Complex catabolic effects of central alpha-MSH infusion in rats of altered nutritional states: differences from leptin.

The hypothalamic melanocortin (MC) system is a major catabolic regulator of energy balance: it suppresses food intake (FI), elevates metabolic rate, and reduces body weight (BW). The primary activator of the MC system [mainly via the alpha-melanocyte stimulating hormone (alpha-MSH)] is the adipocyte-derived leptin. With increasing BW, resistance develops to leptin-induced anorexia, but independent of this, in genetically modified animals, some alpha-MSH actions were maintained. We investigated the responsiveness of the MC system in its complexity (FI vs. metabolic correlates) in genetically intact male Wistar rats of different nutritional states (and different leptin sensitivities), i.e., in rats aged 2 months [normally fed (NF2)] or 6 months [calorie-restricted (CR6), fed ad libitum (NF6), and high-fat diet-induced obese (HF6) groups]. A 7-day-long, 1-μg/μl/h intracerebroventricular infusion of alpha-MSH reduced BW in all groups, particularly in NF6 and NF2 animals, and even CR6 rats lost BW upon alpha-MSH infusion (in contrast to leptin administration). Anorexia developed in NF2-NF6 and less in CR6 groups, and some FI fall was also seen in HF6 rats. The hypermetabolic effects (temperature/heart rate elevations) were most pronounced in CR6 and next in HF6 rats. These data suggest that alpha-MSH responsiveness is maintained in various forms (depending on nutritional state), despite obesity-induced leptin resistance.