Age-dependence of alpha-MSH-induced anorexia

Long-term regulation of energy balance involves two major trends: first age-related obesity develops in the middle-aged, later it is followed by anorexia of aging (sarcopenia and/or cachexia). A dynamic balance between orexigenic and anorexigenic neuropeptides is essential for the regulation of energy homeostasis. Special imbalances of neuropeptide effects may be assumed corresponding to different age-periods. Anorexia induced by acute alpha-MSH (alpha-melanocyte stimulating hormone; endogenous melanocortin agonist) injections was analyzed in male Wistar rats aged 6-9 weeks (juvenile), 3-4 months (young adult), 6 or 12 months (two middle-aged groups), 18 months (aging) and 24-26 months (old). Alpha-MSH injected through a preimplanted intracerebroventricular (ICV) cannula (compared with saline injection) dose-dependently suppressed spontaneous food intake and also re-feeding following 24-h fasting, but the rate of suppression varied between age-groups. An ICV injection of 5 microg alpha-MSH attenuated the 2-h re-feeding by 21.9+/-3.2% in juvenile rats, strongly (68.7+/-2.5%) suppressed it in young adults, the suppression became progressively weaker in the two middle-aged groups (55.7+/-4.9%, vs. 26.4+/-4.9%, respectively), but it turned extreme in aging (94.7+/-4.2%) and old (74.3+/-4.5%) rats. Body composition also changed with age: unlike the tibialis anterior muscle, the epididymal and retroperitoneal fat pads increased until middle-age and remained large even in old animals, while the measured indicator of muscle mass decreased in the oldest group. The food intake suppressing and body weight decreasing effects of a 7-day-long ICV infusion of 1 microg/h alpha-MSH were weakest in the 12-month-old and most pronounced in the 24 month-old rats. In conclusion, responsiveness to the anorexic effect of alpha-MSH varies with age, with a nadir of the curve in the middle-aged, and a peak in the aging and old animals. This age-related nadir of melanocortin-responsiveness may promote obesity in middle-aged rats, while the tendency for anorexia and incipient sarcopenia of old (still obese) rats may result from age-related melanocortin-hypersensitivity rather than from adiposity.