Anorexic vs. metabolic effects of central leptin infusion in rats of various ages and nutritional states.

Age-related obesity is known to be adjoined by leptin resistance. It has not been clarified whether the resistance is cause or result of obesity. In the present experiments, the anorexic (suppressing food intake and body weight) and hypermetabolic (increasing body temperature (Tc), activity, and heart rate (HR), indicating metabolic rate) responses to 7-day-long intracerebroventricular leptin infusion were compared in 2- and 6-month-old normally fed (NF2 and NF6 groups), 6-month-old high-fat-diet-induced obese (HF6), and 6-month-old calorie-restricted (CR6) rats. The anorexic effects were inversely related to fat content: They were most pronounced in NF2, less in NF6, non-significant in HF6 rats, but also absent in CR6 animals of the lowest fat content. This virtual leptin resistance in CR6 rats was due to their high orexigenic activity (enhanced feeding response to NPY). In contrast, CR6 rats were hypersensitive to the metabolic effects of leptin infusion (rise in Tc and HR; biotelemetric measurements), NF2 were still sensitive, while NF6 and HF6 rats exhibited moderate or low sensitivity. In conclusion, leptin resistance depends on body fat content rather than on age itself, although with age the proportion of fat tissue increases and contributes to self-perpetuating rise in body weight.