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1.  HOMEOSTASTIC AND NON-HOMEOSTATIC FUNCTIONS OF MELANOCORTIN-3 RECEPTORS IN THE CONTROL OF ENERGY BALANCE AND METABOLISM 
Physiology & behavior  2011;104(4):546-554.
The central nervous melanocortin system is a neural network linking nutrient-sensing systems with hypothalamic, limbic and hindbrain neurons regulating behavior and metabolic homeostasis. Primary melanocortin neurons releasing melanocortin receptor ligands residing in the hypothalamic arcuate nucleus are regulated by nutrient-sensing and metabolic signals. A smaller group of primary neurons releasing melanocortin agonists in the nucleus tractus solitarius in the brainstem are also regulated by signals of metabolic state. Two melanocortin receptors regulate energy homeostasis. Melanocortin-4 receptors regulate satiety and autonomic outputs controlling peripheral metabolism. The functions of melanocortin-3 receptors (MC3R) expressed in hypothalamic and limbic structures are less clear. Here we discuss published data and preliminary observations from our laboratory suggesting that neural MC3R regulate inputs into systems governing the synchronization of rhythms in behavioral and metabolism with nutrient intake. Mice subjected to a restricted feeding protocol, where a limited number of calories are presented at a 24 h interval, rapidly exhibit bouts of increased wakefulness and activity which anticipate food presentation. The full expression of these responses is dependent on MC3R. Moreover, MC3R knockout mice are unique in exhibiting a dissociation of weight loss from improved glucose homeostasis when subject to a restricted feeding protocol. While mice lacking MC3R fed ad libitum exhibit normal to moderate hyperinsulinemia, when subjected to a restricted protocol they develop hyperglycemia, glucose intolerance, and dyslipidemia. Collectively, our data suggest that the central nervous melanocortin system is a point convergence in the control of energy balance and the expression of rhythms anticipating nutrient intake.
The paper represents an invited review by a symposium, award winner or keynote speaker at the Society for the Study of Ingestive Behavior [SSIB] Annual Meeting in Pittsburg, July 2010.
doi:10.1016/j.physbeh.2011.04.007
PMCID: PMC3139773  PMID: 21497617
Circadian rhythm; anticipation; food anticipatory activity; satiety; homeostasis; clock; melanocortin; hypothalamus
2.  Hormonal regulation of the hypothalamic melanocortin system 
Regulation of energy homeostasis is fundamental for life. In animal species and humans, the Central Nervous System (CNS) plays a critical role in such regulation by integrating peripheral signals and modulating behavior and the activity of peripheral organs. A precise interplay between CNS and peripheral signals is necessary for the regulation of food intake and energy expenditure in the maintenance of energy balance. Within the CNS, the hypothalamus is a critical center for monitoring, processing and responding to peripheral signals, including hormones such as ghrelin, leptin, and insulin. Once in the brain, peripheral signals regulate neuronal systems involved in the modulation of energy homeostasis. The main hypothalamic neuronal circuit in the regulation of energy metabolism is the melanocortin system. This review will give a summary of the most recent discoveries on the hormonal regulation of the hypothalamic melanocortin system in the control of energy homeostasis.
doi:10.3389/fphys.2014.00480
PMCID: PMC4260486  PMID: 25538630
hypothalamic melanocortin system; arcuate nucleus; pro-opiomelanocortin (POMC); neuropeptide Y (NPY); agouti-related peptide (AgRP); hormones; obesity
3.  Modulation of the central melanocortin system by leptin, insulin, and serotonin: co-ordinated actions in a dispersed neuronal network 
Over the past century, prevalent models of energy and glucose homeostasis have been developed from a better understanding of the neural circuits underlying obesity and diabetes. From the early hypothalamic lesion reports to the more recent pharmacological and molecular/genetic studies, the hypothalamic melanocortin system has been shown to play a critical role in the regulation of metabolism. This review attempts to highlight contributions to our current understanding of how numerous neuromodulators (leptin, insulin, and serotonin) integrate with the central melanocortin system to coordinate alterations in energy and glucose balance.
doi:10.1016/j.ejphar.2010.11.042
PMCID: PMC3085544  PMID: 21211525
leptin; insulin; serotonin; obesity; diabetes; patch-clamp
4.  Central melanocortin receptors regulate insulin action 
Journal of Clinical Investigation  2001;108(7):1079-1085.
Energy balance and insulin action are tightly coregulated. Leptin regulates energy intake and expenditure partly by modulation of the melanocortin pathway in the hypothalamus. Here we demonstrate potent effects of the melanocortin pathway on insulin action and body distribution of adiposity. Conscious rats received week-long infusions of either a melanocortin receptor agonist, α-melanocyte-stimulating hormone (α-MSH), or antagonist, SHU9119, in the third cerebral ventricle while food intake was maintained constant in each group. α-MSH decreased intra-abdominal fat and markedly enhanced the actions of insulin on both glucose uptake and production, while SHU9119 exerted opposite effects. Our findings elucidate a neuroendocrine network that is likely to play a central role in the coupling of energy intake and insulin action.
PMCID: PMC200952  PMID: 11581309
5.  Development of an Assay for High-Throughput Energy Expenditure Monitoring in the Zebrafish 
Zebrafish  2013;10(3):343-352.
Abstract
Energy homeostasis is maintained by balancing energy intake and expenditure. Many signals regulating energy intake are conserved between the human and teleost. However, before this work, there was no sensitive high-throughput system to monitor energy expenditure in the teleost. We exploit the nonfluorescent and fluorescent properties of resazurin and its reduced form resorufin (alamarBlue®) to monitor energy expenditure responses to drug application and genetic manipulation. We show that leptin, insulin, and alpha-melanocyte-stimulating hormone (α-MSH) increase energy expenditure dose dependently in the larval zebrafish. As previously established in the mouse, etomoxir, a carnitine palmitoyl transferase I inhibitor, blocks leptin-induced energy expenditure in the zebrafish. Metformin, the most commonly prescribed insulin sensitizer, increases the insulin-induced metabolic rate. Using genetic knockdown, we observed that α-MSH treatment increases the metabolic rate, as does knockdown of the melanocortin antagonist, agouti-related protein. The agouti-related protein and multiple melanocortin receptors are shown to be involved in these effects. These studies confirm that aspects of hormonal regulation of energy expenditure are conserved in the teleost, and suggest that this assay may provide a unique tool to perform in vivo screens for drugs or genes that affect the metabolic rate, including insulin or leptin sensitizers.
doi:10.1089/zeb.2012.0841
PMCID: PMC3806375  PMID: 23705823
6.  Functional Heterogeneity of Arcuate Nucleus Pro-Opiomelanocortin Neurons: Implications for Diverging Melanocortin Pathways 
Molecular neurobiology  2012;45(2):225-233.
Arcuate nucleus (ARC) pro-opiomelanocortin (POMC) neurons are essential regulators of food intake, energy expenditure, and glucose homeostasis. POMC neurons integrate several key metabolic signals that include neurotransmitters and hormones. The change in activity of POMC neurons is relayed to melanocortin receptors in distinct regions of the central nervous system. This review will summarize the role of leptin and serotonin receptors in regulating the activity of POMC neurons and provide a model in which different melanocortin pathways regulate energy and glucose homeostasis.
doi:10.1007/s12035-012-8240-6
PMCID: PMC3755591  PMID: 22328135
Melanocortin; Leptin; Serotonin; Segregation; Insulin; Energy expenditure; Body weight; Adiposity; Hyperglycemia; TRPC; PI3K
7.  Neural melanocortin receptors in obesity and related metabolic disorders 
Biochimica et biophysica acta  2013;1842(3):482-494.
Obesity is a global health issue, as it is associated with increased risk of developing chronic conditions associated with disorders of metabolism such as type 2 diabetes and cardiovascular disease. A better understanding of how excessive fat accumulation develops and causes diseases of the metabolic syndrome is urgently needed. The hypothalamic melanocortin system is an important point of convergence connecting signals of metabolic status with the neural circuitry that governs appetite and the autonomic and neuroendocrine system controling metabolism. This system has a critical role in the defense of body weight and maintenance of homeostasis. Two neural melanocortin receptors, melanocortin 3 and 4 receptors (MC3R and MC4R), play crucial roles in the regulation of energy balance. Mutations in the MC4R gene are the most common cause of monogenic obesity in humans, and a large literature indicates a role in regulating both energy intake through the control of satiety and energy expenditure. In contrast, MC3Rs have a more subtle role in energy homeostasis. Results from our lab indicate an important role for MC3Rs in synchronizing rhythms in foraging behavior with caloric cues and maintaining metabolic homeostasis during periods of nutrient scarcity. However, while deletion of the Mc3r gene in mice alters nutrient partitioning to favor accumulation of fat mass no obvious role for MC3R haploinsufficiency in human obesity has been reported.
doi:10.1016/j.bbadis.2013.05.004
PMCID: PMC3819409  PMID: 23680515
Melanocortin receptors; Nervous system; Metabolic homeostasis; Genetic models; Humans
8.  AMPK is essential for energy homeostasis regulation and glucose sensing by POMC and AgRP neurons 
Journal of Clinical Investigation  2007;117(8):2325-2336.
Hypothalamic AMP-activated protein kinase (AMPK) has been suggested to act as a key sensing mechanism, responding to hormones and nutrients in the regulation of energy homeostasis. However, the precise neuronal populations and cellular mechanisms involved are unclear. The effects of long-term manipulation of hypothalamic AMPK on energy balance are also unknown. To directly address such issues, we generated POMCα2KO and AgRPα2KO mice lacking AMPKα2 in proopiomelanocortin– (POMC-) and agouti-related protein–expressing (AgRP-expressing) neurons, key regulators of energy homeostasis. POMCα2KO mice developed obesity due to reduced energy expenditure and dysregulated food intake but remained sensitive to leptin. In contrast, AgRPα2KO mice developed an age-dependent lean phenotype with increased sensitivity to a melanocortin agonist. Electrophysiological studies in AMPKα2-deficient POMC or AgRP neurons revealed normal leptin or insulin action but absent responses to alterations in extracellular glucose levels, showing that glucose-sensing signaling mechanisms in these neurons are distinct from those pathways utilized by leptin or insulin. Taken together with the divergent phenotypes of POMCα2KO and AgRPα2KO mice, our findings suggest that while AMPK plays a key role in hypothalamic function, it does not act as a general sensor and integrator of energy homeostasis in the mediobasal hypothalamus.
doi:10.1172/JCI31516
PMCID: PMC1934578  PMID: 17671657
9.  60 YEARS OF POMC 
Journal of molecular endocrinology  2016;56(4):T157-T174.
The melanocortin peptides derived from pro-opiomelanocortin (POMC) were originally understood in terms of the biological actions of α-melanocyte-stimulating hormone (α-MSH) on pigmentation and adrenocorticotrophic hormone on adrenocortical glucocorticoid production. However, the discovery of POMC mRNA and melanocortin peptides in the CNS generated activities directed at understanding the direct biological actions of melanocortins in the brain. Ultimately, discovery of unique melanocortin receptors expressed in the CNS, the melanocortin-3 (MC3R) and melanocortin-4 (MC4R) receptors, led to the development of pharmacological tools and genetic models leading to the demonstration that the central melanocortin system plays a critical role in the regulation of energy homeostasis. Indeed, mutations in MC4R are now known to be the most common cause of early onset syndromic obesity, accounting for 2–5% of all cases. This review discusses the history of these discoveries, as well as the latest work attempting to understand the molecular and cellular basis of regulation of feeding and energy homeostasis by the predominant melanocortin peptide in the CNS, α-MSH.
doi:10.1530/JME-16-0014
PMCID: PMC5027135  PMID: 26939593
α-MSH; POMC; melanocortin; MC4R; food intake
10.  The melanocortin system and insulin resistance in humans: insights from a patient with complete POMC deficiency and type 1 diabetes mellitus 
The central melanocortin system is essential for the regulation of long-term energy homeostasis in humans. Rodent experiments suggest that this system also affects glucose metabolism, in particular by modulating peripheral insulin sensitivity independently of its effect on adiposity. Rare patients with complete genetic defects in the central melanocortin system can provide insight into the role of this system in glucose homeostasis in humans.
We here describe the eighth individual with complete POMC deficiency and the first with coincidental concomitant Type I Diabetes, which provides a unique opportunity to determine the role of melanocortins in glucose homeostasis in human. Direct sequencing of the POMC gene in this severely obese patient with isolated ACTH deficiency identified a homozygous 5′ UTR mutation −11C>A which we find to abolish normal POMC protein synthesis, as assessed in vitro. The patient’s insulin requirements were as expected for his age and pubertal developmental. This unique patient suggests that in humans, the central melanocortin system does not seem to affect peripheral insulin sensitivity, independently of its effect on adiposity.
doi:10.1038/ijo.2013.53
PMCID: PMC4648369  PMID: 23649472
POMC mutation; obesity; type 1 diabetes mellitus; melanocortin system and insulin resistance
11.  α-Melanocyte stimulating hormone promotes muscle glucose uptake via melanocortin 5 receptors 
Molecular Metabolism  2016;5(10):807-822.
Objective
Central melanocortin pathways are well-established regulators of energy balance. However, scant data exist about the role of systemic melanocortin peptides. We set out to determine if peripheral α-melanocyte stimulating hormone (α-MSH) plays a role in glucose homeostasis and tested the hypothesis that the pituitary is able to sense a physiological increase in circulating glucose and responds by secreting α-MSH.
Methods
We established glucose-stimulated α-MSH secretion using humans, non-human primates, and mouse models. Continuous α-MSH infusions were performed during glucose tolerance tests and hyperinsulinemic-euglycemic clamps to evaluate the systemic effect of α-MSH in glucose regulation. Complementary ex vivo and in vitro techniques were employed to delineate the direct action of α-MSH via the melanocortin 5 receptor (MC5R)–PKA axis in skeletal muscles. Combined treatment of non-selective/selective phosphodiesterase inhibitor and α-MSH was adopted to restore glucose tolerance in obese mice.
Results
Here we demonstrate that pituitary secretion of α-MSH is increased by glucose. Peripheral α-MSH increases temperature in skeletal muscles, acts directly on soleus and gastrocnemius muscles to significantly increase glucose uptake, and enhances whole-body glucose clearance via the activation of muscle MC5R and protein kinase A. These actions are absent in obese mice, accompanied by a blunting of α-MSH-induced cAMP levels in skeletal muscles of obese mice. Both selective and non-selective phosphodiesterase inhibition restores α-MSH induced skeletal muscle glucose uptake and improves glucose disposal in obese mice.
Conclusion
These data describe a novel endocrine circuit that modulates glucose homeostasis by pituitary α-MSH, which increases muscle glucose uptake and thermogenesis through the activation of a MC5R-PKA-pathway, which is disrupted in obesity.
Graphical abstract
Highlights
•Glucose stimulates α-MSH release from the pituitary.•Systemic α-MSH drives glucose disposal and thermogenesis in skeletal muscles.•α-MSH acts on MC5R expressed on skeletal muscles and activate cAMP-PKA pathway.•The combined treatment of nonselective or selective PDE 4 inhibitor and α-MSH ameliorates glucose intolerance in obese mice.
doi:10.1016/j.molmet.2016.07.009
PMCID: PMC5034615  PMID: 27688995
α-MSH; Pituitary; Skeletal muscles; MC5R; PKA; Glucose homeostasis
12.  Unacylated Ghrelin Suppresses Ghrelin-Induced Neuronal Activity in the Hypothalamus and Brainstem of Male Rats 
PLoS ONE  2014;9(5):e98180.
Ghrelin, the endogenous growth hormone secretagogue, has an important role in metabolic homeostasis. It exists in two major molecular forms: acylated (AG) and unacylated (UAG). Many studies suggest different roles for these two forms of ghrelin in energy balance regulation. In the present study, we compared the effects of acute intracerebroventricular administration of AG, UAG and their combination (AG+UAG) to young adult Wistar rats on food intake and central melanocortin system modulation. Although UAG did not affect food intake it significantly increased the number of c-Fos positive neurons in the arcuate (ARC), paraventricular (PVN) and solitary tract (NTS) nuclei. In contrast, UAG suppressed AG-induced neuronal activity in PVN and NTS. Central UAG also modulated hypothalamic expression of Mc4r and Bmp8b, which were increased and Mc3r, Pomc, Agrp and Ucp2, which were decreased. Finally, UAG, AG and combination treatments caused activation of c-Fos in POMC expressing neurons in the arcuate, substantiating a physiologic effect of these peptides on the central melanocortin system. Together, these results demonstrate that UAG can act directly to increase neuronal activity in the hypothalamus and is able to counteract AG-induced neuronal activity in the PVN and NTS. UAG also modulates expression of members of the melanocortin signaling system in the hypothalamus. In the absence of an effect on energy intake, these findings indicate that UAG could affect energy homeostasis by modulation of the central melanocortin system.
doi:10.1371/journal.pone.0098180
PMCID: PMC4031147  PMID: 24852945
13.  The role of the central melanocortin system in the regulation of food intake and energy homeostasis: lessons from mouse models 
A little more than a decade ago, the molecular basis of the lipostat was largely unknown. At that time, many laboratories were at work attempting to clone the genes encoding the obesity, diabetes, fatty, tubby and agouti loci, with the hope that identification of these obesity genes would help shed light on the process of energy homeostasis, appetite and energy expenditure. Characterization of obesity and diabetes elucidated the nature of the adipostatic hormone leptin and its receptor, respectively, while cloning of the agouti gene eventually led to the identification and characterization of one of the key neural systems upon which leptin acts to regulate intake and expenditure. In this review, we describe the neural circuitry known as the central melanocortin system and discuss the current understanding of its role in feeding and other processes involved in energy homeostasis.
doi:10.1098/rstb.2006.1861
PMCID: PMC1642695  PMID: 16815803
melanocortin; leptin; MC4-R; agouti
14.  Melanocortin-4-receptors Expressed by Cholinergic Neurons Regulate Energy Balance and Glucose Homeostasis 
Cell metabolism  2011;13(2):195-204.
Summary
Melanocortin-4-receptor (MC4R) mutations cause dysregulation of energy balance and hyperinsulinemia. We have used mouse models to study the physiological roles of extrahypothalamic MC4Rs. Re-expression of MC4Rs in cholinergic neurons (ChAT-Cre, loxTB MC4R mice) modestly reduced body weight gain without altering food intake and was sufficient to normalize energy expenditure and attenuate hyperglycemia and hyperinsulinemia. In contrast, restoration of MC4R expression in brainstem neurons including those in the dorsal motor nucleus of the vagus (Phox2b-Cre, loxTB MC4R mice) was sufficient to attenuate hyperinsulinemia, while the hyperglycemia and energy balance were not normalized. Additionally, hepatic insulin action and insulin mediated-suppression of hepatic glucose production were improved in ChAT-Cre, loxTB MC4R mice. These findings suggest that MC4Rs expressed by cholinergic neurons regulate energy expenditure and hepatic glucose production. Our results also provide further evidence of the dissociation in pathways mediating the effects of melanocortins on energy balance and glucose homeostasis.
doi:10.1016/j.cmet.2011.01.010
PMCID: PMC3033043  PMID: 21284986
15.  Neuronal control of energy homeostasis 
FEBS letters  2007;582(1):132-141.
Neuronal control of body energy homeostasis is the key mechanism by which animals and humans regulate their long-term energy balance. Various hypothalamic neuronal circuits (which include the hypothalamic melanocortin, midbrain dopamine reward and caudal brainstem autonomic feeding systems) control energy intake and expenditure to maintain body weight within a narrow range for long periods of a life span. Numerous peripheral metabolic hormones and nutrients target these structures providing feedback signals that modify the default “settings” of neuronal activity to accomplish this balance. A number of molecular genetic tools for manipulating individual components of brain energy homeostatic machineries, in combination with anatomical, electrophysiological, pharmacological and behavioral techniques, have been developed, which provide a means for elucidating the complex molecular and cellular mechanisms of feeding behavior and metabolism. This review will highlight some of these advancements and focus on the neuronal circuitries of energy homeostasis.
doi:10.1016/j.febslet.2007.11.063
PMCID: PMC4113225  PMID: 18061579
Leptin; Ghrelin; Arcuate nucleus; NPY; POMC; GABA; glutamate
16.  Neuropeptide Y and gamma-melanocyte stimulating hormone (γ-MSH) share a common pressor mechanism of action 
Endocrine  2009;35(3):312-324.
Central circuits known to regulate food intake and energy expenditure also affect central cardiovascular regulation. For example, both the melanocortin and neuropeptide Y (NPY) peptide families, known to regulate food intake, also produce central hypertensive effects. Members of both families share a similar C-terminal amino acid residue sequence, RF(Y) amide, a sequence distinct from that required for melanocortin receptor binding. A recently delineated family of RFamide receptors recognizes both of these C-terminal motifs. We now present evidence that an antagonist with Y1 and RFamide receptor activity, BIBO3304, will attenuate the central cardiovascular effects of both gamma-melanocyte stimulating hormone (γ-MSH) and NPY. The use of synthetic melanocortin and NPY peptide analogs excluded an interaction with melanocortin or Y family receptors. We suggest that the anatomical convergence of NPY and melanocortin neurons on cardiovascular control centers may have pathophysiological implications through a common or similar RFamide receptor(s), much as they converge on other nuclei to coordinately control energy homeostasis.
doi:10.1007/s12020-008-9141-3
PMCID: PMC2714906  PMID: 19363600
γ-MSH; Neuropeptide Y; Hypertensive effects; Central nervous system; RFamide peptides; RFamide receptors; Y1 antagonists; Central vasopressin system
17.  PTP1B and SHP2 in POMC neurons reciprocally regulate energy balance in mice 
Protein tyrosine phosphatase 1B (PTP1B) and SH2 domain–containing protein tyrosine phosphatase–2 (SHP2) have been shown in mice to regulate metabolism via the central nervous system, but the specific neurons mediating these effects are unknown. Here, we have shown that proopiomelanocortin (POMC) neuron–specific deficiency in PTP1B or SHP2 in mice results in reciprocal effects on weight gain, adiposity, and energy balance induced by high-fat diet. Mice with POMC neuron–specific deletion of the gene encoding PTP1B (referred to herein as POMC-Ptp1b–/– mice) had reduced adiposity, improved leptin sensitivity, and increased energy expenditure compared with wild-type mice, whereas mice with POMC neuron–specific deletion of the gene encoding SHP2 (referred to herein as POMC-Shp2–/– mice) had elevated adiposity, decreased leptin sensitivity, and reduced energy expenditure. POMC-Ptp1b–/– mice showed substantially improved glucose homeostasis on a high-fat diet, and hyperinsulinemic-euglycemic clamp studies revealed that insulin sensitivity in these mice was improved on a standard chow diet in the absence of any weight difference. In contrast, POMC-Shp2–/– mice displayed impaired glucose tolerance only secondary to their increased weight gain. Interestingly, hypothalamic Pomc mRNA and α–melanocyte-stimulating hormone (αMSH) peptide levels were markedly reduced in POMC-Shp2–/– mice. These studies implicate PTP1B and SHP2 as important components of POMC neuron regulation of energy balance and point to what we believe to be a novel role for SHP2 in the normal function of the melanocortin system.
doi:10.1172/JCI39620
PMCID: PMC2827947  PMID: 20160350
18.  Leveraging melanocortin pathways to treat glomerular diseases 
The melanocortin system is a neuroimmunoendocrine hormone system that constitutes the fulcrum in the homeostatic control of a diverse array of physiological functions, including melanogenesis, inflammation, immunomodulation, adrenocortical steroidogenesis, hemodynamics, natriuresis, energy homeostasis, sexual function and exocrine secretion. The kidney is a quintessential effector organ of the melanocortin hormone system with melanocortin receptors abundantly expressed by multiple renal paranchymal cells, including podocytes, mesangial cells, glomerular endothelial cells and renal tubular cells. Converging evidence unequivocally demonstrates that the melanocortin based therapy by using the melanocortin peptide adrenocorticotropic hormone (ACTH) is prominently effective in inducing remission of steroid resistant nephrotic syndrome caused by a variety of glomerular diseases, including membranous nephropathy and podocytopathies such as minimal change disease and focal segmental glomerulosclerosis, suggesting a steroidogenic independent melanocortin mechanism. Mechanistically, ACTH and other melanocortin peptides as well as synthetic melanocortin analogues possess potent proteinuria reducing and renoprotective effects that could be attributable to both direct protection of glomerular cells and systemic immunomodulation. Thus, leveraging melanocortin signaling pathways by using either the existing U.S. Food and Drug Administration approved melanocorin peptide ACTH or novel synthetic melanocortin analogues represents a promising and pragmatic therapeutic strategy for glomerular diseases. This review article introduces the biophysiology of melanocortin hormone system with emphasis on the kidney as the target organ, discusses the existing clinical and experimental data on melanocortin treatments for glomerular diseases, elucidates the potential mechanisms of action, and describes the potential side effects of melanocortin based therapy.
doi:10.1053/j.ackd.2013.09.004
PMCID: PMC3950821  PMID: 24602463
glomerulopathy; nephrotic syndrome; melanocortin; adrenocorticotropic hormone; podocyte; proteinuria; inflammation; immunomodulation
19.  Feeding Induced by Cannabinoids Is Mediated Independently of the Melanocortin System 
PLoS ONE  2008;3(5):e2202.
Background
Cannabinoids, the active components of marijuana, stimulate appetite, and cannabinoid receptor-1 (CB1-R) antagonists suppress appetite and promote weight loss. Little is known about how CB1-R antagonists affect the central neurocircuitry, specifically the melanocortin system that regulates energy balance.
Methodology/Principal Findings
Here, we show that peripherally administered CB1-R antagonist (AM251) or agonist equally suppressed or stimulated feeding respectively in Ay , which lack a functional melanocortin system, and wildtype mice, demonstrating that cannabinoid effects on feeding do not require melanocortin circuitry. CB1-R antagonist or agonist administered into the ventral tegmental area (VTA) equally suppressed or stimulated feeding respectively, in both genotypes. In addition, peripheral and central cannabinoid administration similarly induced c-Fos activation in brain sites suggesting mediation via motivational dopaminergic circuitry. Amperometry-detected increases in evoked dopamine (DA) release by the CB1-R antagonist in nucleus accumbens slices indicates that AM251 modulates DA release from VTA terminals.
Conclusions/Significance
Our results demonstrate that the effects of cannabinoids on energy balance are independent of hypothalamic melanocortin circuitry and is primarily driven by the reward system.
doi:10.1371/journal.pone.0002202
PMCID: PMC2386290  PMID: 18493584
20.  The Role of PVH Circuits in Leptin Action and Energy Balance 
Annual review of physiology  2016;78:207-221.
Summary
While it has been clear that the brain regulates feeding behaviour and energy expenditure, the major determinants of energy balance and adiposity, roles for individual brain regions (and specific cell types within these regions) in the control of energy balance were not understood until very recently; these details continue to emerge rapidly. Much of what we now know flows from the discoveries of leptin and the hypothalamic melanocortin system, which define circuits crucial for the control of energy balance. Within the brain, hypothalamic circuits play a crucial role in the control of feeding and energy expenditure. Within the hypothalamus, the arcuate nucleus (ARC) functions as an entry point gateway for hormonal signals of energy balance, such as leptin; the ARC also contains the soma of melanocortinergic neurons. The paraventricular hypothalamic nucleus (PVH) receives direct melanocortin input, along with other integrated signals regarding energy balance, and mediates the majority of hypothalamic output to control feeding and energy expenditure. Herein, we review the structure and function of the ARC-PVH circuit in leptin action, in addition to it’s role in the control of feeding behavior and energy expenditure.
doi:10.1146/annurev-physiol-021115-105347
PMCID: PMC5087283  PMID: 26863324
Leptin; melanocortins; PVH; hypothalamus; brainstem; neuropeptides; NOS1; feeding; obesity
21.  The melanocortin system and energy balance 
Peptides  2006;27(2):281-290.
The melanocortins, a family of peptides produced from the post-translational processing of pro-opiomelanocortin (POMC), regulate ingestive behavior and energy expenditure. Loss of function mutations of genes encoding POMC, or of either of two melanocortin receptors expressed in the central nervous system (MC3R, MC4R), are associated with obesity. The analyses of MC4R knockout mice indicate that activation of this receptor is involved in the regulation of appetite, the adaptive metabolic response to excess caloric consumption, and negative energy balance associated with cachexia induced by cytokines. In contrast, MC3R knockout mice exhibit a normal, or even exaggerated, response to signals that induce a state of negative energy balance. However, loss of the MC3R also results in an increase in adiposity. This article discusses the regulation of energy balance by the melanocortins. Published and newly presented data from studies analyzing of energy balance of MC3R and MC4R knockout mice indicate that increased adiposity observed in both models involves an imbalance in fat intake and oxidation.
doi:10.1016/j.peptides.2005.02.029
PMCID: PMC2735083  PMID: 16434123
Melanocortin; Energy balance; MC3R
22.  GABAergic signaling by AgRP neurons prevents anorexia via a melanocortin-independent mechanism 
European journal of pharmacology  2011;660(1):21-27.
The hypothalamic arcuate nucleus contains two anatomically and functionally distinct populations of neurons – the agouti-related peptide (AgRP)- and pro-opiomelanocortin (POMC)-expressing neurons that integrate various nutritional, hormonal, and neuronal signals to regulate food intake and energy expenditure, and thereby help achieve energy homeostasis. AgRP neurons, also co-release neuropeptide Y and γ-aminobutyric acid (GABA) to promote feeding and inhibit metabolism through at least three possible mechanisms: (1) suppression of the melanocortin signaling system through competitive binding of AgRP with the melanocortin 4 receptors; (2) neuropeptide Y-mediated inhibition of post-synaptic neurons that reside in hypothalamic nuclei; (3) GABAergic inhibition of POMC neurons in their post-synaptic targets including the parabrachial nucleus (parabrachial nucleus), a brainstem structure that relays gustatory and visceral sensory information. Acute ablation of AgRP neurons in adult mice by the action of diphtheria toxin (DT) results in precipitous reduction of food intake, and eventually leads to starvation within 6 days of DT treatment. Chronic delivery of bretazenil, a GABAA receptor partial agonist, into the parabrachial nucleus is sufficient to restore feeding and body weight when AgRP neurons are ablated, whereas chronic blockade of melanocortin 4 receptor signaling is inadequate. This review summarizes the physiological roles of a neural circuitry regulated by AgRP neurons in control of feeding behavior with particular emphasis of the GABA output to the parabrachial nucleus. We also describe a compensatory mechanism that is gradually engaged after ablation of AgRP neurons that allows mice to continue eating without them.
doi:10.1016/j.ejphar.2010.10.110
PMCID: PMC3108334  PMID: 21211531
Agouti-related protein; Anorexia; Benzodiazepine; Feeding behavior; Fos; Synaptic plasticity
23.  α-MSH Stimulates Glucose Uptake in Mouse Muscle and Phosphorylates Rab-GTPase-Activating Protein TBC1D1 Independently of AMPK 
PLoS ONE  2016;11(7):e0157027.
The melanocortin system includes five G-protein coupled receptors (family A) defined as MC1R-MC5R, which are stimulated by endogenous agonists derived from proopiomelanocortin (POMC). The melanocortin system has been intensely studied for its central actions in body weight and energy expenditure regulation, which are mainly mediated by MC4R. The pituitary gland is the source of various POMC-derived hormones released to the circulation, which raises the possibility that there may be actions of the melanocortins on peripheral energy homeostasis. In this study, we examined the molecular signaling pathway involved in α-MSH-stimulated glucose uptake in differentiated L6 myotubes and mouse muscle explants. In order to examine the involvement of AMPK, we investigate α-MSH stimulation in both wild type and AMPK deficient mice. We found that α-MSH significantly induces phosphorylation of TBC1 domain (TBC1D) family member 1 (S237 and T596), which is independent of upstream PKA and AMPK. We find no evidence to support that α-MSH-stimulated glucose uptake involves TBC1D4 phosphorylation (T642 and S704) or GLUT4 translocation.
doi:10.1371/journal.pone.0157027
PMCID: PMC4965092  PMID: 27467141
24.  Central Nervous System Imprinting of the G Protein Gsα and Its Role in Metabolic Regulation 
Cell metabolism  2009;9(6):548-555.
Summary
Albright hereditary osteodystrophy is a monogenic obesity disorder due to heterozygous mutations of Gsα, the G protein which mediates receptor-stimulated cAMP generation, in which obesity only develops when the mutation is on the maternal allele. Likewise, mice with maternal (but not paternal) germline Gsα mutation develop obesity, insulin resistance, and diabetes. These parent-of-origin effects are due to Gsα imprinting with preferential expression from the maternal allele in some tissues. As Gsα is ubiquitously expressed, the tissue involved in this metabolic imprinting effect is unknown. Using brain-specific Gsα knockout mice we show that Gsα imprinting within the central nervous system underlies these effects and that Gsα is imprinted in the paraventricular nucleus of the hypothalamus. Maternal Gsα mutation impaired melanocortin stimulation of energy expenditure but did not affect melanocortin's effect on food intake, suggesting that melanocortins may regulate energy balance in the central nervous system through both Gsα-dependent and -independent pathways.
doi:10.1016/j.cmet.2009.05.004
PMCID: PMC2698878  PMID: 19490909
25.  Neuroanatomy of melanocortin-4 receptor pathway in the lateral hypothalamic area 
The Journal of comparative neurology  2012;520(18):4168-4183.
The central melanocortin system regulates body energy homeostasis including the melanocortin-4 receptor (MC4R). The lateral hypothalamic area (LHA) receives dense melanocortinergic inputs from the arcuate nucleus of hypothalamus and regulates multiple processes including food intake, reward behaviors and autonomic function. Using a mouse line in which green fluorescent protein (GFP) is expressed under control of MC4R gene promoter, we systemically investigated MC4R signaling in the LHA by combining double immunohistochemistry, electrophysiology and retrograde tracing techniques. We found that LHA MC4R-GFP neurons co-express neurotensin as well as the leptin receptor but not with other peptide neurotransmitters found in the LHA including orexin, melanin concentrating hormone and nesfatin-1. Furthermore, electrophysiological recording demonstrated that leptin, but not the MC4R agonist melanotan II, hyperpolarizes the majority of LHA MC4R-GFP neurons in an ATP-sensitive potassium channel-dependent manner. Retrograde tracing revealed that LHA MC4R-GFP neurons do not project to the ventral tegmental area, dorsal raphe nucleus, nucleus accumbens and spinal cord, and only limited number of neurons project to the nucleus of solitary tract and parabrachial nucleus. Our findings provide new insight into MC4R signaling in the LHA and its potential implication in homeostatic regulation of body energy balance.
doi:10.1002/cne.23145
PMCID: PMC3652326  PMID: 22605619
Leptin receptor; neurotensin; electrophyiosology; orexin; melanin concentrating hormone; nesfatin

Results 1-25 (1315450)