143]. Perivascular WAT is able to produce vasoactive thromboxane A2 via thromboxane A2 synthase [144]. Recently, also prostaglandin F2α synthase was identified in 3T3-L1 cells [145]. The expression of membrane receptors for PGE2, PGF2α and PGI2 (i.e. EP, FP, and IP receptors, respectively) was explored in both preadipocytes and mouse mature adipocytes [146], and a crucial role for EP3 in modulation of lipolysis was identified ([146,147]; see Fig. 1). It has been demonstrated by Horillo et al. that WAT could express all the enzymes necessary for leukotriene biosynthesis: 5-lipoxygenase, 5-lipoxygenase activating protein, leukotriene A4 hydrolase, and leukotriene C4 synthase including leukotriene receptors: BLT1, BLT2, CysLT1, and CysLT2 [120]. In fact, the whole panel of lipoxygenases, differentially expressed during adipogenesis, was detected in WAT of mice and humans [148], and signs of depot specialization was identified in human 15-lipoxygenase, where selective expression was found in omental but not in subcutaneous fat [119]. The presence of enzymes for the production (N-acyl-phosphatidylethanolamine-specific phospholipase D, diacylglycerol lipase; see Fig. 2) and degradation (FA amide hydrolase) of endocannabinoids and its main receptor CB1 was demonstrated in adipocytes and WAT [130,149–151]. Also other enzymes of monoacylglycerol metabolism (e.g. MGL) are involved in the synthesis and degradation of endocannabinoids ([19,21]; see Fig. 1).

512 513

5. Mutual links between adipocytes and macrophages in WAT

544

Despite the fact that immune cells and adipocytes represent a functional unit, the mechanistic links between the two major cell types involved, ATMs and adipocytes, remain largely unknown. In obesity, visceral WAT compared to subcutaneous WAT accumulates more inflammatory ATMs, produces more proinflammatory mediators, and is more metabolically active, which includes both basal and stimulated lipolysis (reviewed in [152,153]). Relatively high rates of basal lipolysis in obesity could induce WAT inflammation and accumulation of proinflammatory M1 ATMs by activating PRRs [123,127]. In accordance with this, it has been demonstrated that endogenous oils derived from human WAT could induce neutrophil and M1-macrophage recruitment into the peritoneum [154]. In addition, sex-dependent differences also exist, with female rodents showing lower propensity to obesity-associated ATM accumulation as well as development of metabolic syndrome [153]. In contrast to the traditional view of the association between the obesity-driven ATM accumulation and inflammation in WAT, it has been demonstrated by Kosteli et al. [152] that weight loss and adrenergically-activated lipolysis promote a dynamic immune response in murine gonadal WAT, with an initial transient increase in ATM

545

F

Endocannabinoids, which are arachidonic acid (AA; C20:4n−6)-derivatives, represent another important class of lipid mediators involved in the regulation of WAT metabolism as well as whole-body energy homeostasis. The endocannabinoid system (ECS) was identified in the early 1990s during investigations into the mechanism of action of the major cannabisderived psychotropic compound, Δ9-tetrahydrocannabinol. The classical endocannabinoids, such as anandamide (arachidonoylethanolamide; AEA) and 2-arachidonoylglycerol (2-AG; see Fig. 2), exert cannabimimetic activities, partly through binding and activating cannabinoid receptors type 1 or 2 (CB1 or CB2), as well as through transient receptor potential vaniloid type-1 (TRPV1; ref. [21]). These endocannabinoids, their anabolic and catabolic enzymes, together with their receptors constitute the ECS (for review see ref. [129]). Besides regulating the basic processes such as food intake, the ECS participates in the control of lipid and glucose metabolism, and its dysregulation (mostly over-activity) in obesity might contribute to excessive fat accumulation and related metabolic disturbances [130,131]. The most convincing evidence linking a dysregulated ECS with obesity, type 2 diabetes, and hepatosteatosis came from studies carried out in animals (for instance, see [132–134]). Endocannabinoids and acyl-glycerols are important modulators of inflammation and insulin sensitivity of WAT (see Section 6). Of the less known mediators besides AEA and 2-AG, oleoylethanolamide inhibits insulin action and impairs glucose uptake in adipocytes [135], while palmitoleoylethanolamide increases β-oxidation of FA in response to phosphorylation/activation of AMP-activated protein kinase (AMPK) leading to increased carnitine palmitoyltransferase 1 (CPT-1) gene transcription in WAT (see Fig. 1), together with polarization

446 447

O

477

445

R O

4.2. Endocannabinoids

443 444

503 504

P

476

441 442

of ATMs to M2 type [136]. Prostaglandin F2 ethanolamide, similarly to its precursor AEA, inhibits adipogenesis in mouse 3T3-L1 or human preadipocytes [137]. Furthermore, the anti-inflammatory properties of omega-3 PUFA-derived endocannabinoids, namely eicosapentaenoylethanolamide and docosahexaenoylethanolamide, were documented in mouse WAT [138]. Part of the anti-inflammatory effects of endocannabinoids results from their interactions with PPARs [139].

T

474 475

differentiation of 3T3-L1 preadipocytes [116,117]. Another evidence links lipoxygenase metabolites and activation of PPARγ to glucose uptake in 3T3-L1 adipocytes [118]. Products of lipoxygenase activity, especially of the 12/15lipoxygenase and 5-lipoxygenase pathways, are important for regulation of both adipogenesis [116–118] and WAT inflammation [119–121]. In obese Zucker rats, 12-HETE, 5-HETE and LTB4 contribute to inflammatory state of visceral adipose tissue [122] and 12/15 lipoxygenase products 12(S)-HETE and 12(S)HpETE impair insulin signaling in 3T3-L1 cells [121]. Production of LTC4 by macrophages previously stimulated by FA from adipocyte lipolysis has been linked to IR of adipose tissue [123]. In contrast, several pro-resolving lipid mediators (reviewed in [66–69]), including those derived from eicosapentaenoic acid (C20:5n− 3, EPA; E-series resolvins, RvE1, RvE2, and RvE3) and from DHA (D-series resolvins, and protectins; PD; see also ref. [68]), as well as lipoxins (LXA4, 15-epi-LXA4), are involved in resolution of WAT inflammation. Indeed, the administration of RvD1 [124] and 17-hydroxydocosahexaenoic acid (17-HDoHE) [125], to obese diabetic mice improved glucose tolerance and insulin sensitivity, while reducing ATM accumulation and expression of inflammatory cytokines in WAT. Recently, a wide range of lipid mediators including RvD1, RvD2, PD1, lipoxin A4, and 17-HDoHE, 18-HEPE and 14-hydroxydocosahexaenoic acid (14-HDoHE) were identified in human subcutaneous WAT, while the levels of PD1 and 17-HDoHE decreased in patients with peripheral vascular disease [126]. In addition, an impairment in pro-resolving mediators production such as RvD1, PD1 and 17-HDoHE in inflamed WAT from obese mice has been reported [124]. This deficiency can be the result of impaired bioavailability of their respective precursors, i.e. omega-3 PUFA [125,127], or acceleration in their inactivation and clearance. This is further supported by findings that a key enzyme in metabolic conversion of pro-resolvins, 15-PG-dehydrogenase/eicosanoid oxidoreductase, is up-regulated in WAT under obese state [124]. Of note, some results previously assigned to PD1 might be related to its isomer protectin DX (PDX) [68]. PDX, also known to be produced in WAT, alleviated IR in diabetic db/db mice, but did not resolve WAT inflammation [128].

D

439 440


E

8


505 506 507 508 509 510

514 515 516 517 518 519 520 521 522 523 524 525 526 527 528 529 530 531 532 533 534 535 536 537 538 539 540 541 542 543

546 547 548 549 550 551 552 553 554 555 556 557 558 559 560 561 562 563 564


586 587 588 589 590 591 592 593 594 595 596 597 598 599 600 601

F

O

R O

584 585

P

582 583

D

580 581

Lipolysis and TAG/FA cycle acvaon in adipocytes

β -AR

FA

Furthermore, it has been demonstrated by Kosteli et al. that ATM depletion results in increased lipolysis in WAT, suggesting that M2 ATMs could release antilipolytic factor(s) of unknown chemical nature [152]. We extend here (see Fig. 3) the above model of Kosteli et al. by stressing the importance of the TAG/FA cycle in adipocytes. Its activity is tightly linked with lipolysis, thus affecting the storage of TAG and adiposity, as well as the levels of circulating free FA and systemic lipid metabolism (see Section 2.2). That M2 ATMs cause TAG/FA cycle activity to change in parallel to the lipolysis cycle has been documented by the simultaneous upregulation of ATGL (a marker of stimulated lipolysis) and DGAT1 (linked to FA re-esterification [26]) when ATMs are depleted [152]. We have observed in mice fed HF diet [159] that activity of mitochondrial oxidative phosphorylation in adipocytes was induced in an additive manner in response to a combined treatment using mild calorie restriction and dietary omega-3 PUFA (see Section 6). At the same time, ATM content and systemic inflammation decreased, while the levels of WAT anti-inflammatory lipid mediators increased. These changes that occurred in gonadal but not in subcutaneous WAT, could contribute to reduced accumulation of body fat under these treatment conditions. The induction of oxidative phosphorylation in adipocytes was associated with activation of the TAG/FA cycle, depending on the complex interplay of the intracellular regulatory pathways including PPARα, PPARγ, AMPK, ECS, and G-protein coupled receptors (see Sections 2.3 and 4.3). Our results suggest that adipocyte endowed with a high capacity of both oxidative phosphorylation and TAG/FA cycle represent a “healthy” and metabolically flexible cell type, which is associated with lean phenotype (for details, see ref. [17]). Based on the above data we hypothesize (see Fig. 3) that induction of pro-resolving lipid mediators in WAT, both in adipocytes and ATMs, for instance in response to omega-3 PUFA supplementation, could augment the “healthy” metabolic phenotype in adipocytes during the activation of lipolysis. This would reflect an egress of M2 ATMs that results in their reduced tissue content and the removal of the inhibitory effect of M2 ATMs on the adipocyte lipolysis and TAG/FA activity (see Fig. 3). This model is also supported by the fact that M2 ATMs are

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recruitment. These ATMs express markers that are typical of the anti-inflammatory M2 state. Conversely, manipulations reducing lipolysis decreased ATM accumulation. These observations in animals are consistent with findings in humans demonstrating that a short-term low-calorie diet induces accumulation of ATMs of M2 phenotype [155]. It has been hypothesized that the short-term activation of lipolysis in WAT could lead to recruitment of M2 ATMs depending on lipolysis-released FA from adipocytes [152]. It remains unclear why long-lasting accumulation of FA released from hypertrophic adipocytes could induce accumulation of M1 ATMs, while acute stimulation of lipolysis in WAT could result in the accumulation of M2 ATMs. It can be speculated that the differential effect of FA accumulated in WAT in response to the increased lipolysis (basal and stimulated), could reflect either different FA species accumulated under these conditions [156,157] or a formation of PPARα agonists during the stimulated lipolysis [30], which could also affect the interplay between the immune and metabolic systems ([38,48,49]; see Section 3). Very recently, the role of lipolysis of TAG in lipid droplets mediated by lysosomal acid lipase (but not by either ATGL or HSL; see Section 2.2) in the induction of M2 ATMs has been demonstrated [89]. The emerging role of adipocyte-borne extracellular vesicles in the paracrine signaling between adipocytes and ATMs and the polarization of ATMs should be further explored [158]. M2 ATMs, which accumulate transiently in WAT during stimulation of lipolysis could buffer locally released FA by incorporating them into intracellular TAG [152]. Indeed, M2-macrophages exhibit high activity of mitochondrial oxidative phosphorylation [38,49], i.e. they can efficiently form ATP, which is required for lipogenesis, while enhanced β-oxidation drives the ATP formation and helps to further reduce FA levels. As suggested by O'Neil and Hardie [49], the switch between the M2-linked oxidative metabolism and the glycolytic metabolism typical of M1 macrophages [89] could be regulated by AMPK; the more energy-efficient oxidative metabolism of M2 ATMs could be essential for long-term tissue repair, while the glycolytic M1-linked metabolism could support rapid metabolic responses during inflammation. Thus both AMPK activation and short-term starvation could reflect an ancient starvation pathway depressing energy-costly inflammatory response.

↑ OXPHOS ↑ FA oxidaon

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An-inflammatory and pro-resolving lipid mediators (15d-PGJ2, PD1/PDX) Fig. 3. Involvement of ATMs in response of WAT to the combination treatment using calorie restriction and omega-3 PUFA. Prolonged mild calorie restriction, i.e. a modest stimulation of βadrenergically mediated lipolysis (red triangle) and TAG/FA activity (red circular arrows) in adipocytes, results in increased extracellular free fatty acids levels (A) and recruitment of ATMs of M2 phenotype. ATMs can buffer local increases in free fatty acids concentrations through their uptake and incorporation into intracellular triacylglycerols, while depressing lipolysis and TAG/FA activity in adipocytes via an unknown secreted factor (B). Pro-resolving lipid mediators formed from omega-3 PUFA (C) accelerate a decrease in ATM content, thus eliminating the basis for the existence of above mentioned negative regulatory loop (B) and allowing for a full manifestation of both the lipolytic and TAG/FA activity in adipocytes. The capacity of these biochemical pathways as well as mitochondrial oxidative phosphorylation is enhanced in response to stimulation of PPARα-, PPARγ-, and AMPK-signaling and suppression of the activity of the ECS in adipocytes in response to the combination treatment. Thus, resolution of inflammation supports flexible healthy metabolic phenotype of adipocytes (for details, see ref. [17]). This scheme represents a modified version of Fig. 10 of the original article by Kosteli et al. [152]. β-AR, β-adrenergic receptor; OXPHOS, oxidative phosphorylation.


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IR seems to be a pathogenic link between obesity and associated metabolic dysfunctions. In this respect, hypertrophic WAT expansion in obesity associated with the influx of immune cells [160] triggers a cascade of inflammatory responses that negatively affect insulin signaling and glucose uptake in insulin sensitive tissues, thus contributing to systemic IR (for review see [55]). The quantity and type of dietary fat have lasting and powerful effects on obesity-associated IR and inflammation. For instance, it has been shown in healthy as well as obese subjects that various inflammatory markers were lower in individuals consuming the so called Mediterranean diet, whose principal source of fat is olive oil (rich in monounsaturated FA) and which is also rich in fish (reviewed in [161]). These data are also supported by the multicenter KANWU study of healthy subjects receiving various isoenergetic diets for 3 months [162], showing that saturated FA-rich diet impaired while monounsaturated FA-rich diet improved insulin sensitivity when total fat intake did not exceed 37% of energy. Besides proinflammatory cytokines such as IL-1β, IL-6 and TNF-α, also saturated FA are known to activate inflammatory signaling pathways, in this case through Toll-like receptor 4, thus initiating a cascade of events leading to IR (reviewed in [55]; see Section 3). Conversely, proinflammatory cytokines such as IL-1β also upregulate serine palmitoyltransferase [163], i.e. an enzyme involved in the biosynthesis of ceramide that is capable of antagonizing insulin signaling in the muscle [164]. At the same time, ceramides can activate NLRP3-caspase 1 inflammasome complex, which is involved in the cleavage of pro-IL-1β precursor and generation of active IL-1β ([55]; see Section 3). These results suggest that targeting nutrient-sensitive inflammatory pathways by using dietary interventions aimed at specific FA/lipid composition may antagonize inflammation and consequently IR. There has been a lot of progress in our understanding how dietary omega-3 PUFA, namely DHA and EPA might reduce the incidence of cardiovascular disease (for review, see [165]), augment the efficacy of lipid-lowering drugs [166], or even help to reduce adiposity in humans [167–169], reduce hepatic steatosis [170], and contribute to prevention of IR (reviewed in [171]). Furthermore, large amount of experimental evidence comes from rodent studies, showing that dietary omega-3 PUFA can prevent HF diet-induced obesity, IR, dyslipidemia and WAT inflammation [159,172–176], while they can also revert some of the obesity-associated pathologies [175,177]. However, the omega-3 PUFA's effects on glycemic control and insulin sensitivity in diabetic human subjects are usually weak or even negative [178], although this group of patients might still benefit from omega-3 PUFA supplementation when its protective effect against cardiovascular disease is considered [171,179]. Moreover, the combinations of omega-3 PUFA

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with various anti-diabetic drugs or mild calorie restriction (see Section 5) might hold great promise especially in the treatment of diabetic patients [159,175]. An important part of omega-3 PUFA's effects on obesity-associated metabolic disorders and cardiovascular disease resides in their strong anti-inflammatory action in various tissues including WAT as well as in modulation of eicosanoid production (see the reviews [180–182]; see Section 4 and 5). In general, the beneficial effects of omega-3 PUFA, especially under obesogenic conditions, are associated with a profound modulation of WAT metabolism and function (reviewed in [180]). Thus, dietary intake of omega-3 PUFA stimulates the expression and secretion of insulin-sensitizing hormone adiponectin in WAT of HF diet-fed mice [183,184] as well as in humans [185] while inducing mitochondrial biogenesis and FA oxidation in adipocytes [186], i.e. the effects specific to abdominal WAT depot. Adiponectin exerts its beneficial metabolic effects (e.g. increased FA oxidation and glucose uptake) in part by stimulating AMPK activity in target tissues such as liver and skeletal muscle [187], which is likely the mechanism that contributes to the insulin-sensitizing effects of omega-3 PUFA, at least in the liver [176]. Moreover, adiponectin improves insulin sensitivity through catabolism of ceramides (see Section 3). A new direction in the study of alternative approaches for the treatment of obesity-related inflammation and metabolic dysfunction has been recently investigated, with a focus on the modulation of ECS by dietary omega-3 PUFA. It is known that stimulation of the ECS activity in WAT, it promotes adipogenesis, lipid accumulation, and reduces mitochondrial biogenesis, while its blockade, e.g. by CB1 antagonist rimonabant, results in elevated lipolysis, mitochondrial biogenesis, increased adiponectin production, and reduced inflammation, in part also through the effect on WAT ATMs and possibly other cell types present in WAT (reviewed in [188]). Although the downregulation of the elevated ECS tone in obesity by rimonabant produced desired metabolic effects, its use in the clinics has been halted due to psychiatric side effects [189]. On the other hand, selectively blocking the peripheral CB receptors through nutritional interventions based on the modification of dietary FA composition (e.g. omega-6/omega-3 PUFA ratio) and subsequent changes in the concentrations of various lipid-derived ligands including endocannabinoids might represent an optimal solution (reviewed in [129] and more recently by [190]). In this respect, Alvheim et al. [133] showed in mice that by increasing dietary content of linoleic acid (LA; C18:2n− 6), i.e. the precursor for the synthesis of AA, from 1% to 8% of energy, (i) tissue levels of AA as well as of 2-AG and AEA were elevated, which resulted in the development of obesity, and (ii) adipogenic effect of LA could be prevented by consuming sufficient amounts of EPA and DHA to reduce the AA-phospholipid pool and normalize the levels of endocannabinoids. In accordance with these data, dietary omega-3 PUFA have been shown to modulate the levels of endocannabinoids in various organs including WAT of rodents with genetic or dietary obesity [134,138, 191,192]. Interestingly, Rossmeisl et al. [138] showed in obesity-prone C57BL/6 mice fed a corn oil-based high-fat diet (rich in LA), that besides decreasing 2-AG and AEA in abdominal WAT, dietary omega-3 PUFA also elevated tissue levels of N-acyl ethanolamines DHEA and EPEA, the endocannbinoid-like molecules derived from DHA and EPA, respectively, which are known to be produced by adipocytes and possess antiinflammatory properties [193]. Furthermore, omega-3 PUFA-induced changes in plasma profile of various endocannabinoids were similar to those observed in abdominal WAT, raising a question to what extent WAT and especially abdominal WAT determines systemic levels of various endocannabinoids. Further evidence suggests that the efficiency of dietary omega-3 PUFA to modulate tissue levels of endocannabinoids partly depends on the lipid form of omega-3 PUFA supplementation. Thus, dietary omega-3 PUFA administered as marine phospholipids (omega-3 PL) either in the form of krill oil [191,192,194] or isolated from fish meat [138] were able to efficiently modify tissue endocannabinoid levels in

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involved in active remodeling of WAT [69], while perhaps helping the formation of the “healthy” adipocytes (see above). It is based in large on our observations in mice fed the HF-diet, in which the positive effects of the combined treatment using omega-3 PUFA and calorie restriction on WAT metabolism was only detected in the gonadal but not subcutaneous WAT. This is consistent with a relatively high accumulation of ATMs in the former depot under obesity-promoting conditions (see ref. [17]). The mutual functional links between the immune cells and adipocytes in WAT, mediated possibly by both cytokines and lipid mediators, require further studies. Parenthetically, very recent studies in mice demonstrated the importance of M2 ATM recruitment for the induction of thermogenic brite/beige cells in WAT, depending possibly on the production of catecholamines in M2 ATMs [94,95]. This recruitment is triggered by cytokines released from tissue eosinophils (refs. [93–95]; see Section 3.2). However, this process could be only transient and rather specific for the subcutaneous WAT containing brite/beige precursor cells, since these cells are virtually absent in abdominal WAT of rodents [2–4].

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Supported by the EU FP7 project DIABAT (HEALTH-F2-2011-278373), by the Czech Science Foundation (13-00871S), by the Ministry of Education, Youth and Sports (LH14040) and Nestlé Institute of Health Sciences.

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Systemic effects of WAT not only reflect the role of this tissue in serving as an energy buffer, but also point to its involvement in the control of circulating free FA levels and insulin sensitivity via secretion of various adipokines, cytokines, and lipid mediators. All the major functions of WAT are closely related and regulated by hormones and by the activity of nervous system. Both metabolic and secretory functions of WAT largely depend on adipocytes themselves, since these cells have the remarkable ability to change their volume as well as their numbers depending on systemic requirements. This kind of tissue plasticity involves not only adipocytes, but also other WAT cell types, such as immune cells and the cells comprising microcirculation inside the tissue. It is becoming increasingly apparent that various lipid mediators formed both in adipocytes and immune cells, namely in the ATMs, are involved not only in endocrine but also in paracrine and autocrine signaling within WAT. Besides classical eicosanoids, prostanoids and endocannabinoids, also specialized pro-resolving lipid mediators are formed in WAT, as also evidenced by the presence of their synthesizing enzymes in the tissue, and participate in various physiological as well as pathophysiological processes, including tissue responses to activated lipolysis and metabolic inflammation in obesity, respectively. At the same time, lipid mediators within WAT together with adipokines and cytokines are likely involved in the control of tissue remodeling, which is the key feature underlying tissue plasticity. Under physiological conditions such as during activation of lipolysis in WAT of lean individuals, M2 ATMs help to control extracellular levels of FA by a negative feedback regulation of lipolysis and TAG/FA activity. The nature of this anti-lipolytic factor(s) remains unclear; however, it could be also represented by some lipid mediator(s). Moreover, M2

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ATMs could contribute to remodeling of WAT under the conditions that lead to “healthy” adipocyte formation, i.e. lean, metabolically flexible adipocytes that are endowed with high TAG/FA cycling and mitochondrial oxidative phosphorylation activity. This situation could be exemplified by a combined intervention using mild calorie restriction and dietary supplementation with EPA/DHA, and possibly potentiated by lower intake of LA, which enhances the formation of “healthy” adipocytes. The mechanisms involved include increased formation of pro-resolving lipid mediators partly derived from omega-3 PUFA, the activation of lipid catabolism by a PPARαmediated mechanism, the decreased activity of ECS, and the activation of AMPK and adrenergically-stimulated lipolysis in WAT, all of which are involved in the formation of metabolically flexible adipocytes. On the other hand, when lipid supply exceeds the storage capacity of fat cells, e.g. in WAT atrophy or obesity, M1 ATMs infiltrate the tissue to remove dead adipocytes while secreting pro-inflammatory molecules; in this respect, pro-resolving lipid mediators are essential for the resolution of inflammation by stimulating the egress of ATMs and the return of WAT to a physiological state. In spite of the recent substantial advances in the characterization of various lipid mediators in WAT, especially under conditions of metabolic inflammation, our understanding of their involvement in the mutual interactions between adipocytes and ATMs is insufficient. We are limited by a scarcity of appropriate in vitro models, as well as the short life of many of these signaling molecules. Nevertheless, the ability to modulate the formation of pro-resolving lipid mediators, e.g. in response to dietary supplementation with omega-3 PUFA (which would also lead to the suppression of ECS activity), or even in response to a topical administration of specific lipid mediators, opens new avenues for the treatment of many diseases linked to the state of chronic inflammation.

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genetically obese fa/fa rats [191] or in dietary obese mice [138,192,194]. Furthermore, when directly compared with fish oils containing omega-3 as triacylglycerols (omega-3 TAG), omega-3 PL were more effective in reducing the levels of 2-AG and AEA in visceral WAT [138, 191] and the levels of AEA in the liver and heart [191]. Dietary omega-3 PL also ameliorated dyslipidemia and markedly reduced hepatic steatosis in obese rodents [138,194,195]. Thus, it seems that supplementation of omega-3 PL can exert stronger metabolic effects when compared with omega-3 TAG, possibly due to: (i) improved bioavailability of DHA and especially EPA, as demonstrated in rodents [138] as well as in humans [196–198]; (ii) stronger modulation of the ECS (see above); (iii) regulation of cellular metabolism by yet unidentified omega-3 PL species possibly functioning as ligands to specific nuclear receptors [199,200], which are also involved in the transcriptional regulation of lipid metabolism. Although the superior effects of omega-3 PL have been linked primarily to improved DHA and/or EPA bioavailability (see above and an excellent review published recently by Schuchardt and Hahn [201]), it is still unclear whether there are also other mechanisms involved. Similarly to omega-3 TAG, a relatively high potency has been demonstrated in the case of omega-3 PUFA contained in the extract from the zooplankton Calanus finmarchicus (Calanus oil), especially when the effect on diet-induced obesity and obesity-related disorders in mice is considered [202]. Thus, anti-inflammatory nutritional interventions with omega-3 PUFA, especially those in the form of omega-3 PL, seem to represent an efficient tool also for manipulating the activity of the ECS in various tissues including WAT. The displacement of AA by DHA and EPA in the relevant membrane phospholipid fractions in response to dietary omega-3 PUFA supplementation has been shown to be associated with decreased production of AA-derived EC molecules. However, the precise role of omega-3 PUFA-induced changes in the ECS tone in various tissues, especially in WAT, and their contribution to improved metabolic function under obesity-related conditions remains to be fully elucidated.

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Regulation of lipid metabolism in adipose tissue and heart.

Estradiol regulates insulin signaling and inflammation in adipose tissue.

Cytosolic aconitase activity sustains adipogenic capacity of adipose tissue connecting iron metabolism and adipogenesis.

Effects of Anthocyanin and Flavanol Compounds on Lipid Metabolism and Adipose Tissue Associated Systemic Inflammation in Diet-Induced Obesity.

Perivascular adipose tissue and inflammation.

Connecting proline metabolism and signaling pathways in plant senescence.

Loss of Oncostatin M Signaling in Adipocytes Induces Insulin Resistance and Adipose Tissue Inflammation in Vivo.

Influence of somatotropin on lipid metabolism and IGF gene expression in porcine adipose tissue.

Lipopolysaccharide challenge significantly influences lipid metabolism and proteome of white adipose tissue in growing pigs.

Gene expression related to lipid and glucose metabolism in white adipose tissue.

Brown Adipose Tissue Activation Is Linked to Distinct Systemic Effects on Lipid Metabolism in Humans.

Repin1 deficiency in adipose tissue improves whole-body insulin sensitivity, and lipid metabolism.

Bone marrow leptin signaling mediates obesity-associated adipose tissue inflammation in male mice.

Dietary Fructose Activates Insulin Signaling and Inflammation in Adipose Tissue: Modulatory Role of Resveratrol.

Dietary cholesterol effects on adipose tissue inflammation.

Leptin-mediated increases in catecholamine signaling reduce adipose tissue inflammation via activation of macrophage HDAC4.

Alcohol, Adipose Tissue and Lipid Dysregulation.

Lipid metabolism and signaling in cardiac lipotoxicity.

Mechanisms of glucocorticoid-induced insulin resistance: focus on adipose tissue function and lipid metabolism.

Erythropoietin signaling: a novel regulator of white adipose tissue inflammation during diet-induced obesity.

Selective suppression of adipose tissue apoE expression impacts systemic metabolic phenotype and adipose tissue inflammation.

Connecting Myokines and Metabolism.

Assessment of in situ adipose tissue inflammation by microdialysis.

Macrophage Migration Inhibitory Factor in Acute Adipose Tissue Inflammation.