The melanocortin system as a central integrator of direct and indirect controls of food intake

EDITORIAL FOCUSThe melanocortin system as a central integrator of direct and indirect controls of food intakeDiana L. Williams, and Michael W. SchwartzDiana L. Williams, and Michael W. SchwartzPublished Online:01 Jul 2005https://doi.org/10.1152/ajpregu.00226.2005MoreSectionsPDF (41 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations the neural control of food intake and body weight is a complex function in which cognitive and emotional variables, as well as long-term signals of metabolic status and fuel storage, are integrated with short-term signals related to individual meals. Several years ago, Smith (20) proposed a useful classification of the myriad signals that influence the amount of food eaten during individual meals: direct controls, which arise from the interaction of ingested stimuli with receptors in the gastrointestinal tract; and indirect controls, which comprise all other controls of food intake, including signals pertaining to the status of body fat stores, such as leptin and insulin. According to this model, indirect controls affect meal size by increasing or decreasing the potency of direct controls. Early support for this concept was supplied by Woods and colleagues (7, 19), who showed that infusion of insulin into the brain increases sensitivity to the gut-derived "satiety factor" cholecystokinin (CCK), and similar interactions between CCK and other indirect controls, including leptin and estrogen, have since been documented (2, 4, 5).An important strength of this model is the framework it provides for identifying the neural circuits that detect and integrate these direct and indirect signals. It is widely accepted that excitatory gustatory and inhibitory gastrointestinal feedback, major determinants of meal size, are relayed to the brain through cranial nerve nuclei in the caudal brain stem. Taste information supplied by the facial, glossopharyngeal, and vagus nerves is first processed by the nucleus of the solitary tract (NTS) (21), and relevant visceral sensory information, such as gastric and intestinal distension or the release of CCK, is relayed to the central nervous system (CNS) through vagal afferents that synapse in the same hindbrain area (15). Indirect controls of food intake are more diverse and do not enter the brain through a single afferent route. The adipocyte-derived hormone leptin is an important example of an indirect control that communicates information regarding body energy stores to the brain. Leptin circulates at levels proportionate to body fat mass, crosses the blood-brain barrier, binds to its receptors on neurons in key brain areas for food intake control, and in so doing ultimately favors the consumption of smaller meals (8). The concept that leptin action in the forebrain reduces meal size by enhancing the hindbrain response to gastrointestinal satiety signals has recently received direct experimental support (16).The forebrain melanocortin system, including subsets of neurons that contain either pro-opiomelanocortin (POMC, the melanocortin precursor polypeptide) or agouti-related peptide (AgRP, an endogenous melanocortin receptor antagonist) in the arcuate nucleus of the hypothalamus (ARC), is strongly implicated as a central mediator of the actions of leptin and of other hormonal and nutrient-related indirect controls of food intake (1). These ARC neurons influence feeding behavior and energy expenditure through their effects on melanocortin 3 and 4 receptors (MC3/4-R) in adjacent brain regions, including the hypothalamic paraventricular nucleus and lateral hypothalamic area (3, 9). Neurons in these areas, in turn, project to the caudal brain stem where they can interact with neural circuits that process meal-related signals from the gastrointestinal tract. In addition, both POMC neurons and MC4-R are present in the NTS itself (13, 17, 18), and melanocortin signaling in this hindbrain area is clearly implicated in the control of food intake (25). Since the NTS is also supplied by projections from a subset of POMC neurons in the ARC (18, 26, 27), melanocortin signaling pertinent to the processing of direct controls of meal size can potentially originate from POMC cells in both forebrain and hindbrain.The existence of a descending ARC-NTS POMC projection was established decades ago though the use of immunohistochemical staining and radioimmunoassays for POMC cleavage products combined with lesions and transections (12, 18, 26). Because POMC is expressed in cell bodies in both the ARC and NTS, these techniques were critical for demonstrating that POMC-derived products in the hindbrain originate from cells located in both brain areas. These early studies also suggested that NTS POMC cells project exclusively within the caudal medulla, while ARC POMC cells project more widely throughout the brain. In this issue of the American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, Zheng and colleagues (27) provide new insights regarding those POMC cells that project from the ARC to the NTS and expand on earlier evidence for the relevance of hindbrain MC4-R in the control of meal size and energy expenditure (23, 24). These investigators employed the combination of retrograde tracing and immunohistochemical staining to identify a small subpopulation of ARC POMC cells that send axons to the NTS. They also show that fibers containing α-melanocyte-stimulating hormone (α-MSH, a POMC cleavage product and agonist of MC3/4-R) are found in the NTS in close proximity with neurons that are activated (as judged by c-fos staining) by gastrointestinal nutrient infusion, but whether these melanocortinergic fibers originate in the ARC or from within the NTS remains uncertain. In addition, this group performed pharmacological experiments that expand on previous evidence that hindbrain MC-R influence meal size (24), including the demonstration that injection of MTII, a MC3/4-R agonist, directly into the dorsal vagal complex (DVC) decreases meal size, whereas intra-DVC administration of SHU9119, an antagonist at these receptors, exerts the opposite effect. The effect of intra-DVC SHU9119 treatment is especially important in that it confirms a role for endogenous tonic MC3/4-R agonist activity within the NTS in the control of meal size. Taken together, these findings support a model in which a leptin-sensitive descending ARC-NTS POMC projection can interact with direct controls of meal size as they are transduced in the hindbrain.Further research is required to determine whether melanocortinergic input to NTS neurons involved in meal termination is supplied by the ARC-NTS POMC projection or from the POMC cells that reside within the NTS. While it seems likely that both populations of POMC cells provide significant stimulation to NTS MC4-R, our understanding of the role played by the hindbrain POMC neuron population in food intake control has lagged behind that of its hypothalamic counterpart, in part because of difficulties inherent in the immunohistochemical identification of these cells (due to a low abundance of POMC-derived peptides and their rapid transport out of the cell body). Mice that express green fluorescent protein exclusively in POMC cells provide a useful new tool for investigating the role of these hindbrain POMC neurons. Using such mice, Fan and colleagues (6) found that a large subset of NTS POMC cells are activated by peripheral CCK treatment, whereas no such response was observed in ARC POMC cells. In addition, they showed that hindbrain ventricular administration of SHU9119 reversed CCK-induced anorexia to a greater degree than did forebrain ventricular treatment. These data suggest a model in which NTS POMC cells and their stimulation of hindbrain MC4-R are part of a circuit that processes direct controls of meal size in the brain. Whether hindbrain POMC cells are responsive to food deprivation, leptin, insulin, or other signals of peripheral metabolic status, as are POMC cells in the ARC, remains an important unanswered question. Although leptin and insulin receptors are present in the NTS (11, 14, 22), and while intra-DVC leptin treatment effectively reduces food intake (11), additional studies are required to determine whether NTS POMC cells respond directly to these hormones and thus serve as a central mediator of indirect controls of meal size.Available evidence supports the idea that hindbrain MC4-R-bearing neurons receive input from both ARC leptin-responsive POMC cells and NTS CCK-responsive POMC cells, positioning them as true integrators of these indirect and direct controls of meal size. The role of NTS POMC cells in detecting and responding to signals of longer-term metabolic status remains to be clarified, and it is not currently possible to assign greater importance to one source of MC4-R ligand over the other in the control of meal size. 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Williams, Dept. of Medicine, Harborview Medical Center and Univ. of Washington, Seattle, WA 98104 (E-mail [email protected]) Download PDF Previous Back to Top Next FiguresReferencesRelatedInformation Cited ByThe gut signals to AGRP-expressing cells of the pituitary to control glucose homeostasis3 April 2023 | Journal of Clinical Investigation, Vol. 133, No. 7Metformin ameliorates olanzapine-induced disturbances in POMC neuron number, axonal projection, and hypothalamic leptin resistanceBMB Reports, Vol. 55, No. 6Dietary supplements and pro‐opiomelanocortin in Siniperca chuatsi —Letter to the Editor8 July 2021 | Aquaculture Research, Vol. 52, No. 11Loss of the centrosomal protein Cenpj leads to dysfunction of the hypothalamus and obesity in mice13 August 2020 | Science China Life Sciences, Vol. 64, No. 3Injections of the α-2 adrenoceptor agonist clonidine into the dorsal raphe nucleus increases food intake in satiated ratsNeuropharmacology, Vol. 182A POMC-originated circuit regulates stress-induced hypophagia, depression, and anhedonia5 September 2019 | Molecular Psychiatry, Vol. 25, No. 5Genistein improve nicotine toxicity on male mice pancreasAnatomy & Cell Biology, Vol. 52, No. 2Pharmacological Effects and Regulatory Mechanisms of Tobacco Smoking Effects on Food Intake and Weight Control27 July 2018 | Journal of Neuroimmune Pharmacology, Vol. 13, No. 4Central regulation of energy metabolism by estrogensMolecular Metabolism, Vol. 15Prolyl carboxypeptidase activity in the circulation and its correlation with body weight and adipose tissue in lean and obese subjects17 May 2018 | PLOS ONE, Vol. 13, No. 5Tobacco Smoking, Food Intake, and Weight Control3 March 2018Melanocortin 4 Receptor Activation Attenuates Mitochondrial Dysfunction in Skeletal Muscle of Diabetic Rats22 June 2017 | Journal of Cellular Biochemistry, Vol. 118, No. 115-Aminoimidazole-4-carboxamide ribonucleotide prevents fat gain following the cessation of voluntary physical activity19 September 2017 | Experimental Physiology, Vol. 102, No. 11Chick subcutaneous and abdominal adipose tissue depots respond differently in lipolytic and adipogenic activity to α-melanocyte stimulating hormone (α-MSH)Comparative Biochemistry and Physiology Part A: Molecular & Integrative Physiology, Vol. 209Brain nuclear receptors and body weight regulationJournal of Clinical Investigation, Vol. 127, No. 4Brain Estrogens and Feeding Behavior10 December 2017Evidence for the role of β2* nAChR desensitization in regulating body weight in obese miceNeuropharmacology, Vol. 110Hypothalamic Npy mRNA is correlated with increased wheel running and decreased body fat in calorie-restricted ratsNeuroscience Letters, Vol. 618Ion Channels in Obesity: Pathophysiology and Potential Therapeutic Targets30 March 2016 | Frontiers in Pharmacology, Vol. 7Reduced metabolic disease risk profile by voluntary wheel running accompanying juvenile Western diet in rats bred for high and low voluntary exercisePhysiology & Behavior, Vol. 152Circadian Dysfunction Induces Leptin Resistance in MiceCell Metabolism, Vol. 22, No. 3Progress in the molecular understanding of central regulation of body weight by estrogens10 April 2015 | Obesity, Vol. 23, No. 5Genetic and pharmacological mouse models of chronic melanocortin activation show enhanced baroreflex control of heart rateRegulatory Peptides, Vol. 182Central nervous control of energy and glucose balance: focus on the central melanocortin system23 December 2011 | Annals of the New York Academy of Sciences, Vol. 1243, No. 1Nicotine Decreases Food Intake Through Activation of POMC NeuronsScience, Vol. 332, No. 6035Appetite and Hedonism: Gut Hormones and the BrainEndocrinology and Metabolism Clinics of North America, Vol. 39, No. 4A Serotonin and Melanocortin Circuit Mediates d-Fenfluramine Anorexia3 November 2010 | The Journal of Neuroscience, Vol. 30, No. 44A β3-Adrenergic-Leptin-Melanocortin Circuit Regulates Behavioral and Metabolic Changes Induced by Chronic StressBiological Psychiatry, Vol. 67, No. 11Arcuate nucleus destruction does not block food deprivation-induced increases in food foraging and hoardingBrain Research, Vol. 1323Transcription factors in the development of medial hypothalamic structuresYoung-Hwan Jo and Streamson Chua1 September 2009 | American Journal of Physiology-Endocrinology and Metabolism, Vol. 297, No. 3Prolylcarboxypeptidase regulates food intake by inactivating α-MSH in rodents20 July 2009 | Journal of Clinical Investigation, Vol. 20Microarray gene expression profiles of fasting induced changes in liver and adipose tissues of pigs expressing the melanocortin-4 receptor D298N variantSender Lkhagvadorj, Long Qu, Weiguo Cai, Oliver P. 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