Regulated energy homeostasis is fundamental for maintaining life. Unfortunately, this critical process is affected in a high number of mentally ill patients. Eating disorders such as anorexia nervosa are prevalent in modern societies. Impaired appetite and weight loss are common in patients with depression. In addition, the use of neuroleptics frequently produces obesity and diabetes mellitus. However, the neural mechanisms underlying the pathophysiology of these behavioral and metabolic conditions are largely unknown. In this review, we first concentrate on the established brain machinery of food intake and body weight, especially on the melanocortin and neuropeptide Y (NPY) systems as illustration. These systems play a critical role in receiving and processing critical peripheral metabolic cues such as leptin and ghrelin. It is also notable that both systems modulate emotion and motivated behavior as well. Secondly, we discuss the significance and potential promise of multidisciplinary molecular and neuroanatomic techniques that will likely increase the understanding of brain circuitries coordinating energy homeostasis and emotion. Finally, we introduce several lines of evidence suggesting a link between the melanocortin/NPY systems and several neurotransmitter systems on which many of the psychotropic agents exert their influence.
Maintaining energy homeostasis is fundamental for survival. However, obesity due to over-nutrition is an increasing worldwide public health problem.1 In psychiatric practice, on the other hand, impaired appetite is one of the crucial issues. Anorexia and weight loss are common, for example, in patients suffering from depression. Eating disorders are medically intractable and life threatening. In addition, the so-called ‘atypical’ antipsychotic agents, currently and widely used to treat psychoses, often induce hyperphagia, obesity, and diabetes mellitus.2,3,4
In the past decade, fortunately, there has been remarkable progress in understanding the molecular mechanisms of food intake and body weight. This is due in large part to increased research activity towards combating the rising incidences of obesity and associated metabolic disorders. As a result, it is now established that the central nervous system (CNS) senses and processes peripheral metabolic cues including leptin5 and ghrelin,6,7 resulting in coordinated energy homeostasis. However, the pathophysiology of the disequilibrium between energy intake and expenditure in psychiatric disorders remains largely unknown. Nevertheless, evidence suggests that several CNS systems regulating energy balance may be dysregulated in patients with mental illnesses, for example, eating disorders, and drug addiction.8,9,10,11,12,13,14
In the current review, we will illustrate the neuroanatomic and molecular genetic aspects of the melanocortin and neuropeptide Y (NPY) systems residing in the CNS downstream of leptin and ghrelin, to discuss the neural bases of feeding, metabolism, and emotion. Additionally, we point the reader to recent reviews for other critical CNS systems regulating food intake and body weight, including those by Barsh and Schwartz,15 Elmquist et al,16 Friedman and Halaas,17 Friedman,1 Grill and Kaplan,18 O'Rahilly et al,19 Saper et al,20 Sawchenko,21 Schwartz et al,22 Spiegelman and Flier,23 van den Pol,24 Woods et al,25 Zigman and Elmquist.26
Anatomic and molecular bases for metabolic/autonomic control of body weight
The classic ‘dual-center’ model has been modified
A primary CNS site controlling food intake and body weight is the hypothalamus. The underpinnings of this view are largely due to classic descriptions that date back to Bramwell27 and Fröhlich.28 These are based on clinical observations in many patients with pituitary tumors who developed excessive fat mass and hypogonadism (see Elmquist et al16 for discussion). Whether this syndrome resulted from the tumor per se or its intrusion into the hypothalamus was controversial at that time. Subsequently, the resection of the dog pituitary gland without hypothalamic damage was demonstrated not to produce obesity by Aschner.29
In 1940, Hetherington and Ranson30 performed a seminal study to further investigate the role of the hypothalamus in maintaining body weight homeostasis, in which bilateral and extensive hypothalamic lesions were made. Subsequent studies including those by Anand and Brobeck placed smaller lesions in the lateral hypothalamus.31 Such a sequence of attempts led to the ‘dual-center’ model that defines the lateral hypothalamus as a ‘feeding’ center, and the ventromedial hypothalamic nucleus as a ‘satiety’ center (Figure 1). Moreover, data developed over ensuing years challenged components of this model.32 However, the anatomic substrate underlying coordinated food intake control still remained obscure, as scientists in the field lacked key tools to unravel this complex hypothalamic puzzle. Nevertheless, several molecular discoveries in 1990s, especially identification of leptin5 and melanocortin receptors33,34,35 implicated other hypothalamic and extra-hypothalamic sites in regulating energy homeostasis.
Leptin as an antiobesity hormone
A fundamental hormone was discovered in 1994 and named ‘leptin’ for a Greek root ‘leptos’ meaning thin.5 Leptin is produced mainly by adipose tissue, circulates, and reaches the CNS.5,17 Leptin inhibits ingestive behavior and stimulates energy expenditure by normalizing reduced sympathetic activity, thermogenesis, oxygen consumption, and locomotor activity. Accordingly, mutations in the ob gene encoding leptin produce hyperphagia and morbid obesity in mice (ob/ob mice)5,17 and humans.36,37,38,39,40 Similar to states of starvation, leptin deficiency also leads to deficits in the reproductive, thyroid, and adrenal axes.41,42,43,44 Moreover, exogenous leptin corrects these manifestations in leptin-deficient mice45,46,47,48 and humans.38,40 Finally, the significance of leptin in adaptive endocrine and metabolic responses to fasting was demonstrated in healthy subjects.49 In this study, a replacement dose of recombinant human leptin administered during fasting prevented the starvation-induced changes of endocrine axes.
The leptin receptor (Ob-R) belongs to the class-1 cytokine receptor superfamily.50,51 The Ob-R has a single transmembrane spanning domain and functions via the JAK-STAT pathway.51,52 Thus far, splice variants of Ob-R mRNA encoding six isoforms have been identified, and only the long form (Ob-Rb) has intracellular signaling motifs of leptin.51 Consequently, the db/db mice lacking Ob-Rbs and ob/ob mice exhibit an almost identical obesity phenotype.53,54,55 Moreover, the phenotype in db/db mice is not corrected by exogenous leptin.53,54,55 Mutations in the human Ob-Rb also produce morbid obesity.56 Importantly, the gene expression of the Ob-Rb is evident in the mediobasal hypothalamic sites including the arcuate nucleus.57,58,59,60 The leptin receptor has also been identified in the human brain.61
The arcuate nucleus: a site of leptin action
Evidence indicates that leptin directly acts on the arcuate nucleus of the hypothalamus (Arc; Figure 1): (i) Radiolabeled leptin binds highly to the mediobasal hypothalamic region involving the Arc;62 (ii) cells expressing Ob-Rb mRNA populate in the Arc and several other brain sites;57,58,59,60,61 (iii) leptin induces the expression of an immediate early gene, c-fos (a marker of neuronal activation)63,64,65,66 and suppressor of cytokine signaling-3 (SOCS-3, a cellular marker of direct leptin action)65,66,67 in the Arc; (iv) Arc cells are directly hyperpolarized and depolarized by leptin.68,69
The central melanocortin system mediates leptin action
The term ‘melanocortin’ indicates a series of peptides that are cleaved from pro-opiomelanocortin (POMC).70 One of the POMC products, adrenocorticotropic hormone, is secreted by the anterior pituitary and stimulates adrenocortical cells. In the CNS, POMC neurons are localized in two sites in rodents and humans, the Arc (Figure 2a, c)71,72 and the nucleus of the solitary tract (NTS).70 Currently, considerable attention has focused on another POMC product, α-melanocyte-stimulating hormone (α-MSH). Accumulating evidence strongly suggests that α-MSH is a critical regulator of food intake, body weight, and glucose homeostasis, and that α-MSH mediates several of the biological effects of leptin. For example, most of POMC-expressing Arc neurons coexpress Ob-Rb mRNA.73 Leptin increases POMC mRNA in the Arc74 and induces the expression of c-fos and SOCS-3 mRNA in Arc POMC neurons.65,66 In addition, POMC mRNA in the Arc is markedly reduced in leptin-deficient ob/ob mice as well as in fasted rodents (when leptin levels rapidly fall).75,76 The decrease in POMC expression is prevented by leptin administration.74,75,76 Finally, leptin directly depolarizes POMC neurons.69
Of importance, α-MSH acts as an agonist for the melanocortin-4 receptor (MC4-R),70,77,78 a Gs-protein-coupled receptor distributed in the CNS.35,79,80 The MC4-R is an established regulator of food intake and body weight, and blockade of this receptor causes obesity.77,78 An overeating/obesity syndrome is produced, for example, by targeted deletion of the MC4-R81 and by mutations in the human MC4-R.82,83,84,85,86,87,88 The importance of MC4-Rs in humans is highlighted by an estimate that 3–5% of the population suffering from morbid obesity may result from MC4-R mutations.89 Another important piece of data supporting this model is that POMC-deficient mice and humans display similar obesity phenotypes.90,91
A unique component of the melanocortin regulatory system is an endogenous MC4-R antagonist, agouti-related protein (AgRP).92,93,94 Interestingly, AgRP is produced exclusively in the Arc in rodents, monkeys, and humans.71,72,93,94,95,96,97 Alpha-MSH-producing (Figure 2a, c) and AgRP-producing (Figure 3c, e) neurons are distributed and segregated in the medial and lateral regions of the Arc, respectively.71,72 In line with the results from the aforementioned molecular genetic studies on the MC4-R, transgenic overexpression of AgRP produces obesity.93,94 In contrast to POMC mRNA, AgRP mRNA is increased in leptin-deficient ob/ob mice and leptin-resistant db/db mice, and during periods of fasting when leptin levels rapidly fall.97,98 Finally, it is important to note that AgRP is coexpressed with NPY in the Arc (see the section ‘the NPY/Y1-receptor system’).71,98
A popular current model suggests that leptin stimulates melanocortin signaling, resulting in decreased energy intake and increased energy expenditure, whereas opposite effects by AgRP are inhibited by leptin (Figure 4). Such an interrelation between leptin and melanocortins is supported by pharmacological evidence demonstrating that leptin-induced anorexia can be attenuated by coadministration of MC4-R antagonists,99 as can the effects of leptin on heat production.100,101 Brown adipose tissue (BAT), located at the interscapular region, regulates body temperature and diet-induced thermogenesis, and is therefore critical in energy expenditure.100,101 Leptin increases uncoupling protein-1 (UCP-1) via the sympathetic nervous system, which is produced by BAT in the process of thermogenesis. MC4-R antagonism suppresses the expression of UCP-1 mRNA by leptin.102
Recently, our laboratory provided evidence concerning the functional importance of leptin action on POMC neurons by deleting leptin receptors specifically from this cellular population in mice.103 Notably, mice lacking leptin signaling in POMC neurons display mild obesity, hyperleptinemia, and altered expression levels of hypothalamic peptides. The significance of this study will be discussed in a later section.
Moreover, Cowley et al69 substantiated that NPY/AgRP neurons inhibited POMC neurons in the Arc. By using a strain of transgenic mice expressing green fluorescent protein (GFP) under the control of the POMC promoter, the authors demonstrated that leptin increased the frequency of action potentials in POMC neurons by two mechanisms: depolarization through a cation channel; and disinhibition by inhibiting NPY/AgRP neurons that contain γ-amino butyric acid (GABA) and tonically inhibit POMC neurons.
Apparently, MC4-R-mediated melanocortin signaling is one of the targets of leptin action. Clearly, however, several other CNS systems are also involved in leptin-signaling brain systems. Indeed, it is now clear that leptin-independent melanocortinergic CNS pathways exist.103,104,105 Nonetheless, it is clearly established that α-MSH acting through MC4-Rs is a fundamental regulator of coordinated energy homeostasis. Key questions that remain include what metabolic and neural cues, beside leptin, drive the melanocortinergic neural circuits. The MC4-R-positive sites that function to suppress excessive weight gain are also to be identified.
Melanocortin neurons project to MC4-R-positive CNS sites involved in regulating food intake and body weight
Despite the very limited distribution of POMC and AgRP cells bodies,71,72,106 their axonal projections are widespread across the CNS. Several immunohistochemical studies have demonstrated CNS distributions of α-MSH-positive and AgRP-positive axons in rodents, monkeys, and humans.71,72,96,106,107 The CNS localization of MC4-R has also been examined in the rat and mouse.35,79,80 For this purpose, radioisotopic in situ hybridization histochemistry has been applied, as high-affinity antibodies against MC4-R protein are unavailable. Notably, nearly all the CNS sites thought to be critical for energy balance regulation display overlapping distributions of melanocortinergic axons and MC4-R mRNA in rodents.35,79,80 Some of these representative sites are discussed below.
1. Paraventricular nucleus of the hypothalamus (PVH): Lesions of the PVH cause hyperphagia in the rat, indicating that a regulator of food intake resides in this nucleus.32 Several lines of evidence nominate subsets of MC4-R-positive PVH neurons as candidates for the regulator (Figure 5). For example, microinjections of a synthetic MC4-R agonist MT-II into the rat PVH inhibit food intake, whereas PVH administration of a synthetic MC4-R antagonist SHU9119 exerts opposite effects.108,109 In addition, levels of POMC mRNA in the Arc and α-MSH in the PVH are lower in genetically obese Zucker rats that have a mutant Ob-Rb isoforms, than are those in lean rats, suggesting a role of the melanocortinergic Arc-PVH projection in energy homeostasis regulation.110
In the rat, the PVH is composed of parvicellular and magnocellular divisions, and the former is further divided into several subdivisions (Figure 5).111,112,113 These divisions and subdivisions can be readily and cytoarchitectonically distinguished by Nissl staining. In the rat, neurons innervating parasympathetic and sympathetic preganglionic neurons are located in the dorsal, ventral, and lateral parvicellular subdivisions, while hypophysiotropic neurons are characteristically distributed in the medial parvicellular subdivision.111,112,113 Relevant to current discussions, these subdivisions display overlapping distributions of MC4-R mRNA and axon terminals containing α-MSH or AgRP. First, a population of MC4-R-positive PVH neurons may relay inputs from leptin-responsive α-MSH neurons in the Arc to autonomic preganglionic neurons, supporting the implication of melanocortins and MC4-Rs in autonomic regulation.35,79,80
Secondly, Lu and colleagues provided evidence that melanocortins regulate the hypothalamic–pituitary–adrenal axis via MC4-R-positive PVH neurons.114 The authors demonstrated a subset of PVH cells that coexpresses MC4-R and corticotropin-releasing hormone (CRH) mRNAs. Centrally administered MT-II (a melanocortin receptor agonist) rapidly induced CRH gene transcription, and MT-II-induced increase in plasma corticosterone levels was suppressed by a selective MC4-R antagonist HS014.
Thirdly, evidence supporting the role of leptin and melanocortin action on the thyroid axis is also increasing. For example, the PVH contains a number of cells coexpressing pro-thyrotropin-releasing hormone (proTRH) and MC4-R mRNAs.115 Transcriptional control of the TRH gene is regulated by leptin and melanocortin signaling.115 An electron-microscopic study demonstrated α-MSH-positive terminals that synapse on TRH-producing PVH neurons.116 Recently, the effect of AgRP on the thyroid axis was examined in wild-type (WT) and MC4-R-deficient mice.117 As a result, centrally administered AgRP suppressed circulating levels of thyroxine and inhibited proTRH mRNA expression in the PVH of WT mice, whereas these effects were not observed in mice lacking MC4-Rs.
Taken together, once again, these observations suggest that subsets of PVH neurons expressing MC4-Rs may mediate leptin action to control the autonomic and neuroendocrine systems responsible for maintaining energy equilibrium.
2. Lateral hypothalamic area (LHA): Alpha-MSH-positive and AgRP-positive fibers densely terminate in LHA, especially in the perifornical region (Figures 2b, d and 3d, f).71,72 Notably, subsets of these neurons providing these inputs are leptin-responsive.66 As noted, the LHA has long been considered to play an essential role in regulating food intake. Recently, two orexigenic peptides produced by discrete populations of LHA neurons in rodents and humans refocused attention on the LHA: melanin-concentrating hormone (MCH)118,119,120 and the orexins (ORX, also called hypocretins).121 One of the unique features of both sets of neurons is that they provide monosynaptic projections to a variety of CNS sites including the cerebral cortex, amygdala, and the spinal cord.118,119,120,121 Similarly, a broad distribution of the receptors that bind these peptides has also been reported.122,123,124,125
MCH stimulates feeding behavior when administered centrally.119 Levels of MCH mRNA are increased during fasting when leptin levels rapidly fall. Importantly, mice lacking MCH are hypophagic and lean despite lowered levels of POMC mRNA and leptin,120 whereas mice overexpressing MCH are obese and hyperleptinemic.126 More importantly, mice lacking both MCH and Ob-Rbs display a significant reduction in fat mass, compared with ob/ob mice.127 Taken together, it is persuasive that MCH signaling is downstream of leptin.
ORX knockout mice exhibit deficits in sleep/wake control and a narcolepsy-like phenotype.128 Dogs lacking the ORX-2 receptor are also narcoleptic.129 Notably, a very high percentage of narcoleptic patients are ORX-deficient.130,131 Like MCH, ORX exerts a stimulatory effect on food intake, although the effect on consolidating sleep/wake states is more profound and clearly established.121,128,129,130,131,132 Therefore, it is conceivable that ORX may maintain arousal and locomotor activity, both of which are essential for food-seeking behavior following periods of fasting.133 Finally, as noted, the distribution of MCH- and ORX-positive terminals is widespread not only in subcortical regions but also in cortical regions.118,119,120,121,133 This unique hypothalamo-cortical innervation pattern implicates both peptides in regulating complex cognitive function. This concept is worth noting when attempting to link sites regulating body weight homeostasis and those involved in several psychiatric disorders. Clearly, feeding represents a fundamental goal-oriented behavior.
Based on the aforementioned neuroanatomic data,71,72 one might expect that MCH and/or ORX neurons coexpress MC4-Rs. However, the levels of MC4-R mRNA expression in the rodent LHA are relatively low, and only a few MC4-R-positive cells are scattered in the perifornical region.79,80 In addition, an electrophysiological study reported no detectable effect of synthetic MC4-R/MC3-R ligands on membrane potentials or firing rate in MCH cells.134 On the other hand, a presynaptic action of α-MSH on PVH-projecting GABAergic neurons has been demonstrated electrophysiologically.135 Thus, whether endogenous melanocortins act presynaptically on MC4-Rs expressed on axon terminals that synapse on MCH and/or ORX neurons deserves future analysis.
3. Central nucleus of the amygdala (CeA): The amygdala has received relatively little attention in the field of obesity research; however, this limbic site is potentially important in regulating food intake. For example, amygdala lesions produce hyperphagia and obesity in rodents.136 Bilateral microinjections of a selective MC4-R antagonist HS014 into the CeA increase food intake.137 Within the CeA (Figure 1b), a subnucleus of the amygdala, α-MSH- or AgRP-positive axons are accumulated preferentially in the medial region107 in which MC4-R-positive cells populate.35,79,80 Thus, although relatively understudied, the CeA represents a potentially important site of melanocortin action.
4. Intermediolateral nucleus of the spinal cord (IML): Subsets of Arc POMC neurons project to the IML in which sympathetic preganglionic cholinergic neurons113 and cells expressing MC4-R mRNA reside.79 These MC4-R-positive cells are sympathetic preganglionic neurons, as they coexpress choline acetyltransferase mRNA.79 Notably, a population of Arc POMC neurons projecting to the IML is leptin-responsive.65 Additionally, cholinergic cells in the dorsal motor nucleus of the vagus (ie, parasympathetic preganglionic neurons) also express MC4-R mRNA.79 These findings support a critical role of MC4-Rs in autonomic regulation, as did the expression of MC4-R mRNA in the PVH. Put another way, this model predicts that both the direct Arc-IML and indirect Arc-PVH-IML pathways likely contribute to the autonomic and metabolic effects of melanocortin receptor agonists.138,139,140,141
Combinations of genetic and anatomic approaches to characterize leptin–melanocortin signaling CNS circuits
1. Deletion of leptin receptors specifically from POMC neurons: As stressed above, a large body of evidence indicates that POMC neurons in the Arc mediate leptin action. However, Ob-Rbs are not localized exclusively in the Arc. As noted, leptin-independent melanocortinergic pathways also exist.103,104,105 Therefore, our laboratory has recently tested the extent to which Arc POMC neurons contribute to CNS leptin signaling by using the Cre/loxP system.103 First, transgenic mice expressing Cre in POMC neurons (POMC-Cre mice) were generated by using a POMC bacterial artificial chromosome. Subsequently, POMC-Cre mice were crossed with mice bearing the lox-modified leptin receptor allele (POMC-Cre, Leprflox/flox mice). This cross successfully deleted leptin receptors specifically from POMC neurons, resulting in increased fat mass, hyperleptinemia, and altered hypothalamic peptide levels. However, the loss of leptin receptors on POMC neurons did not significantly affect food intake and energy expenditure.
These observations indicate that Ob-Rb expression by POMC neurons is required for normal body weight homeostasis and that leptin action on neurons other than POMC neurons contributes to the varied effects of this hormone. Deletion of leptin receptors in other brain sites (alone and in combination with POMC deletion) may help to unravel this complex web of circuitries. This attempt will include the use of other transgenic mice expressing Cre in selected neuronal populations, as well as of stereotaxic injections of an adenoassociated viral vector that drive the Cre expression.142 Clearly, these combined approaches will continue to evolve strategies to survey the physiologically important CNS circuitries mediating the effects of key metabolic signals including leptin, glucose, and ghrelin.
2. Labeling of MC4-R-positive cells with GFP: The melanocortinergic CNS network has hitherto been difficult to trace, as sensitive and specific antibodies against the MC4-R protein are unavailable. Therefore, it remains unknown whether α-MSH- and/or AgRP-positive terminals synapse on MC4-R-positive cell bodies, dendrites, or axon terminals. The brain sites downstream of neurons expressing MC4-Rs are also to be determined. Moreover, relevant research is behind in identifying chemical profiles of MC4-R-positive neurons (ie, potential neurotransmitters by which melanocortinergic pathways are engaged), with only a few notable exceptions such as TRH-producing or CRH-producing PVH cells,114,115 and cholinergic autonomic preganglionic cells in the DMV and IML.79,80
To help address these issues, we recently validated a transgenic mouse line expressing GFP under the control of the MC4-R promoter, which had been generated by Friedman and coworkers.80 For this purpose, we confirmed that the brain distribution patterns of GFP-immunoreactive cells are reconciled with those of cells expressing MC4-R mRNA in WT mice (Figure 6), that MC4-R mRNA is expressed on nearly all the GFP-immunoreactive cells, and that MT-II, a synthetic MC3-R/MC4-R agonist, depolarizes GFP-positive cells. This animal model will facilitate the demonstration of melanocortinergic axon terminals that make synaptic contacts with MC4-R-positive cells using electron microscopy. Moreover, the projection patterns of MC4-R-positive neurons can be determined by using retrograde tract tracing, an established neuroanatomic technique that is based on the ability of axon terminals to take up substances (eg, cholera toxin B subunit and fluorogold) from extracellular space and transport them back to cell bodies. This mouse model will also promote the identification of the chemical phenotypes of cells expressing MC4-Rs. In this model, for example, we identified oxytocin-positive, GABAergic, and CRH-positive GFP cells, respectively, in the PVH, LHA, and in the CeA by using a combination of immunohistochemistry for GFP and in situ hybridization histochemistry.80 Consistent with the electrophysiological evidence introduced earlier,134 no GFP cells coexpressed MCH mRNA in the LHA. ORX cells were also MC4-R-negative.
Clearly, this approach is useful for identifying the MC4-R system in the CNS. A larger point is that the use of several similar mouse models will drive the field of ‘molecular neuroanatomy’. Moreover, these tools provide more invaluable information concerning a multitude of neuropeptide and neurotransmitter systems that have so far been difficult to study due to the inherent lack of specific and sensitive regents.
The MC3-R underlying diverse melanocortin effects on energy homeostasis
Another melanocortin receptor subtype, the MC3-R coupled to Gs/Gq, is also expressed in the brain and plays a role in regulating metabolism, albeit much less studied.33,34,143 Notably, another POMC-derived peptide γ-MSH binds to MC3-Rs with a high affinity, and AgRP antagonizes γ-MSH action on MC3-Rs.33,143 The brain distribution of MC3-Rs also significantly differs from that of MC4-Rs. The rat PVH, for example, expresses MC4-R mRNA but apparently not MC3-R mRNA.33,79 Conversely, the ventromedial nucleus of the hypothalamus (VMH) is one of the sites that express high levels of MC3-R mRNA, whereas MC4-R-positive VMH cells are relatively few.33,79 Another noticeable difference is that POMC and AgRP neurons in the Arc express MC3-Rs but not MC4-Rs, suggesting a potential role of MC3-Rs in regulating the melanocortinergic local circuits within the Arc.107 Although MC3-R-deficient mice are not hyperphagic, they do display an increased fat mass.144,145 Clearly, more studies are needed to identify the MC3-R-positive sites responsible for energy balance regulation. Nevertheless, these observations indicate the existence of anatomically and functionally divergent melanocortinergic CNS pathways.
The NPY/Y1-receptor system: another feeding regulator counterpoised to the melanocortin system
NPY is an established potent stimulator of food intake.146,147,148 NPY also affects endocrine/autonomic responses, seizures, and anxiety.146,147,148 NPY neurons are distributed in many CNS sites, including the Arc.149,150 Importantly, NPY-producing Arc neurons coexpress AgRP and are inhibited by leptin.66,68,69,97,98 Of NPY receptor subtypes, the Y1-, (Y1-R), Y2-, and Y5-receptors have been implicated in the regulation of feeding.146,147,148,151,152,153,154,155 NPY neurons in the Arc may contribute to ORX's effects on food intake, as ORX neurons innervate this NPY neuronal population and stimulate it.156 Presently, we will focus on the Y1-R, as accumulating evidence suggests that this Y-receptor subtype contributes to NPY action not only on consummatory behavior but also on emotional responses.
Here, it should also be noted that several genetic studies do not generally support a role of NPY/Y1-R system in food intake. For example, NPY−/− and Y1-R−/− mice are not hypophagic,157,158,159,160 although this may be dependent on the background strain of the mouse studied. Nevertheless, other lines of evidence indicate that such discrepancies do not diminish the potential therapeutic efficacy of NPYergic agents. When ob/ob mice are crossed with NPY−/− mice, the obesity phenotype is partially corrected.161 Moreover, Y1-R−/− mice display a markedly blunted feeding response to fasting.159 Finally, the stomach-derived hormone, ghrelin, increases food intake and can directly act on Arc NPY neurons,6,7,26,162,163,164 supporting an important role of Arc NPY/AgRP neurons in feeding regulation. Ghrelin is the endogenous ligand for the growth hormone secretagogue receptor.6,7,26,162,163,164 Ghrelin administration not only increases food intake but also causes hypothermia and decreased oxygen consumption. Deletion of ghrelin also affects metabolic responses to high-fat diet feeding in mice.165
Like MC4-R mRNA, Y1-R mRNA is expressed in several brain sites critical for energy balance regulation in rodents, including the PVH and CeA.166,167,168 Moreover, by using the MC4-R/GFP mice line, we identified MC4-R-positive cells coexpressing Y1-R mRNA in these forebrain sites that receive both NPY and melanocortinergic inputs.80,107,149,150 Consequently, relevant to current discussions,15,23 we hypothesize that the convergence of leptin/melanocortin and NPY signaling pathways likely contributes to their counterpoised relationship in energy balance regulation (Figure 4).
The intersection of body weight homeostasis, classic neurotransmitters, and psychiatry
Ideally, when discussing body weight homeostasis, one could distinguish ‘appetite’ from other metabolic processes such as the regulation of energy storage and expenditure, insulin secretion, and gastrointestinal mobility. However, this is inherently difficult as various homeostatic control systems are intrinsically linked and interconnected. Nonetheless, in this section, we will discuss the melanocortin and NPY systems once again from this point of view, and classic neurotransmitters, as well on which many of psychotropic agents exert their influence. We will also discuss a link between feeding and emotion, and relevant several psychiatric issues.
The brain reward mechanism is a key to trace the neural mechanism of appetite. The reader is referred to reviews by Saper et al,20 and by Figlewicz and Woods169 that outline the hedonic aspect of feeding.
The dopaminergic projection to the nucleus accumbens (Acb) from the ventral tegmental area (VTA) is clearly important in reward processes.170 The VTA–Acb pathway has also been implicated in motivating and rewarding aspects of food intake, for example, by electrochemically monitoring dopamine transmission in the Acb of rats lever-pressing to feed.171 Here, it is interesting to note that high levels of MC3-R mRNA are expressed in the VTA, where γ-MSH-positive axon terminals are distributed.33,107 As opioid receptor antagonists block the feeding-stimulatory effect of AgRP, the melanocortin system may regulate appetite.172 Thus, whether dopaminergic VTA neurons projecting to the Acb coexpress MC3-Rs is worth exploring.
Cancer-induced cachexia (ie, anorexia and weight loss) is another example that implicates the melanocortin system in the control of appetite. Notably, in anorectic tumor-bearing rats, food intake can be markedly increased by treatment with a synthetic MC4-R antagonist SHU9119.173 MC4-R−/− mice and mice treated with AgRP also resist tumor-induced weight loss.174
It has also been speculated that melanocortins may counteract addiction. Chronic morphine administration reduces levels of MC4-R mRNA in the olfactory tubercle, striatum, Acb, and the periaqueductal gray (PAG) in the rat.12,13,14 Interestingly, the μ-opioid receptor (μ-R) is enriched in these sites.175 Melanocortins can antagonize the addictive properties of opiates and can provoke signs analogous to those by opiate withdrawal in drug-naive animals.13,176 In addition, β-endorphin, like α-MSH and γ-MSH, is cleaved from POMC,13,70,177 suggesting that the endogenous opioid peptide and melanocortins may be coreleased.13,77 Moreover, mice lacking β-endorphin display a deficit in the ability of food reward to increase bar-pressing behavior.178 As hypothesized by Alvaro et al,13 melanocortin and opioid signaling may converge on neurons coexpressing the MC4-R and μ-R, in which functional antagonism could occur intracellularly at the second messenger level. Interestingly, the PAG receives melanocortin inputs and expresses MC4-R mRNA and μ-R mRNAs.77,79,80,107,175 In addition, the PAG is more deeply implicated in morphine dependence than is the VTA.179 Collectively, it is attractive to speculate that melanocortinergic agents may be effective in treating addiction.
Alcohol can also be regarded as a reward. Evidence suggests that the NPY/Y1-R system regulates ethanol consumption and resistance. NPY-deficient mice consume significantly more ethanol than do WT mice, and are less sensitive to the sedative effect.180 In contrast, transgenic overexpression of the NPY gene in neurons results in a lower preference for ethanol in mice.180 Moreover, Y1-R−/− mice exhibit significantly increased voluntary consumption of ethanol solutions, compared to WT control mice.181 Evidence that implicates the dopaminergic reward system in alcoholism is also growing.182 Clearly, however, more studies are required to better understand the relation between the NPY/Y1-R and reward systems, and that between these systems and alcoholism. Nonetheless, it has been demonstrated that the Acb receives NPY inputs149,150 and expresses Y1-R mRNA in rodents.166,167,168 Additionally, Y1-R mRNA is faintly expressed in the mouse VTA but not at all in the rat VTA.166,167,168
Historically, serotonin 5-hydroxytryptamine (5-HT) remains one of the amines most intensively studied in psychopharmacology.183 Currently, serotonin-selective reuptake inhibitors (SSRIs) are widely used for the treatment of depression and bulimia nervosa. Melanocortins including α-MSH also influence several classes of emotion and motivated behavior.70 In addition, the significance of MC4-Rs in regulating emotion has been re-evaluated pharmacologically. When administered centrally, for example, a MC4-R-selective antagonist HS014 attenuates anorexia induced by restraint stress.184 A novel MC4-R-selective antagonist MCL0020 also prevents stress-induced behavioral changes in rodents.185
As noted above, the melanocortin system is involved in regulating the hypothalamo–pituitary–adrenal (HPA) axis.114 The dysregulation of this axis is likely associated with mood disorders including depression, although it remains unclear whether deficits in the HPA axis cause depression or are secondary to it.186,187 In either case, excessive activation of the HPA axis is common in patients with depressive mood and is corrected by treatment with antidepressants.186 Interestingly, an electrophysiological study demonstrated that MT-II, a synthetic agonist for MC3-R/MC4-R, increased the firing rate of 5-HTergic dorsal raphe (DR) neurons that may play a role in regulating emotion and behavior.188 Consistent with this finding, the DR contains cells expressing MC4-R mRNA in rodents.35,79,80 Collectively, PVH and DR neurons expressing MC4-Rs may be involved in the pathophysiology of anxiety and mood disorders.
Serotonergic drugs significantly reduce appetite, whereas 5-TH2cR-deficient mice are hyperphagic and obese.189 Notably, the Arc receives inputs from 5-HT-positive raphe nucleus neurons.190 Recently, Heisler et al191 reported that a subset of Arc POMC cells coexpressed 5-TH2c receptors (5-HT2cRs) and was activated by anorectic doses of d-fenfluramine (d-Fen), a drug that blocks the reuptake of 5-HT and stimulates its release. In the mid-1990s, d-Fen was prescribed to millions of patients suffering from morbid obesity in the United States, frequently in combination with phentermine.192 This treatment regimen proved to be very effective in decreasing food intake and body weight. However, after reports of adverse cardiopulmonary events, the Food and Drug Administration withdrew d-Fen from clinical use in 1997.193 Nevertheless, the existence of 5-HT-responsive POMC cells strongly suggests that the central melanocortin system contributes to the anorectic effects of 5-HT. It is also interesting to speculate based on the observation that auto-antibodies are raised against α-MSH and adrenocorticotropic hormone in patients with anorexia and bulimia nervosa.9 Taken together, it is conceivable that 5-HT action on Arc melanocortinergic neurons may contribute to the pathophysiology of morbid ingestive behavior. The Arc provides reciprocal innervation to the DR nucleus,194,195 supporting an interaction between these two brain sites. In mood disorders, however, the relationship between 5-HT and prevalent anorexia is paradoxical. Serotonergic agents apparently suppress appetite, whereas 5-HT levels in anorectic depressed patients are presumably low. Many of the commonly used antidepressants inhibit the uptake of serotonin. As serotonergic innervation is widespread across the brain, 5-HT neural circuits underlying feeding and emotion have been inherently difficult to discern. However, the serotonergic pathway to the Arc from raphe nuclei merits further investigation.
Antipsychotic agents, especially ‘atypical’ antipsychotics, often produce obesity and diabetes mellitus, and infrequently diabetic ketoacidosis or coma.2,3,4 On one hand, there is a possibility that antipsychotics directly influence peripheral organs per se, including pancreatic β-cells, liver, adipose tissue, and skeletal muscle, resulting in impaired glucose tolerance.196,197 On the other hand, antipsychotics may affect CNS systems regulating glucose metabolism. The 5-HT/5-HT2cR system is one of the candidates, as several antipsychotic agents bind to 5-HT2cRs with high affinities.198 As noted, a population of Arc α-MSH neurons expresses 5-HT2cRs and is leptin-responsive. In addition, the MC4-R likely regulates pancreatic β-cell function, as MC4-R−/− mice exhibit hyperglycemia and impaired insulin tolerance before the onset of obesity.138 The MC4-R is also involved in sensitizing peripheral tissue to insulin action.139,140,141 Centrally administered α-MSH markedly enhances insulin action on glucose uptake as well as on hepatic glucose production, whereas MC4-R antagonism exerts opposite effects.139 Finally, patients with MC4-R mutations are very insulin-resistant.84 Collectively, these findings suggest that dysregulation of the 5-HT-driven melanocortin system may be involved in obesity and diabetes as adverse effects of antipsychotic agents.
Additionally, the use of antipsychotics often produces hyperleptinemia.2,3,4 It is unknown, though, whether this condition is due to the use of antipsychotics itself or obesity resulting from it. Nonetheless, rapid increases in leptin levels may be a marker to predict long-term weight gain in patients on medication with clozapine.199
Acetylcholine has also been indicated to influence MCH signaling; for example, a cholinergic agonist carbachol increases MCH mRNA expression in hypothalamic slices.200 MCH is, as stressed, an established regulator of energy balance118,119,120,126,127 and is produced at the LHA that receives leptin and melanocortinergic signals.66,71,72 Notably, a subset of MCH neurons coexpresses the M3 muscarinic acetylcholine receptor (M3Ach-R), and M3Ach-R−/− mice are hypophagic despite extremely low levels of serum leptin.201 MCH accelerates feeding in M3Ach-R−/− mice when administered centrally, whereas an AgRP analogue does not. This study indicates that M3Ach-R-mediated acetylcholine signaling at a site downstream of the leptin/melanocortin system and upstream of the MCH system is critical in facilitating food intake.201 Anticholinergic agents are occasionally used to alleviate extrapyramidal adverse effects by neuroleptics. It is significant to examine if and how anticholinergic medication in psychiatric practice influences body weight homeostasis.
The ascending cholinergic projections to the lateral hypothalamus originate in the laterodorsal tegmental and pedunculopontine tegmental nuclei in the brainstem.200,202 These nuclei are responsible for regulating sleep and wakefulness, especially for rapid-eye-movement (REM) sleep.132 Thus, it is plausible that subsets of MCH neurons may integrate sleep and metabolic cues into coordinated behavioral responses.
Cognitive function, regulated by cortical circuits, should also be mentioned to discuss feeding, a class of goal-oriented behavior. The hippocampus is noteworthy in this respect, as this limbic structure is thought to integrate neocortical information, resulting in coordinated emotional and behavioral responses to external stimuli.203 The efferent pathways from the hippocampus are glutamatergic.203 Importantly, the medial and perifornical hypothalamic regions receive dense hippocampal inputs204 and are enriched with ionotropic glutamate receptors.205 A recent electrophysiological study demonstrated that glutamate release excited MCH cells, in which a viral approach was used to label MCH cells with GFP expression.134 In contrast, NPY was found to be inhibitory by pre- and postsynaptic mechanisms in this study.
NPY-positive fibers densely terminate in the perifornical area of the lateral hypothalamus (PFA), many of which originate in the Arc.71,72 Whereas levels of Y1-R mRNA expression are relatively low in the PFA, the subiculum (a major output source of the hippocampus203,204) expresses high levels of Y1-R mRNA in rodents.166,167,168 The expression of Y1-R mRNA in the hippocampus has also been demonstrated in humans.206 Collectively, these findings imply that multi-modal cortical information may influence the activity of MCH neurons via the hippocampus–hypothalamus pathway to regulate ingestive behavior. In addition, Arc-derived NPY may act presynaptically on Y1-Rs expressed on hippocampal axon terminals that synapse on a subset of MCH neurons, in order to modulate the cortical information by mediating peripheral metabolic cues. Consistent with this hypothesis, Y1-R-immunoreactive axons are densely distributed in the lateral hypothalamus.167
When administered centrally, an antisense oligodeoxynucleotide for the Y1-R produces behavioral signs of anxiety measured with plus maze testing.207 Transgenic overexpression of NPY in the rat markedly attenuated behavioral sensitivity to restraint stress and decreased NPY-Y1-R binding in the hippocampus.208 Thus, Y1-R-mediated hippocampal NPY signaling may be involved in anxiety and related disorders.
As mentioned earlier, the hypothalamus innervates a wide extent of cortical areas via neurons producing MCH or ORX.118,121,133 Thus, metabolic, emotional, and cognitive information may be assimilated at the hypothalamus, and in turn forwarded to the neocortex, resulting in the ultimate decision to eat or not to eat. An interrelation between cortical glutamatergic and ascending dopaminergic systems has also been discussed to re-evaluate the classic dopamine hypothesis of schizophrenia,209 which may also be relevant to the CNS mechanisms of feeding as a motivated behavior. Needless to say, GABA is also important not only in cortico-subcortical circuits but also in subcortical circuits.24 It is notable that GABA plays a role in regulating key hypothalamic circuits, as illustrated by Cowley et al,69 and van den Pol et al.134 Clearly, neuropeptides have received much attention in the field of obesity research. However, the regulation of hypothalamic synaptic activity critical for coordinated food intake and body weight likely relies on the action of amino-acid transmitters including glutamate and GABA.
Conclusion and perspectives
A series of classic lesion studies established that certain hypothalamic cell groups regulate food intake and body weight. The discovery of leptin in 1994 catalyzed a remarkable increase in understanding of hypothalamic mechanisms of energy homeostasis regulation.5 Since then, an enormous amount of work traced the CNS machinery downstream of leptin signaling, including the central melanocortin and NPY systems. These systems are critical to explore the mechanism of the disequilibrium between energy intake and expenditure by mental disorders and/or by psychotropic agents. In addition to a variety of molecules involved in feeding regulation, neuromedin U (NMU) has recently been established as a novel anorexigenic hypothalamic peptide independent of leptin signaling.210 Like the MC4-R and Y1-R, a subtype of NMU receptors is expressed in the rat hypothalamus.211,212 If and how NMU affects CNS systems regulating emotion and behavior remain open to future analysis. Moreover, there are undoubtedly other molecules that will be discovered and may serve as links between obesity and psychiatry research.
Apparently, focusing on such functionally and anatomically defined brain systems should promote a new line of psychiatric research. These types of studies have long been very difficult to undertake despite a large body of evidence that several CNS neurotransmitter systems mediate psychotropic action. This was due in large part to the lack of CNS molecules that define respective psychiatric disorders, and therefore the target brain sites have been unspecified. Nevertheless, food intake and body weight are psychiatric parameters that are readily quantified, and thus, relevant genetically modified animals are useful in psychiatry research. Moreover, as discussed, several CNS systems responsible for energy balance are also involved in regulating emotion and several classes of behavior. We believe that the use of multidisciplinary molecular and neuroanatomic techniques illustrated in this article will elucidate the brain circuits underlying energy homeostasis and emotion, and will contribute to establishing new therapeutic strategies for psychiatric illnesses.
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This work was supported by the National Institute of Health; Grant number DK56116; Grant number DK53301; Grant number MH61583; Grant number DK 567658; Grant number 2 R01 DK041096-14A1, as well as by the Yamada Science Foundation and Kato Memorial Bioscience Foundation.
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Kishi, T., Elmquist, J. Body weight is regulated by the brain: a link between feeding and emotion. Mol Psychiatry 10, 132–146 (2005). https://doi.org/10.1038/sj.mp.4001638
- energy homeostasis
- neuropeptide Y
- amino-acid transmitters
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