Integrated control of appetite and fat metabolism by the leptin-proopiomelanocortin pathway

Abstract

Leptin deficiency results in a complex obesity phenotype comprising both hyperphagia and lowered metabolism. The hyperphagia results, at least in part, from the absence of induction by leptin of melanocyte stimulating hormone (MSH) secretion in the hypothalamus; the MSH normally then binds to melanocortin-4 receptor expressing neurons and inhibits food intake. The basis for the reduced metabolic rate has been unknown. Here we show that leptin administered to leptin-deficient (ob͞ob) mice results in a large increase in peripheral MSH levels; further, peripheral administration of an MSH analogue results in a reversal of their abnormally low metabolic rate, in an acceleration of weight loss during a fast, in partial restoration of thermoregulation in a cold challenge, and in inducing serum free fatty acid levels. These results support an important peripheral role for MSH in the integration of metabolism with appetite in response to perceived fat stores indicated by leptin levels.R ecent research has outlined a pathway for control of body weight (1-4): leptin, the product of the ob gene in mouse, is produced by adipocytes (5). It circulates to the hypothalamus where it binds to cells expressing the leptin receptor, the product of the db gene in mouse (6-9). Proopiomelanocortin (POMC) neurons are among the hypothalamic neurons expressing the leptin receptor (10). This leptin binding leads to the secretion of melanocyte stimulating hormone (MSH), which in turn binds to neurons expressing the melanocortin-4 receptor (MC4-R) (11); these neurons then suppress appetite (12)(13)(14). This outline is based on the phenotypes of spontaneous and induced mouse mutants (5,9,13,(15)(16)(17)(18)(19) as well as on the phenotype of homologous mutations in humans (20-24). These interpretations are in agreement that leptin is the signal from the fat stores (adipocytes) to the center, and further that MSH regulates appetite. However, there are significant aspects of the mutant phenotypes that suggest both a greater complexity of body weight homeostasis, specifically the integration of appetite and metabolism, and a factor from the central nervous system (CNS) to the periphery mediating this integration.First, pomc͞pomc mutants that completely lack POMC peptides, including MSH, show a phenotype of altered lipid metabolism in addition to hyperphagia. As the fat content of the diet increases, the mice gain weight out of proportion to their food intake (17). This shows a particular inability to use dietary fat for sustaining metabolic rate. And when these pomc͞pomc mutants are treated by peripheral administration of an ␣-MSH analog the mice lose weight and eat less, but the weight loss is much greater than the decrease in appetite (17). Again, this result is consistent with a role for MSH in mobilizing peripheral fat stores.Second, leptin-deficient mice (ob͞ob) show decreased metabolic rate (increased metabolic efficiency; ref. 25), which precedes the onset of obesity. Notably these mutants show: (i) weight gain when pair-fed with normal c...

Gene-gun particle with pro-opiomelanocortin cDNA produces analgesia against formalin-induced pain in rats

“…10 Although metabolic changes were not studied here, it is well known that POMC plays an important role in adjusting lipid metabolism because MSH produced in the CNS diffuses to the periphery and alters lipid metabolism thus encouraging its catabolism. 11 A variety of viral vectors, including adenovirus and vaccinia virus, as well as physical methods such as liposomes and the gene gun, have been used for DNA delivery during vaccine development. Finegold et al 12 delivered ␤-endorphin cDNA into the spinal space using an adenoviral vector, and successfully transfected cells on the pia mater to secrete ␤-endorphin, hence setting a paradigm for paracrine therapy for chronic pain.…”

Central blockade of melanocortin receptors attenuates the metabolic and locomotor responses to peripheral interleukin-1β administration

“…These two neuropeptides are expressed in separate neuronal populations within the arcuate nucleus and both cell types express MC3R, suggesting either auto-regulation and/or cross talk between these two neuronal populations (Bagnol et al, 1999). One of the more intensely studied aspects of melanocortin biology is their involvement in the regulation of both food intake and energy metabolism (Forbes et al, 2001); α-MSH inhibits food intake (Ludwig et al, 1998), while AgRP is a potent stimulator of food intake (Rossi et al, 1998). With regard to receptors, MC3R knockout mice demonstrate increased adiposity and enhanced feed efficiency (Chen et al, 2000), while MC4R knockout mice are hyperphagic and obese (Huszar et al, 1997).…”

AgRP(83–132) and SHU9119 differently affect activity-based anorexia

“…In contrast, AgRP neurons in the ARC are stimulated by fasting and inhibited by leptin treatment (Mizuno and Mobbs, 1999). Activation of the MC system by central injections of the endogenous agonist Amelanocyte-stimulating hormone (A-MSH) results in hypophagia, increased energy expenditure and activation of the HPA axis (Forbes et al, 2001;Haynes et al, 1999;Vergoni and Bertolini, 2000;Von Frijtag et al, 1998). Central injections of the synthetic competitive antagonist SHU9119 antagonize these effects (Adage et al, 2001;Fan et al, 1997).…”