Search

Exercise is a mechanism for maintenance of body weight in humans. Morbidly obese human patients have been shown to possess single nucleotide polymorphisms in the melanocortin-4 receptor (MCAR). MC4R knockout mice have been well characterized as genetic: model that possesses phenotypic metabolic disorders, including obesity, hyperphagia, hyperinsulinemia, and hyperleptinemia, similar to those observed in humans possessing dysfunctional hMC4Rs. Using this model, we examined the effect of voluntary exercise MC4R knockout mice that were allowed access to running wheel for a duration of 8 wk. Physiological parameters that were measured included body weight, body composition of fat and lean mass, food consumption, body length, and blood levels of cholesterol and nonfasted glucose, insulin, and leptin. At the termination of the experiment, hypothalamic mRNA expression levels of neuropeptide Y (NPY), agouti-related protein (AGRP), proopiomelanocorlin (POMC), cocaine- and amphetamine-regulated transcript (CART), orexin, brain-derived neurotropic factor (BDNF), phosphatase with tensin homology (Pten), melanocortin-3 receptor (MC3R), and NPY-Y1R were determined. In addition, islet cell distribution and function in the pancreas were examined. In the exercising MC4R knockout mice, the pancreatic islet cell morphology and other physiological parameters resembled those observed in the wild-type littermate controls. Gene expression profiles identified exercise as having a significant effect on hypothalamic POMC, orexin, and MC3R levels. Genotype had a significant effect on AGRP, POMC, CART, and NPY-Y1R, with an exercise and genotype interaction effect on NPY gene expression. These data support the hypothesis that voluntary exercise can prevent the genetic predisposition of melanocortin-4 receptor-associated obesity and diabetes. [ABSTRACT FROM AUTHOR]

The MC4R is a G-protein coupled receptor(GPCR) expressed in the brain, and has a role in regulating food intake and obesity. We have pharmacologically characterized eleven reported human MC4R polymorphisms in vitro that do not respond normally to the endogenous agonists a-MSH, b-MSH, g2-MSH, ACTH(1-24), but are expressed at the cell surface. The agonist ligand AMW3-130 possess a sub-nM stimulatory potency at these dysfunctional hMC4Rs. Central administration of a derivative of AMW3-130 into ad libium fed cannulated mice resulted in a statistically significant decrease in food intake, with no observed adverse behavior. These data are in agreement with the role of an MC4R agonist to decrease food intake. This is the first report we are aware of, identifying a ligand that can correct for functional defects of hMC4R polymorphic receptors and provides a potential lead therapeutic agent to treat children and adults with these mutations to increase their quality of life. [ABSTRACT FROM AUTHOR]