Glucocorticoids and the melanocortin system: Regulation of metabolic phenotype

The incidence of obesity in the U.S. has increased dramatically in recent years to reach epidemic proportions. However, there is no effective treatment for obesity with the exception of bariatric surgery. In mice models, reduction of elevated plasma glucocorticoid level reverses the obese phenotype of leptin deficiency. Leptin deficient mice display a characteristic neuroendocrine profile including reduced melanocortin tone (characterized by reduced hypothalamic proopiomelanocortin [POMC] and increased hypothalamic agouti-related peptide [AGRP]) leading to suggestions that the reduction in melanocortin tone itself causes the development of the obese phenotype. We hypothesized that adrenalectomy reverses the metabolic phenotypes of obesity by normalizing melanocortin tone. Reduction of elevated plasma glucocorticoids by adrenalectomy improved melanocortin tone and reversed the metabolic phenotypes of leptin deficient obesity, as well as that of insulin deficient diabetes, and fasting. In addition, we demonstrated that elevated glucocorticoids are both necessary and sufficient to induce AGRP. Furthermore, we demonstrated a potential role for adiponectin, an adipose derived peptide, in mediating the improved insulin sensitivity resulting from adrenalectomy of leptin deficient mice. It was apparent from these studies that glucocorticoids profoundly affect melanocortin tone and metabolic phenotype independent of leptin. Fatty acid synthase inhibitors, cerulenin and C75, reduce food intake and body weight through a central mechanism. We hypothesized that fatty acid synthase inhibitors work through the melanocortin system similarly to adrenalectomy. However, cerulenin failed to block the neuroendocrine response to fasting. More importantly, cerulenin reduced food intake and body weight in agouti mice, which have impaired melanocortin signaling. Therefore cerulenin, unlike adrenalectomy, works either independent or down stream of the melanocortin system. Nonetheless, fatty acid synthase inhibitors may constitute a potential therapeutic option for the treatment of obesity. Finally, we demonstrated, for the first time, the reduction of an endogenous mammalian gene using a novel technique, RNA interference. Reducing AGRP levels by RNA interference resulted in increased metabolic rate and loss of body weight without any changes in food intake, demonstrating the importance of AGRP in regulating metabolic phenotype and the value of RNA interference as a tool for assessing the function of various genes in vivo.