Endocrine DOI 10.1007/s12020-015-0658-y

REVIEW

Hypothalamic-autonomic control of energy homeostasis Patricia Seoane-Collazo1,2 • Johan Fernø1,3 • Francisco Gonzalez4,5 • Carlos Die´guez1,2 • Rosaura Leis6 • Rube´n Nogueiras1,2 • Miguel Lo´pez1,2

Received: 23 December 2014 / Accepted: 6 June 2015 Ó Springer Science+Business Media New York 2015

Abstract Regulation of energy homeostasis is tightly controlled by the central nervous system (CNS). Several key areas such as the hypothalamus and brainstem receive and integrate signals conveying energy status from the periphery, such as leptin, thyroid hormones, and insulin, ultimately leading to modulation of food intake, energy expenditure (EE), and peripheral metabolism. The autonomic nervous system (ANS) plays a key role in the response to such signals, innervating peripheral metabolic tissues, including brown and white adipose tissue (BAT and WAT), liver, pancreas, and skeletal muscle. The ANS

& Patricia Seoane-Collazo [email protected] & Miguel Lo´pez [email protected]

consists of two parts, the sympathetic and parasympathetic nervous systems (SNS and PSNS). The SNS regulates BAT thermogenesis and EE, controlled by central areas such as the preoptic area (POA) and the ventromedial, dorsomedial, and arcuate hypothalamic nuclei (VMH, DMH, and ARC). The SNS also regulates lipid metabolism in WAT, controlled by the lateral hypothalamic area (LHA), VMH, and ARC. Control of hepatic glucose production and pancreatic insulin secretion also involves the LHA, VMH, and ARC as well as the dorsal vagal complex (DVC), via splanchnic sympathetic and the vagal parasympathetic nerves. Muscle glucose uptake is also controlled by the SNS via hypothalamic nuclei such as the VMH. There is recent evidence of novel pathways connecting the CNS and ANS. These include the hypothalamic AMP-activated protein kinase–SNS–BAT axis which has been demonstrated to be a key modulator of thermogenesis. In this review, we summarize current knowledge of the role of the ANS in the modulation of energy balance.

1

NeurObesity Group, Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigacio´n Sanitaria, 15782 Santiago de Compostela, Spain

2

CIBER Fisiopatologı´a de la Obesidad y Nutricio´n (CIBERobn), 15706 Santiago de Compostela, Spain

Keywords Hypothalamus
Autonomic nervous system
Energy balance

3

Department of Clinical Science, K. G. Jebsen Center for Diabetes Research, University of Bergen, 5021 Bergen, Norway

Introduction

4

Department of Surgery, CIMUS, University of Santiago de Compostela-Instituto de Investigacio´n Sanitaria, 15782 Santiago de Compostela, Spain

5

Service of Ophthalmology, Complejo Hospitalario Universitario de Santiago de Compostela, 15706 Santiago de Compostela, Spain

6

Unit of Investigation in Nutrition, Growth and Human Development of Galicia, Pediatric Department (USC), Complexo Hospitalario Universitario de Santiago (IDIS/ SERGAS), Santiago de Compostela, Spain

Energy homeostasis is crucial to the maintenance of health in an organism and is precisely controlled by the central nervous system (CNS) which receives and integrates signals of energy status from the periphery and in response modulates food intake and energy expenditure (EE) [1–5]. In conditions such as obesity and its comorbidities, an imbalance in these signals can occur, weakening the counterregulation that controls energy status [6]. Thus,

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obesity is characterized by a positive energy balance and increased fat mass which ultimately triggers coronary disease, type II diabetes, non-alcoholic hepatic steatosis, biliary disease, and certain types of cancer [6–8]. On the other hand, cancers and diseases such as rheumatoid arthritis may cause a negative energy balance and cachexia, leading to a marked reduction in body weight and higher mortality due to tissue wasting [9–12]. The autonomic nervous system (ANS) innervates and regulates metabolic organs and plays an important role in physiological responses to endogenous and exogenous stimuli. The ANS consists of two parts, the sympathetic nervous system (SNS) and the parasympathetic nervous system (PSNS) [13–16]. Traditionally, the SNS has been associated with catabolic responses and the PSNS with anabolic responses [14–17]. Under some physiological circumstances, both the SNS and PSNS can be activated or inhibited at the same time, but usually when one is activated the other is inhibited [18]. Adipose tissue is known to be innervated by the SNS, whereas PSNS innervation to some fat depots is still controversial [19, 20]. The liver and pancreas are innervated by splanchnic sympathetic and vagal parasympathetic nerves [14, 21–23], while skeletal muscle also receives both sympathetic and parasympathetic innervation [18].

Autonomic modulation of adipose tissue: BAT thermogenesis versus WAT lipolysis Adipose tissue is a key regulator of energy homeostasis and can be classified into two types: (1) brown adipose tissue (BAT), a specialized tissue that dissipates energy in the form of heat through non-shivering thermogenesis (NST), and (2) white adipose tissue (WAT), traditionally associated with energy storage but for the last two decades also recognized as an important endocrine tissue [24–26]. Autonomic modulation of BAT thermogenesis BAT is a specialized tissue responsible for heat production through NST. Physiological activation of BAT occurs when the organism needs extra heat, but BAT can also be activated in response to particular diets [26–29]. Until recently, BAT was considered to be important only in small or hibernating mammals and in newborn humans. Recent studies have challenged that view by using positron emission and computed tomographic (PET-CT) scans to identify functional BAT in adult humans [30–33], and BAT is now recognized as a potential target organ in the treatment of obesity [27, 28, 34]. In rats, there are several brown fat pads: cervical, mediastinal, perirenal, and pericardial, as well as interscapular BAT which is the principal

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BAT depot in rodents [26–28, 35]. In addition, brown adipocytes are found in WAT, a phenomenon known as ‘browning’ [36–38]. All BAT depots receive sympathetic innervation, but only mediastinal and pericardial BAT appears to receive parasympathetic innervation [36, 39]. The CNS is able to control BAT function via the ANS. BAT is activated by increased firing rate in sympathetic nerves, which leads to the release of noradrenaline (NA) and activation of BAT b-adrenergic receptors, mainly b3receptors [26–29]. Activation of adrenergic receptors triggers cAMP production by adenylyl cyclase and subsequent activation of protein kinase A (PKA) and p38 MAPK kinase pathways which increase gene expression of uncoupling protein 1 (UCP1) [26–28]. Several regions of the spinal cord, brainstem, midbrain, and forebrain have been found to innervate pre-autonomic neurons that control ANS afferents in BAT. Viruses such as pseudorabies and herpes simplex virus1, which spread in a directed manner via synaptically connected neurons [40], have been used to trace CNS neuronal connectivity with BAT. By the injection of a transneuronal viral tract tracer in the interscapular BAT of Siberian hamsters, Bamshad et al. were able to infect neurons in the medial preoptic area (MPOA), paraventricular (PVH), ventromedial (VMH), and suprachiasmatic (SCN) nuclei of the hypothalamus, as well as the lateral hypothalamic area (LHA), suggesting a neuronal connection between BAT and these hypothalamic areas [41]. Oldfield et al. obtained comparable results in rats using the same technique. They found cocaine- and amphetamineregulated transcript (CART)- and proopiomelanocortin (POMC)-expressing neurons in the lateral arcuate nucleus (ARC), and melanin-concentrating hormone (MCH)- and orexin-expressing neurons in the LHA to be infected [42]. Thus, several hypothalamic nuclei are associated with the regulation of BAT NST, as will now be discussed. The VMH was the first hypothalamic site to be identified as important in thermoregulation by BAT. Electrical stimulation of VMH increased interscapular BAT temperature, an effect that was abolished by b-adrenergic blockade [43–45]. VMH neurons are known to exert some of their functions through SNS activation, with steroidogenic factor 1 (SF1)-expressing neurons projecting from the VMH to autonomic centers, e.g., the parabrachial nucleus, locus ceruleus (LC), and retrotrapezoid nucleus, as well as the C1 catecholamine cell group of the rostral ventrolateral medulla (RVLM) and the nucleus of the solitary tract (NTS). These neuronal fibers also reach other hypothalamic regions involved in sympathetic outflow, including the ARC and PVH [46]. In this context, a VMH-specific knockdown of SF1 reduced EE and BAT UCP1 expression in mice [47]. The VMH is also connected to other brainstem regions linked to the regulation of BAT NST, such as

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the raphe pallidus (RPa) and inferior olive (IO) [28, 29, 48, 49]. Activation of BAT NST can be modulated in the VMH by glutamate, hydroxybutyrate, NA, serotonin and tryptophan [50–52], and by peripheral hormones. Recent evidence from our group has revealed molecular mechanisms by which the VMH controls BAT NST. These data point toward a key role for AMP-activated protein kinase (AMPK) in the VMH, as a negative regulator of BAT activation via the SNS, integrating diverse peripheral signals such as thyroid hormones (THs), estradiol (E2), leptin, and bone morphogenetic protein 8B (BMP8B), and drugs such as nicotine and liraglutide [53–58]. We have therefore named this canonical mechanism the AMPK (VMH)– SNS–BAT axis. It is not yet known whether other peripheral hormones, such as fibroblast growth factor 21 (FGF21) [59] or amylin [60, 61], act in the same axis. In this context, alterations in hypothalamic lipid composition, in particular ceramides, have been shown to induce endoplasmic reticulum (ER) stress, leading to a reduction in SNS firing and NST, and thus to weight gain [62]. The RPa and IO are also important players in the regulation of NST and are under the control of the dorsomedial nucleus of the hypothalamus (DMH). The DMH is known as a key site in the control of feeding and metabolic regulation, as well as body temperature through NST [63, 64]. However, neurons of the DMH do not project directly to sympathetic pre-ganglionic neurons in the spinal cord, but instead send monosynaptic projections to the RPa, which mediates the effects of DMH neurons on BAT activity [65]. Thus, the disinhibition of neurons in the DMH activates glutamate receptors in the RPa, triggering BAT sympathetic activation and NST [65]. Parallel evidence suggests that the IO also has a role in SNS control of BAT and that this nucleus is also involved in the functional interactions between the motor and thermoregulatory systems via the DMH [27, 49]. Recent studies have shown another possible mechanism, in which BAT NST is modulated via leptin receptors [66, 67] or neuropeptide Y (NPY) [68] in the DMH. Thus, leptin receptors in the DMH mediate the thermogenic response to hyperleptinemia in obese animals by increasing sympathetic nerve activity, which leads to increased EE by BAT [66]. In addition, activation of leptin receptor-expressing neurons in the DMH is sufficient to increase EE and regulate body weight [69]. Recently, it was found that knocking down NPY in the DMH leads to an increase in interscapular BAT and inguinal WAT (iWAT) UCP1 levels and stimulates the formation of brown adipocytes in iWAT, promoting a rise in NST and EE [68]. Leptin is probably involved in this process by modulating DMH NPY neuronal activation [70]. In addition, recent studies have demonstrated that leptin receptors in the ARC are necessary for leptin-induced increases in BAT sympathetic discharge, with deletion of

leptin receptors in the ARC attenuating the response of BAT to leptin [71]. It has also been demonstrated that ARC orexigenic neurons inhibit BAT NST and that a partial loss of agouti-related protein (AgRP)/NPY neurons leads to a lean, hypophagic phenotype, also characterized by activated sympathetic innervation of BAT [72, 73]. Regulation of NST by the ARC is closely linked to the central melanocortin system. Melanocortins are a family of peptides produced by post-translational processing of POMC. This family of neuropeptides has an endogenous agonist, alphamelanocyte-stimulating hormone (a-MSH), and an antagonist, AgRP, both of which share common melanocortin receptors (MCRs) [74, 75]. Loss of function in POMC and its putative receptor melanocortin receptor 4 (MC4R) induces an obese phenotype, both in humans and rodents [76–79]. In this context, sympathetic cholinergic pre-ganglionic neurons, but not parasympathetic neurons, need functional MC4R to regulate NST in response to cold exposure and for browning of inguinal iWAT to occur [80]. Moreover, a lack of MC4R blocks the ability of leptin to increase UCP1 expression in BAT and WAT [81]. Recent evidence also suggests that correct protein folding in the ER of POMC neurons is required to maintain EE [82] and that POMC activation leads to browning of WAT which counteracts diet-induced obesity (DIO) [83]. In line with this, AgRP neurons in the ARC are also important in attenuating browning of WAT [84]. Thus, fasting and chemical-genetic activation of AgRP neurons suppress browning in WAT through a mechanism involving OGlcNAc transferase (OGT) [84]. Hence, the ARC, previously known as the master control nucleus of feeding [85, 86], can now also be considered to have a role in the modulation of BAT NST. Finally, a recent study has revealed a rat insulin promoter (Rip)-Cre neuronal population that intermingles with POMC and AgRP neurons in the ARC, which is able to increase EE without affecting food intake through the synaptic release of GABA [87, 88]. In fact, mice lacking synaptic GABA release from Rip-Cre neurons showed a reduced potency of leptin in stimulating BAT NST, without any effects on food consumption [87, 88]. The Rip-Cre neurons project to the PVH and could be a source of the GABAergic input to the PVH that triggers sympathetic outflow and BAT NST [87, 88]. Autonomic control of body temperature Maintenance of body temperature is achieved mainly by the ability of BAT and skeletal muscle to generate heat and secondarily by regulation of heat loss through the skin by vasoconstriction and vasodilation, under SNS control and accompanied by adrenergic cardiac stimulation [26–28]. In response to cold, somatic motor nerves promote the

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generation of heat by skeletal muscle through shivering. The thyroid and adrenal axes also participate in heat generation [28, 53, 89]. All these changes are coordinated centrally, with a key region being the preoptic area (POA). The POA contains cold-sensitive neurons and receives input from thermosensitive areas in the abdominal viscera where cold- and heat receptors send signals through the vagus and splanchnic nerves [28, 29, 90]. Temperature changes can also be sensed by thermoreceptors in the spinal cord able to detect cold [91]. The POA also contains heat-sensitive neurons whose tonic discharge is reduced by skin cooling and whose thermosensitivity to preoptic temperature is increased when the skin is cooled [92]. As a result, skin cooling or direct cooling of POA neurons modulates sympathetic stimulation of NST in BAT, as well as shivering thermogenesis [92–94]. The POA is also involved in the febrile response due to the integration of pyrogenic signals, such as prostaglandin E2, that stimulate the POA and activate BAT NST in a cAMP-dependent manner [95]. BAT sympathetic sensory system feedback BAT also has sensory innervation. Injection of an anterograde transneuronal virus into BAT has been used to trace its sensory innervation to the PVH, periaqueductal gray, parabrachial nuclei, raphe nuclei, and reticular area, all of which are associated with sympathetic outflow to BAT, suggesting the existence of BAT sensory system (SS)–SNS NST feedback circuits [96]. In keeping with this, local destruction of capsaicin-sensitive sensory neurons affects the response of interscapular BAT (iBAT) to acute cold exposure [96]. In this context, sympathetic stimulation of iBAT directly activates dorsal root ganglia sensory neurons associated with iBAT [97]. Autonomic modulation of WAT lipolysis Until 20 years ago, WAT was considered only in terms of its function in energy storage. However, since the seminal discovery of leptin by Jeffrey Friedman [24] and the identification of additional adipose hormones [98–100], WAT has been regarded as a true endocrine organ [25, 101]. The CNS regulates metabolic and secretory functions of WAT via the ANS. Abundant anatomical evidence indicates that the regulation of WAT by the CNS is mediated mainly by the SNS (for extensive reviews see [39, 102, 103] ), whereas PSNS innervation of WAT is still controversial [19, 20]. Using a viral retrograde transneuronal tracer in WAT, labeled neurons have been found in the brainstem (noradrenergic neurons of the LC), in hypothalamic nuclei (ARC, DMH, LHA, and VMH), and in some forebrain regions [104, 105]. The precise

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connections from the hypothalamus to the autonomic neurons have not been identified and might include additional projections between different hypothalamic nuclei. Some of the most important functions of WAT to be regulated by the SNS are mediated mainly by NA, including lipolysis, the number of adipocytes, and secretion of WAT proteins [102]. Adipocytes express several adrenergic receptor subtypes, b1, b2, and b3-adrenergic receptors that promote lipolysis, and the a2-adrenergic receptor that inhibits it. In rodents, SNS stimulation of the b3-adrenergic receptor triggers lipolysis in WAT through increased cAMP production by adenylyl cyclase and stimulation of the PKA pathway. In obesity, sensitivity of white adipocytes to adrenergic stimulation is decreased [106], whereas stimulation of the a2-adrenergic receptor inhibits adenylyl cyclase, preventing PKA activation and decreasing lipolysis [107]. Several hypothalamic–SNS–WAT axes regulate WAT lipolysis. These include nuclei with key roles in energy metabolism, such as the LHA, ARC, and VMH, as will now be discussed. The LHA contains orexin-A (OX-A) neurons that project to the brainstem and spinal cord and are able to regulate WAT lipolysis [108]. Results from intracerebroventricular (ICV) injection of high doses of OX-A suggest that it can modulate WAT lipolysis through activation of the SNS. This effect is also driven by histamine neurons through the H1 receptor. However, low doses of OX-A can decrease lipolysis by suppression of sympathetic nerve activity and modulation of H3-receptor activity [108]. MCH is a neuropeptide expressed in the LHA that can mediate white adipocyte metabolism via the SNS. Central infusion of MCH and activation of the MCH receptor in the ARC stimulate lipid storage and decreases lipid mobilization in WAT [109]. Several studies have shown that central administration of MC3/4R agonists in the CNS reduces fat mass in rodents, independent of food intake [110–113]. Central melanocortins regulate turnover of NA, a key initiator of lipolysis in mammals, in the sympathetic neurons innervating WAT. Thus, central injection of an MC3/4R agonist increases NA turnover in specific fat depots [114], whereas blockade of the CNS melanocortin system stimulates lipid storage and de novo fatty acid synthesis in WAT [115]. Consistent with these data, decreased secretion of a-MSH leads to an increase in adiposity and impaired lipolysis, an effect that can be reversed by treatment with isoproterenol, a b-adrenergic agonist [116]. ARC NPY, moreover, regulates adiposity in rats by promoting energy storage in WAT and inhibiting BAT activity [28, 115]. NPY is also expressed in the SNS neurons that innervate WAT and can act both directly on white adipocytes and by increasing hypothalamic levels of NPY, which in turn inhibit SNS outflow and suppress catecholamine release and subsequent lipolysis [116].

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Another hypothalamic nucleus involved in WAT lipolysis is the VMH. Electrical stimulation of the VMH in rats leads to a lipolytic response in WAT [117]. Pretreatment with cholinergic or b-adrenergic blockers blunts this effect, while treatment with a-adrenoreceptor blockers has no additional effect on the stimulation. These data suggest that the effect of VMH stimulation on WAT lipolysis is mainly via the SNS and b-adrenergic receptors within WAT [117, 118]. Recent findings show that VMH neurons can switch the manner in which WAT responds to different diets. Thus, on a chow diet, mice lacking the cannabinoid receptor type 1 (CB1) in the VMH show decreased adiposity due to increased sympathetic activity and lipolysis; on a high-fat diet (HFD), lack of CB1 in VMH neurons leads to leptin resistance, attenuating lipolysis and increasing adiposity [119]. WAT sympathetic sensory system feedback Recent data show the existence of WAT SS–SNS feedback loops in WAT. SNS and SS share central sites of regulation, as well as some circuitries that may be involved in crosstalk between the brain and WAT. It has been found that some individual neurons participate in both central SNS outflow from the brain to subcutaneous WAT and in SS inflow from subcutaneous WAT to the brain [120]. Although the function of these SS–SNS circuits is still unclear, two roles have been proposed: (1) informing the brain of fat depot status and/or (2) interacting with SNS activation of WAT in the regulation of lipolysis [13]. In keeping with these potential functions, increases in SNS signaling to WAT in response to glucose deprivation are accompanied by increased sensory nerve electrophysiological activity in WAT [121].

Autonomic modulation of glucose metabolism Glucose homeostasis is regulated by circulating hormones, autonomic innervation, and the secretory activity of the endocrine pancreas, through the coordinated modulation of hepatic glucose production (HGP) and its release into the circulation and regulation of glucose utilization by peripheral tissues including liver, muscle, BAT, and WAT [122, 123]. Autonomic modulation of hepatic glucose homeostasis The liver is a key organ in the regulation of whole-body metabolic homeostasis. It is involved in amino acid and lipid metabolism, acts as an exocrine gland responsible for the production of bile acids [124, 125], and controls

glucose homeostasis. Besides being the principal site of glucose storage, the liver responds to increases in circulating glucose and insulin levels by reducing HGP. As a regulatory mechanism, glucose output from the liver is increased during hypoglycemia [126]. The CNS innervates the liver through sympathetic and parasympathetic nerves which contain afferent as well as efferent fibers [14, 22]. Transneuronal virus tracing after injection of pseudorabies virus in the liver has detected first-order labeled neurons that correspond to sympathetic and parasympathetic neurons, while second- and third-order labeling has been found in the brainstem, hypothalamus, and in limbic structures [127]. Thus, sympathetic efferent pathways from the liver reach the intermediolateral cell column (IML) in the spinal cord. Pre-ganglionic neurons innervate the celiac and mesenteric ganglia that ultimately innervate the liver. Sympathetic nerves can modulate hepatocyte function directly via a1- and b-adrenergic receptors [128, 129] or indirectly through the release of neuropeptides such as NPY and galanin [130, 131]. Parasympathetic efferent pathways project to the dorsal motor nucleus of the vagus (DMV) and from there send afferent pre-ganglionic nerves to the liver [22]. Several hypothalamic sites send autonomic signals to the liver. The LHA is involved in its parasympathetic innervation [132], the VMH in its sympathetic innervation [133], and the PVH integrates information from several areas including the ARC, VMH, and SCN, as well as sending both sympathetic and parasympathetic signals to the liver [14, 21]. Classical studies demonstrated that electrical stimulation of the LHA induces hepatic glycogen synthesis as well as a decrease in levels of the gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PEPCK) [134]. Correspondingly, activation of orexin-expressing neurons in the LHA increases blood glucose levels through the stimulation of endogenous glucose production; notably, an intact autonomic outflow via the hepatic sympathetic innervation is essential for this effect [135]. A recent study has shown that knocking out orexin impairs daily rhythm in blood glucose levels [136]. In addition, treatment with an adrenergic antagonist or parasympathectomy suppresses the day– night oscillation of blood glucose levels induced by treatment with OX-A in normal and db/db mice [136]. In addition, the VMH has been shown to be involved in hepatic glucose homeostasis. Electrical stimulation of the VMH increased the activity of PEPCK and suppressed the glycolytic enzyme pyruvate kinase (PK) in rat liver [134]. Sympathetic stimulation of the liver increases hepatic glucose output via rapid activation of glycogen phosphorylase, resulting in hyperglycemia and a marked reduction of glycogen within the liver [133]. These effects are not blunted by adrenalectomy [137]. Within the past decade, several studies have linked VMH AMPK to the regulation

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of hypoglycemia. Pharmacological activation of AMPK by AICAR in rats leads to an increase in hormonal counterregulation, resulting in elevated endogenous glucose production [138, 139]. In addition, downregulation of AMPK in the VMH suppresses glucagon and adrenaline in response to hypoglycemia [140]. Recent studies in murine models have investigated the role of the VMH in glucose homeostasis, showing that SF1 neurons are involved in the regulation of glycaemia [141, 142]. Mice lacking vesicular glutamate transporter 2 (VGLUT2) in VMH SF1 neurons show hypoglycemia during fasting that is secondary to impaired fasting-induced glucagon action and impaired hepatic expression of PEPCK and glucose 6 phosphatase (G6Pase) [141]. GABAergic inhibition in the VMH, moreover, appears to modulate glucagon and sympathoadrenal responses to hypoglycemia in non-diabetic and diabetic rat models [143, 144]. The ARC is sensitive to insulin, leptin, and glucose and sends signals to the PVH and other nuclei of the hypothalamus to modulate glucose homeostasis. It has been shown that the ARC mediates the effect of leptin on glucose homeostasis. Thus, restoration of the leptin signaling pathway in mice lacking the leptin receptor is sufficient to improve hyperinsulinemia and normalize blood glucose levels [145]. In addition, re-expression of the long form of the leptin receptor in POMC neurons is able to normalize the hyperglycemia induced in leptin receptor-deficient mice [146]. A recent study suggests that AgRP neurons are sufficient and necessary to mediate leptin-induced reduction of circulating glucose levels, which is not the case for VMH or POMC neurons [147]. In addition, ICV injection of NPY increases endogenous glucose production in rats by decreasing insulin sensitivity via sympathetic innervation [148]. Accordingly, recent studies have shown that glucocorticoid signaling in the ARC induces hepatic insulin resistance and prevention via NPY of the inhibition of HGP during hyperglycemia and that this effect can be blocked by sympathetic denervation [149]. The PVH is connected to the VMH, SCN, and ARC and receives and integrates information from these or other hypothalamic sites as well as from autonomic innervation involved in liver glucose regulation. There is some evidence to suggest a role for the PVH in mediating the effects of the biological clock situated in the SCN. That interaction regulates the daily rhythm of glucose plasma levels via GABAergic and glutamatergic projections that control sympathetic and parasympathetic pre-autonomic neurons of the PVH [150]. In addition, recent findings have linked the PVH to glucose intolerance induced by excess THs levels. Thus, selective administration of T3 to the PVH of euthyroid rats triggers an increased HGP and elevated plasma glucose via the sympathetic projection to the liver [14, 21].

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Autonomic modulation of the pancreas on glucose homeostasis The islets of Langerhans that make up the endocrine pancreas regulate glucose homeostasis by secretion of insulin and glucagon that control increases and decreases in blood glucose [23]. a- and b-cells of the islets control the secretion of glucagon and insulin, respectively. The secretion of insulin by b-cells is a tightly regulated process. Thus, b-cells respond to an increase in blood glucose by correspondingly increasing secretion of insulin. Capacity for insulin secretion is itself controlled by regulation of bcell mass [151–154]. Hormone secretion by the islets is regulated by humoral factors and by the CNS via the ANS [23], with the pancreas receiving both sympathetic and parasympathetic innervation. Several studies have identified central regions that control pancreatic endocrine function, showing overall that the following CNS sites regulate output by both parts of the ANS to the pancreas: PVH, perifornical hypothalamic region, A5 catecholamine cell group, RVLM, and lateral paragigantocellular reticular nucleus [155]. The sympathetic efferents are formed by sympathetic neurons in the IML of the spinal cord that innervate postganglionic neurons, mainly in the prevertebral ganglia, while parasympathetic efferents consist of pre-ganglionic neurons in the DVM and peripheral postganglionic neurons located within the pancreas [156, 157]. Pancreatic parasympathetic afferents originate in the nodose ganglia and reach the NTS, while the sympathetic afferents leave the dorsal root ganglia and synapse with interneurons in spinal cord laminae I and IV [23]. Parasympathetic nerves innervate a- and b-cells, while sympathetic nerves innervate mainly a-cells. A recent study, in a noninvasive in vivo model, showed that the stimulation of b-cells by their parasympathetic supply increased insulin secretion and controlled glycaemia, while the stimulation of their sympathetic supply decreased plasma insulin concentration [158]. Central regulation of the ANS is by glucose-excited or glucose-inhibited neurons, located mainly in the brainstem and hypothalamus. Within the hypothalamus, the VMH plays a key role in the glucose counterregulatory response. The VMH has been shown to regulate glucagon secretion by the pancreas in response to local levels of glucose. Thus, low levels of glucose in the VMH lead to an increase in glucagon secretion, whereas glucose infusion into the VMH suppresses glucagon secretion in response to decreased blood glucose [159, 160]. Thus the VMH is implicated in sensing hypoglycemia and in generating a counterregulatory response, with VMH AMPK playing an important role [139–141]. Previous studies based on lesions of the VMH showed that acute hyperinsulinemia can be blunted by vagotomy [161]. In recent years, studies

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in rats have shown that insulin acts on the VMH, suppressing glucagon secretion in response to insulin-induced hypoglycemia. This effect of insulin in the VMH might be mediated by an increase in local GABAergic tone [162]. In contrast, blockade of insulin in the VMH increases basal glucagon levels. Moreover, chronic reduction of insulin receptors in the VMH impairs glucose metabolism as well as a- and b-cell function [163]. Suppression of GABAergic neurotransmission in the VMH is crucial for normal glucagon and sympathoadrenal responses to hypoglycemia [144]. The VMH’s role in regulating endocrine pancreatic function has also been demonstrated by studying propylendopeptidase (PREP), an enzyme with endopeptidase activity that might be involved in the regulation of neuropeptide levels. PREP knockdown mice show glucose intolerance, decreased fasting insulin levels, increased fasting glucagon levels, and reduced glucose-induced insulin secretion, as well as elevated sympathetic outflow to and NA within the pancreas [164]. In addition to the role of the VMH in glucose homeostasis, recent evidence supports the involvement of AgRP neurons in the ARC in regulating the balance between lipid and carbohydrate metabolism. Ablation of these AgRP neurons leads to a change in SNS output to liver, skeletal muscle, and the pancreas [165]. On a chow diet, mice lacking AgRP neurons become obese and hyperinsulinemic, whereas on a HFD these mice showed reduced body weight and improved glucose tolerance [165]. Another key site of control of glucose homeostasis is the dorsal vagal complex (DVC) which comprises the NTS, DMV, and area postrema (AP) and presents glucosensing neurons that react to changes in blood glucose levels by modulating glucose homeostasis through vagal outflow to the pancreas [166]. Many studies have shown that the DMV, the main source of vagal innervation to the pancreas, has a role in pancreatic secretory function. Recently, the DMV was demonstrated as one of the components of the pancreatic vagovagal reflex that includes pancreatic vagal afferents, the DMV, and pancreatic vagal efferents. Electrical and chemical stimulation of the DMV activates both endocrine and exocrine secretion via cholinergic pathways which can be blunted by vagotomy or chemical inhibition [167–169]. Activation of the DMV by bilateral microinjection of a GABA antagonist results in a rapid increase in glucose-induced insulin secretion, and this effect can be inhibited by a muscarinic receptor antagonist or significantly increased by inhibition of nitric oxide synthesis [168]. Additionally, a population of DMV neurons projects to the pancreas which can be depolarized by exogenous GLP1. This suggests that GLP1 can increase insulin secretion either by acting directly on pancreatic bcells or indirectly through the modulation of inhibitory or excitatory DMV inputs to the pancreas [170, 171].

Autonomic modulation of muscle glucose uptake Skeletal muscle is one of the main sites of insulin-stimulated glucose uptake in the postprandial state [172]. After a meal, hyperglycemia triggers insulin secretion, stimulating glucose uptake in skeletal muscle. In insulin-resistant states, such as type 2 diabetes (T2D) and obesity, insulinstimulated glucose uptake in skeletal muscle is markedly impaired [172, 173]. Nevertheless, there is evidence of non-insulin-mediated pathways of glucose utilization in muscle induced by sympathetic nerve activity and muscle contraction [18]. Recent studies in rodents have described labeling in several areas of the brain, including the hypothalamus, following injection of pseudorabies virus in skeletal muscle [174–176]. Correspondingly, several lines of evidence now show that the hypothalamus plays an important role in the modulation of glucose uptake by skeletal muscle via the SNS [177]. First, VMH stimulation promotes glucose uptake independently of insulin blood concentration [178, 179], an effect that is blunted by blockade of sympathetic activity [173, 180]. Second, the injection of leptin in the VMH increases glucose uptake in peripheral tissues, including skeletal muscle [181], in a manner that is apparently dependent on b-adrenergic stimulation [177]. Third, injection of OX-A into the VMH of rodents enhances glucose uptake and promotes insulin-induced glucose uptake and glycogen synthesis in skeletal muscle through the activation of SNS [182]. These effects of OX-A are abolished in mice lacking b-adrenergic receptors but restored by the expression of b2-adrenergic receptors in myocytes and other cell types in skeletal muscle [182]. Thus, leptin and orexin each play an important role in regulating glucose metabolism, increasing skeletal muscle sympathetic activity via the hypothalamus.

Regulation of energy homeostasis by peripheral hormones acting on the CNS Recent data have shown that signaling by peripheral hormones is important in the control of energy homeostasis, via their effects on the CNS and subsequent outflow by the ANS. These hormones include adipokines (e.g., leptin), classical hormones synthesized in peripheral glands (e.g., THs and estrogens), and gastrointestinal hormones (e.g., insulin and ghrelin). As an illustration of the mechanisms by which these hormones exert their effects on energy homeostasis, we will focus on leptin, THs, and insulin. Leptin Leptin is a hormone secreted by WAT in proportion to fat mass which informs the hypothalamus of the status of

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energy stores [24, 101, 183]. The leptin receptor is expressed in several brain areas that mediate leptin’s central effects. Leptin can exert its satiety effect by inhibiting the orexigenic NPY/AgRP neuronal population and stimulating activity of anorexigenic POMC neurons in the ARC [101, 183, 184]. Leptin can also modulate peripheral lipid [185] and glucose metabolism [186]. In this context, infusion of leptin in the MBH of rats inhibits the synthesis of lipids in adipose tissue [187]. The action of leptin on adipocyte metabolism via the CNS requires intact autonomic innervation since sympathetic denervation of adipose tissue blunts leptin’s effects [187]. Moreover, leptin can regulate NST by modulation of SNS activity in BAT [55, 188]. The binding of leptin to its putative receptor leads to an increase in POMC and a decrease in NPY/ AgRP levels that trigger SNS activation and a consequent increase in UCP1 and NST in BAT [28, 55, 184]. Leptin is also involved in the autonomic regulation of glucose homeostasis [173]. At the central level, leptin infusion decreases circulating insulin levels by acting on the b-cell via the SNS [189], while interaction of leptin with its receptor in the ARC improves hyperinsulinemia and blood glucose levels [145]. In this context, expression of leptin receptors in the ARC of leptin-receptor-deficient rats decreases hepatic expression of gluconeogenic genes and increases hepatic insulin signaling, an effect blunted by hepatic denervation of the vagus nerve [190]. Thyroid hormones THs are produced in the thyroid and play an important role in energy and metabolic homeostasis by influencing food intake and EE in metabolically active tissues, such as BAT, WAT, liver, pancreas, and skeletal muscle [14, 89, 191, 192]. BAT expresses at least two TH receptors (TRs), TRa and TRb1, which make it a direct target of THs. Nevertheless, over the last few years, a large body of evidence has suggested that the CNS is also a key player in thermogenetic regulation and metabolic homeostasis, acting via the ANS and THs. A strong relationship between TH and thermoregulation is shown by the following: (1) direct cooling of the POA leads to the activation of the hypothalamic–pituitary–thyroid (HPT) axis; (2) THs play a critical role in the maintenance of body temperature by influencing NST; and (3) alteration in TH levels leads to clear symptoms related to body temperature in both hypoand hyper-thyroidism. The precise mechanisms through which these effects are mediated have started to be uncovered [14, 89, 191, 192]. Thus, mice with a mutant TRa1 that has a low affinity for T3 show hypermetabolism with increased thermogenesis and EE, while this effect is blunted after functional sympathetic denervation to BAT, indicating that the effect of THs in these mice is mediated

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by the CNS via the ANS [193]. Data generated by our group support the evidence that the stimulation of BAT NST by the SNS depends on T3-mediated activation of de novo lipogenesis in the hypothalamus, due to inhibition of VMH AMPK [53]. Notably, while these data were initially obtained from THs, more recent experiments show that endogenous hormones (estrogens, BMP8B, and probably leptin) and drugs such as liraglutide and nicotine act in a similar manner to THs to promote BAT NST and browning [53–58]. THs can also modulate glucose production and insulin sensitivity [14, 21, 194] through SNS projections from the PVH. Accordingly, sympathectomy attenuates the increase in HGP associated with thyrotoxicosis, whereas parasympathectomy does not affect HGP but decreases hepatic insulin sensitivity [194]. The ARC also expresses TRs [14, 89, 191, 192, 195, 196]. Given that the ARC also modulates HGP [197, 198] and hepatic insulin sensitivity through sympathetic output to the liver [149], it will also be important to investigate the potential relevance of TH signaling and glucose metabolism in this hypothalamic area. Insulin Insulin is secreted by pancreatic b-cells in response to increases in circulating glucose and acts as an anabolic hormone in peripheral tissues. BAT is one of the most insulin-responsive tissues with respect to stimulation of glucose uptake. Thus, under physiological conditions, plasma insulin levels are elevated after feeding and glucose uptake by BAT is increased [26, 28, 199, 200]. Under starvation or fasting, on the other hand, insulin levels are lowered and BAT shows reduced glucose uptake [26, 28, 200]. In keeping with this, in rodents insulin can trigger sympathetic activation to BAT and lead to increased NST through its action within the brain [201]. Besides its effect on BAT, insulin also acts as one of the principal regulators of WAT metabolism. Insulin stimulates glucose and fatty acid uptake and inhibits hormone-sensitive lipase (HSL) activity and thus lipolysis in WAT [202, 203]. Recent data have shown that insulin can exert this effect by acting on the MBH, with mice lacking the neuronal insulin receptor exhibiting uncontrolled lipolysis and decreased de novo lipogenesis in WAT [204]. Thus, insulin action within the brain suppresses basal WAT HSL activation, a marker of sympathetic outflow to WAT [13, 204, 205]. The most characterized role of insulin is its regulation of blood glucose levels. Insulin suppression of HGP is regulated by way of insulin receptors (IRs) in both the liver and brain. Thus, genetic inactivation of IRs in either of these organs abrogates the effect of insulin [206–208]. IRs have been found in several hypothalamic sites involved in sympathetic regulation of glucose homeostasis [209, 210].

Endocrine Leptin, THs, Insulin, BMP8, E2, etc.

POA

Hypothalamus

Food intake

PVH IML

PVH LHA

LHA

SNS RPa IO

SNS

BAT

DMH

DMH

VMH

Enviroment Tª

IML

VMH

ARC

ARC 3V

Projections Possible projections

Hypothalamus SNS

IML

Physical activity

PVH

DVC

Pancreas

PVH

LHA

LHA

PSNS

Muscle

NTS AP SNS

Preganglionic neurons

SNS

Autonomic cell groups

DMV

IML Liver

DMH

DMH

DMV VMH

VMH

ARC

ARC

PSNS

3V

Fig. 1 Autonomic control of energy homeostasis. Energy balance is controlled by the central nervous system (CNS) which receives and integrates signals from peripheral tissues and the external environment, responding by modulating food intake and energy expenditure (EE). The CNS controls autonomic innervation of peripheral tissues through several key areas, such as the hypothalamus and dorsal vagal complex (DVC). Specific projections from the hypothalamic nuclei to pre-autonomic neurons are not known and might include additional connections between different hypothalamic nuclei (dotted lines). Sympathetic nervous system (SNS) output to peripheral tissues involves the intermediolateral nucleus (IML), whereas the parasympathetic nervous system (PSNS) relays in the dorsal nucleus of the vagus nerve (DMV). Within the hypothalamus, the preoptic area (POA) is responsible for temperature regulation and the febrile response; it receives and integrates information pertaining to thermosensitive areas and modulates sympathetically stimulated thermogenesis in brown adipose tissue (BAT). Other hypothalamic

nuclei implicated in sympathetic non-shivering thermogenesis are the ventromedial (VMH), dorsomedial (DMH), and paraventricular nuclei (PVH), which send projections to the raphe pallidus (RPa) to modulate the BAT thermogenic response via the SNS. The CNS also modulates white adipose tissue (WAT) lipolysis and the secretory activity of WAT through sympathetic innervation of different depots. The hypothalamic–SNS axes that regulate WAT lipolysis involve the lateral hypothalamic area (LHA), VMH, and ARC. Glucose homeostasis is regulated by the CNS through SNS and PSNS innervation of the liver and pancreas. Several hypothalamic nuclei are involved in the regulation of hepatic glucose metabolism: the LHA, VMH, ARC, and PVH. The VMH, ARC, and DVC (which comprises the nucleus of the solitary tract (NTS), DMV, and area postrema (AP)) modulate pancreatic secretion of insulin and glucagon via the autonomic nervous system. The CNS regulates glucose uptake by skeletal muscle via the SNS. 3 V: third ventricle

Insulin signaling in the hypothalamus plays a key role in the regulation of HGP and glucose disposal [173, 206]. ICV administration of insulin or an insulin mimetic in rats suppresses HGP independently of changes in circulating levels of insulin or glucose [206], while hepatic vagotomy and sympathectomy independently blunt the inhibitory effect of central insulin on HGP [148, 173].

the pancreas [39, 127, 158, 211], modulating the metabolic and secretory function of these peripheral tissues as a result of signals and drugs that act on homeostatic regulatory sites in the CNS [21, 53, 54, 57, 58, 62, 119, 162]. Lipid metabolism is regulated by modulation of NST in BAT [26] and lipolysis in WAT [212]. The regulation of glucose homeostasis is driven by the balance between glucose production in the liver and secretion of glucagon and insulin by the pancreas, in response to blood glucose levels [126] and glucose uptake in peripheral tissues such as skeletal muscle [18]. Regulation of glucose metabolism occurs via splanchnic sympathetic and vagal parasympathetic nerves and involves several hypothalamic sites and the DVC [22, 23]. Overall, several lines of evidence

Summary and conclusions The CNS regulates energy homeostasis by acting on metabolic organs via the ANS [13–16] (Fig. 1). The SNS and PSNS differentially innervate BAT, WAT, liver, and

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demonstrate that the hypothalamic–ANS axis (afferent and efferent pathways) plays a major role in the regulation of energy metabolism. Further elucidation of the neural and molecules involved, such as AMPK, extracellular signalregulated kinase (ERK), phosphoinositide 3-kinase (PI3K) [15, 213], and mammalian target of rapamycin (mTOR) [53–58, 214], can be expected to provide specific novel pharmacological targets for the treatment of obesity and metabolic disorders, including T2D, hypertension, and CVD [5, 215]. Acknowledgments The research leading to these results has received funding from the European Community’s Seventh Framework Programme (FP7/2007-2013) under Grant agreement No 281854—the ObERStress European Research Council Project (ML), the Xunta de Galicia (ML: 2012-CP070; RN: EM 2012/039 and 2012-CP069), Instituto de Salud Carlos III (ISCIII) (ML: PI12/ 01814), and MINECO co-funded by the European Union FEDER Program (RN: BFU2012-35255; CD: BFU2011-29102). CIBER de Fisiopatologı´a de la Obesidad y Nutricio´n is an initiative of ISCIII. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The manuscript was edited for English language by Dr. Pamela V Lear. Conflict of interest

The authors declare no conflict of interest.

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