Energy homeostasis in leptin deficient Lep(ob/ob) mice

Maintenance of reduced body weight is associated both with reduced energy expenditure per unit metabolic mass and increased hunger in mice and humans. Lowered circulating leptin concentration, due to decreased fat mass, provides a primary signal for this response. However, leptin deficient (Lep(ob/ob)) mice (and leptin receptor deficient Zucker rats) reduce energy expenditure following weight reduction by a necessarily non-leptin dependent mechanisms. To identify these mechanisms, Lep(ob/ob) mice were fed ad libitum (AL group; n = 21) or restricted to 3 kilocalories of chow per day (CR group, n = 21). After losing 20% of initial weight (in approximately 2 weeks), the CR mice were stabilized at 80% of initial body weight for two weeks by titrated refeeding, and then released from food restriction. CR mice conserved energy (-17% below predicted based on body mass and composition during the day; -52% at night); and, when released to ad libitum feeding, CR mice regained fat and lean mass (to AL levels) within 5 weeks. CR mice did so while their ad libitum caloric intake was equal to that of the AL animals. While calorically restricted, the CR mice had a significantly lower respiratory exchange ratio (RER = 0.89) compared to AL (0.94); after release to ad libitum feeding, RER was significantly higher (1.03) than in the AL group (0.93), consistent with their anabolic state. These results confirm that, in congenitally leptin deficient animals, leptin is not required for compensatory reduction in energy expenditure accompanying weight loss, but suggest that the hyperphagia of the weight-reduced state is leptin-dependent.