Transgenic Neuronal Expression of Proopiomelanocortin Attenuates Hyperphagic Response to Fasting and Reverses Metabolic Impairments in Leptin-Deficient Obese Mice

Abstract

Hypothalamic proopiomelanocortin (POMC) gene expression is reduced in many forms of obesity and diabetes, particularly in those attributable to deficiencies in leptin or its receptor. To assess the functional significance of POMC in mediating metabolic phenotypes associated with leptin deficiency, leptin-deficient mice bearing a transgene expressing the POMC gene under control of the neuron-specific enolase promoter were produced. The POMC transgene attenuated fastinginduced hyperphagia in wild-type mice. Furthermore, the POMC transgene partially reversed obesity, hyperphagia, and hypothermia and effectively normalized hyperglycemia, glucosuria, glucose intolerance, and insulin resistance in leptin-deficient mice. Effects of the POMC transgene on glucose homeostasis were independent of the partial correction of hyperphagia and obesity. Furthermore, the POMC transgene normalized the profile of hepatic and adipose gene expression associated with gluconeogenesis, glucose output, and insulin sensitivity. These results indicate that central POMC is a key modulator of glucose homeostasis and that agonists of POMC products may provide effective therapy in treating impairments in glucose homeostasis when hypothalamic POMC expression is reduced, as occurs with leptin deficiency, hypothalamic damage, and aging. Diabetes 52:2675-2683, 2003 M any forms of obesity and diabetes are associated with impairments in the production of (1-5), processing of (6,7), or sensitivity to (8,9) products of the proopiomelanocortin (Pomc) gene. In particular, ablation of leptin or its receptor causes reduced hypothalamic expression of POMC as well as obesity and impairments in glucose metabolism (1-3). Fasting also leads to reduced leptin and reduced expression of hypothalamic POMC (3). Similarly, hypothalamic POMC expression is reduced in other conditions involving impairments in glucose metabolism caused by hypothalamic lesions (10), mutations in the tubby and nhlh2 genes (11,12), aging (13), or insulin deficiency (14). The suggestion that reduced POMC may actually be a cause of the metabolic impairments comes from the observation that mutations in the Pomc gene lead to metabolic impairments in humans (4) and mice (5).It is plausible that the POMC-derived peptide ␣-melanocyte-stimulating hormone (MSH) mediates many of the effects of hypothalamic POMC on metabolic function, as central injection of ␣-MSH or an ␣-MSH agonist decreases food intake and increases energy expenditure (8,15,16), whereas central injection of a melanocortin receptor antagonist increases food intake and decreases energy expenditure (17-19). Because the blockade of ␣-MSH signaling blocks the acute effects of leptin on feeding behavior (20), ␣-MSH may mediate some of leptin's metabolic effects and therefore reduced hypothalamic POMC may mediate effects of leptin deficiency on metabolic and neuroendocrine impairments. Accumulating genetic data also support a role for the melanocortin system in the regulation of glucose metabolism. Agouti mice develop obesity, hyperphagia...

Hypothalamic pro-opiomelanocortin gene delivery ameliorates obesity and glucose intolerance in aged rats

“…Central Pomc gene therapy partially normalised glucose levels during IPGTT, and also reduced serum insulin levels markedly at all time points after glucose loading. These data are indicative of improved glucose metabolism and insulin sensitivity by Pomc gene delivery and in agreement with previous findings that central melanocortin receptor activation suppresses insulin release from the pancreas and enhances glucose metabolism [2,6,22,38,45]. Since glucose metabolism was not significantly improved on day 20 after Pomc gene delivery, when the differences in body weight reduction and visceral adiposity levels were not as large as those on day 36, it suggests that the improvement in glucose metabolism is mainly the consequence of the decreased food consumption and body weight rather than the direct result of central Pomc overexpression.…”

Lean rats with hypothalamic pro-opiomelanocortin overexpression exhibit greater diet-induced obesity and impaired central melanocortin responsiveness

“…Considering this notion, the orexigenic pathway(s) are programmed to prevent anorexia in lean animals and should readily overcome a mild anorectic stimulus such as that exerted by rAAV-Pomc treatment. Our findings are consistent with two previous reports in which transgenic overproduction of POMC-derived peptides in mice did not alter food intake in lean mice [31,32]. Despite the lack of anorexia in the present study, there is evidence that POMC affects the overall central melanocortin system.…”

Pituitary Adenylate Cyclase-Activating Polypeptide Inhibits Food Intake in Mice Through Activation of the Hypothalamic Melanocortin System

“…It has been previously reported that i.c.v. administration of the MC3-R/MC4-R antagonist MTII rapidly suppresses insulin release and elevates glycemia (Fan et al, 2000;Obici et al, 2001;Mizuno et al, 2003;Li et al, 2003Li et al, , 2005. Collectively, these data support the notion that the central effect of PACAP on glucose homeostasis may be mediated through activation of the melanocortin system and does not involve the action of glucocorticoids.…”