Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 109, Issue 23, Pages E1489-E1498Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1201994109
Keywords
energy homeostasis; nonesterified fatty acid; corticotrophin-releasing hormone; hormone-sensitive lipase
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Funding
- National Institutes of Health [DK078850]
- VA Medical Research Service and National Institutes of Health [R01 AR44659]
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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.
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