Hypothalamic Pro-Opiomelanocortin mRNA Is Reduced By Fasting in ob/ob and db/db Mice, but Is Stimulated by Leptin

Reduction in the activity of the a-melanocyte-stimulating hormone (a-MSH) system causes obesity, and infusions of a-MSH can produce satiety, raising the possibility that a-MSH may mediate physiological satiety signals. Since a-MSH is coded for by the pro-opiomelanocortin (POMC) gene, we examined if POMC gene expression would be inhibited by fasting in normal mice or in models of obesity characterized by leptin insufficiency (ob/ob} or leptin insensitivity (dfe/db). In wild-type mice, hypothalamic POMC mRNA was decreased >60% after a 2-day fast and was positively correlated with leptin mRNA. Similarly, compared with controls, POMC mRNA was decreased by at least 60% in both db/db and ob/ob mice. POMC mRNA was negatively correlated with both neuropeptide Y (NPY) and melanin-concentrating hormone (MCH) mRNA. Finally, treatment of both male and female ob/ob mice with leptin stimulated hypothalamic POMC mRNA by about threefold. These results suggest that impairment in production, processing, or responsiveness to a-MSH may be a common feature of obesity and that hypothalamic POMC neurons, stimulated by leptin, may constitute a link between leptin and the melanocortin system. Diabetes 47:294-297, 1997