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Melanocortin-3 receptor regulates the normal fasting response.

ABSTRACT: The melanocortin-3 receptor-deficient (MC3-R(-/-)) mouse exhibits mild obesity without hyperphagia or hypometabolism. MC3-R deletion is reported to increase adiposity, reduce lean mass and white adipose tissue inflammation, and increase sensitivity to salt-induced hypertension. We show here that the MC3-R(-/-) mouse exhibits defective fasting-induced white adipose tissue lipolysis, fasting-induced liver triglyceride accumulation, fasting-induced refeeding, and fasting-induced regulation of the adipostatic and hypothalamic-adrenal-pituitary axes. Close examination of the hypothalamic-pituitary-adrenal axis showed that MC3-R(-/-) mice exhibit elevated nadir corticosterone as well as a blunted fasting-induced activation of the axis. The previously described phenotypes of this animal and the reduced bone density reported here parallel those of Cushing syndrome. Thus, MC3-R is required for communicating nutritional status to both central and peripheral tissues involved in nutrient partitioning, and this defect explains much of the metabolic phenotype in the model.

SUBMITTER: Renquist BJ

PROVIDER: S-EPMC3384161 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature

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Melanocortin-3 receptor regulates the normal fasting response.

Renquist Benjamin J BJ Murphy Jonathan G JG Larson Emily A EA Olsen Dawn D Klein Robert F RF Ellacott Kate L J KL Cone Roger D RD

Proceedings of the National Academy of Sciences of the United States of America 20120509 23

The melanocortin-3 receptor-deficient (MC3-R(-/-)) mouse exhibits mild obesity without hyperphagia or hypometabolism. MC3-R deletion is reported to increase adiposity, reduce lean mass and white adipose tissue inflammation, and increase sensitivity to salt-induced hypertension. We show here that the MC3-R(-/-) mouse exhibits defective fasting-induced white adipose tissue lipolysis, fasting-induced liver triglyceride accumulation, fasting-induced refeeding, and fasting-induced regulation of the a ...[more]

PMID: 22573815

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Project description:The melanocortin 1 receptor (MC1-R) is expressed by monocytes and macrophages, where it exerts anti-inflammatory actions on stimulation with its natural ligand ?-melanocyte-stimulating hormone. The present study was designed to investigate the specific role of MC1-R in the context of atherosclerosis and possible regulatory pathways of MC1-R beyond anti-inflammation.Human and mouse atherosclerotic samples and primary mouse macrophages were used to study the regulatory functions of MC1-R. The impact of pharmacological MC1-R activation on atherosclerosis was assessed in apolipoprotein E-deficient mice.Characterization of human and mouse atherosclerotic plaques revealed that MC1-R expression localizes in lesional macrophages and is significantly associated with the ATP-binding cassette transporters ABCA1 and ABCG1, which are responsible for initiating reverse cholesterol transport. Using bone marrow-derived macrophages, we observed that ?-melanocyte-stimulating hormone and selective MC1-R agonists similarly promoted cholesterol efflux, which is a counterregulatory mechanism against foam cell formation. Mechanistically, MC1-R activation upregulated the levels of ABCA1 and ABCG1. These effects were accompanied by a reduction in cell surface CD36 expression and in cholesterol uptake, further protecting macrophages from excessive lipid accumulation. Conversely, macrophages deficient in functional MC1-R displayed a phenotype with impaired efflux and enhanced uptake of cholesterol. Pharmacological targeting of MC1-R in atherosclerotic apolipoprotein E-deficient mice reduced plasma cholesterol levels and aortic CD36 expression and increased plaque ABCG1 expression and signs of plaque stability.Our findings identify a novel role for MC1-R in macrophage cholesterol transport. Activation of MC1-R confers protection against macrophage foam cell formation through a dual mechanism: It prevents cholesterol uptake while concomitantly promoting ABCA1- and ABCG1-mediated reverse cholesterol transport.

Project description:The existing paradigm of exercise-induced decreases in chronic inflammation focuses on the expression of inflammatory receptors on systemic monocytes in response to exercise training, with the role of anti-inflammatory receptors largely ignored. Our recent preliminary studies indicate that the anti-inflammatory melanocortin receptors (MCRs) may play a role in modulating exercise-induced decreases in chronic inflammation. Here, we present a study designed to determine the effect of intense, resistance exercise training on systemic monocyte MCR expression. Because low-grade chronic inflammation is associated with elevated cardiometabolic risk in healthy populations and exercise decreases chronic inflammation, we investigated the associations between systemic monocyte cell surface expression of MCRs and inflammatory markers as a possible mechanism for the beneficial anti-inflammatory effects of resistance training. To this end, the present study includes 40 adults (aged 19-27 yr) and implements a 12-wk periodized, intensive resistance training intervention. Melanocortin 1 and 3 receptor expression on systemic monocytes and inflammatory markers, including C-reactive protein (CRP), interleukin (IL)-6, IL-1β, and IL-10, were measured before and after the intervention. Resistance training significantly altered MCR systemic monocyte cell surface expression, had no chronic effects on IL-6, IL-1β, or IL-10 expression, but significantly decreased CRP levels from a moderate to a low cardiovascular disease risk category. More specifically, decreased melanocortin 3 receptor expression significantly correlated with decreased CRP, independent of changes in adiposity. These data suggest that the observed responses in MCR expression and decreases in cardiovascular disease risk in response to resistance training represent an important anti-inflammatory mechanism in regulating exercise-induced decreases in chronic inflammation that occur independent of chronic changes in systemic cytokines.

Dataset Information

Melanocortin-3 receptor regulates the normal fasting response.

Publications

Melanocortin-3 receptor regulates the normal fasting response.

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