The Central Melanocortin Receptors and Voluntary Exercise

摘要

The melanocortin system is made up of five G-Protein Coupled receptors (GPCRs), MC1-5R, involved in the regulation and signaling processes of a wide range of physiological functions from skin and hair pigmentation (MC1R), steroidogenesis (MC2R), energy homeostasis (MC3R and MC4R), and exocrine gland function (MC5R) [1-4]. The receptors are bound and activated by a series of endogenous agonists and inhibited by the only known endogenous antagonists of GPCRs, agouti (ASP) and agouti related protein (AGRP) [5]. The melanocortin agonists are derived from post-translational cleavage and modification of the proopiomelanocortin (POMC) gene product [6]. The melanocyte stimulating hormones (MSH), α-MSH, β-MSH, y-MSH, and adrenocorticotropin hormone (ACTH) are capable of binding and activating each of the receptors with the notable exception of the MC2R, which is only capable of being stimulated by ACTH [1]. The melanocortin-3 and -4 receptors are expressed in the brain and are postulated to play important roles in the regulation of food intake and energy homeostasis [2,3,7]. The role of the MC4R in energy homeostasis has been well established with the generation of MC4R knockout (KO) mice which have an obese phenotype [8] and the identification of a subset of the obese human population which possess genetic mutations of their MC4R [9,10]. Previous data has shown that if provided with the means to voluntarily exercise (free access to a running wheel in the home cage), melanocortin-4 knockout mice do not develop the obese phenotype seen in sedentary littermates [11,12]. Over the course of the experiment a variety of parameters were monitored including body weight, body composition (fat mass as determined by quantitative MRI), and the plasma concentrations of the adiposity factors insulin and leptin. At the conclusion of the experiment hypothalamic gene expression levels were evaluated. Herein data is presented to support the hypothesis that voluntary exercise can prevent the onset of obesity and diabetes of the MC4R knockout mice.