Divergence of Melanocortin Pathways in the Control of Food Intake and Energy Expenditure

Department of Medicine, Division of Endocrinology, Beth Israel Deaconess Medical Center, Harvard Medical School, 99 Brookline Avenue, Boston, Massachusetts 02215, USA.
Cell (Impact Factor: 32.24). 12/2005; 123(3):493-505. DOI: 10.1016/j.cell.2005.08.035
Source: PubMed


Activation of melanocortin-4-receptors (MC4Rs) reduces body fat stores by decreasing food intake and increasing energy expenditure. MC4Rs are expressed in multiple CNS sites, any number of which could mediate these effects. To identify the functionally relevant sites of MC4R expression, we generated a loxP-modified, null Mc4r allele (loxTB Mc4r) that can be reactivated by Cre-recombinase. Mice homozygous for the loxTB Mc4r allele do not express MC4Rs and are markedly obese. Restoration of MC4R expression in the paraventricular hypothalamus (PVH) and a subpopulation of amygdala neurons, using Sim1-Cre transgenic mice, prevented 60% of the obesity. Of note, increased food intake, typical of Mc4r null mice, was completely rescued while reduced energy expenditure was unaffected. These findings demonstrate that MC4Rs in the PVH and/or the amygdala control food intake but that MC4Rs elsewhere control energy expenditure. Disassociation of food intake and energy expenditure reveals unexpected divergence in melanocortin pathways controlling energy balance.

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Available from: Charlotte E Lee, Oct 02, 2015
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    • "The MC4R regulates both food intake and energy expenditure [3], with the effect of food intake accounting for 60% of the effect on body weight [4]. Human genetic studies provided further supporting evidence that the MC4R is important in maintaining energy homeostasis in humans. "
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    ABSTRACT: The melanocortin-4 receptor (MC4R) is a critical regulator of mammalian food intake and energy expenditure, with receptor activation resulting in decreased food intake and increased energy expenditure. Recently, studies on role of MC4R in regulation of food intake have been extended to other species, such as chicken. Functional study of mutant MC4Rs is important in proving the causal link between MC4R mutation and production traits. Herein, we cloned chicken MC4R (cMC4R) complementary DNA and generated 4 mutant cMC4Rs (Q18H, G21R, S76L, and L299P) by site-directed mutagenesis and measured their expression by flow cytometry. Pharmacologic characteristics were analyzed with binding and signaling assays using 3 agonists. We showed that G21 R had decreased cell surface and total expression (P < 0.05), whereas the other 3 mutants had similar total and cell surface expression levels as wild-type cMC4R. The 4 mutants had either decreased (Q18H, G21R, S76L; P < 0.05) or no (L299P) binding to radiolabeled [Nle4, D-Phe7]-α-melanocyte-stimulating hormone (MSH). In signaling assays, Q18H was constitutively active. Q18H, G21R, and S76L had decreased responses to α-MSH stimulation (P < 0.05). L299P had decreased basal and ligand-stimulated signaling (P < 0.01). Nle4, D-Phe7-MSH was the most potent agonist for cMC4R and therefore would be better suited for further in vivo studies. We conclude that the cloned cMC4R was a functional receptor and provided detailed functional data for these mutations, contributing to a better understanding of cMC4R variants associated with production traits.
    Domestic Animal Endocrinology 07/2015; DOI:10.1016/j.domaniend.2015.06.003 · 2.17 Impact Factor
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    • "In this context, the melanocortin system, and in particular the receptor 4 (MC4R), has been implicated in both the acute regulation of satiety and feeding behavior and in the integration of long-term appetitive signals (Seeley et al, 2004). Blockade or absence of MC4R induces hyperphagia, reduced energy expenditure and obesity (Balthasar et al, 2005; Butler and Cone, 2003). Interestingly, MC4R are expressed not only in the hypothalamus but also in the amygdala (Mountjoy et al, 1994); melanocortin signaling in the CeA can indeed regulate feeding behavior bidirectionally, with MC4R exerting a tonic inhibitory role on feeding (ie, producing anorexia) (Boghossian et al, 2010; Kask et al, 2000a). "
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    ABSTRACT: Growing evidence suggests that the pituitary adenylate cyclase-activating peptide (PACAP)/PAC1 receptor system represents one of the main regulators of the behavioral, endocrine, and autonomic responses to stress. Although induction of anorexia is a well-documented effect of PACAP, the central sites underlying this phenomenon are poorly understood. The present studies addressed this question by examining the neuroanatomical, behavioral, and pharmacological mechanisms mediating the anorexia produced by PACAP in the central nucleus of the amygdala (CeA), a limbic structure implicated in the emotional components of ingestive behavior. Male rats were microinfused with PACAP (0-1 μg/rat) into the CeA and home-cage food intake, body weight change, microstructural analysis of food intake and locomotor activity were assessed. Intra-CeA (but not intra-basolateral amygdala) PACAP dose-dependently induced anorexia and body weight loss without affecting locomotor activity. PACAP-treated rats ate smaller meals of normal duration. This revealed that PACAP slowed feeding within meals by decreasing the regularity and maintenance of feeding from pellet-to-pellet; postprandial satiety was unaffected. Intra-CeA PACAP-induced anorexia was blocked by coinfusion of either the melanocortin receptor 3/4 antagonist SHU 9119 or the tyrosine kinase B (TrKB) inhibitor k-252a, but not the CRF receptor antagonist D-Phe-CRF(12-41). These results indicate that the CeA is one of the brain areas through which the PACAP system promotes anorexia and that PACAP preferentially lessens the maintenance of feeding in rats, effects opposite to those of palatable food. We also demonstrate that PACAP in the CeA exerts its anorectic effects via local melanocortin and the TrKB systems, and independently from CRF.Neuropsychopharmacology accepted article preview online, 04 February 2015. doi:10.1038/npp.2015.34.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 02/2015; 40(8). DOI:10.1038/npp.2015.34 · 7.05 Impact Factor
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    • "Stimulation of pro-opiomelanocortin (POMC) expressing neurons in the hypothalamic arcuate nucleus results in the synthesis, cleavage and release of several bioactive peptides, including the endogenous MC4R-agonists a-MSH, b-MSH and c-MSH (Castro & Morrison, 1997). Ligand-induced activation of MC4R results in inhibition of food intake and stimulation of energy expenditure, promoting a negative energy balance (McMinn et al, 2000; Balthasar et al, 2005). These observations and the finding that a plethora of MC4R loss-of-function variants predispose to human obesity have made the MC4R an attractive target for the development of novel, anti-obesity pharmacotherapies (Huszar et al, 1997; Yeo et al, 1998; Farooqi et al, 2003). "
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    ABSTRACT: We assessed the efficacy of simultaneous agonism at the glucagon-like peptide-1 receptor (GLP-1R) and the melanocortin-4 receptor (MC4R) for the treatment of obesity and diabetes in rodents. Diet-induced obese (DIO) mice were chronically treated with either the long-acting GLP-1R agonist liraglutide, the MC4R agonist RM-493 or a combination of RM-493 and liraglutide. Co-treatment of DIO mice with RM-493 and liraglutide improves body weight loss and enhances glycemic control and cholesterol metabolism beyond what can be achieved with either mono-therapy. The superior metabolic efficacy of this combination therapy is attributed to the anorectic and glycemic actions of both drugs, along with the ability of RM-493 to increase energy expenditure. Interestingly, compared to mice treated with liraglutide alone, hypothalamic Glp-1r expression was higher in mice treated with the combination therapy after both acute and chronic treatment. Further, RM-493 enhanced hypothalamic Mc4r expression. Hence, co-dosing with MC4R and GLP-1R agonists increases expression of each receptor, indicative of minimized receptor desensitization. Together, these findings suggest potential opportunities for employing combination treatments that comprise parallel MC4R and GLP-1R agonism for the treatment of obesity and diabetes.
    EMBO Molecular Medicine 02/2015; 7(3). DOI:10.15252/emmm.201404508 · 8.67 Impact Factor
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