Effect of leptin deficiency on metabolic rate in ob/ob mice

Reduced metabolic rate may contribute to weight gain in leptin-deficient (ob/ob) mice; however, available studies have been criticized for referencing O-2 consumption ((V) over dot o(2)) to estimated rather than true lean body mass. To evaluate whether leptin deficiency reduces energy expenditure, four separate experiments were performed: 1) NMR spectroscopy was used to measure fat and nonfat mass, permitting (V) over dot o(2) to be referenced to true nonfat mass; 2) dietary manipulation was used in an attempt to eliminate differences in body weight and composition between ob/ob and C57BL/6J mice; 3) short-term effects of exogenous leptin (0.3 mg kg(-1)day(-1)) on (V) over dot o(2) were examined; and 4)body weight and composition were compared in leptin-repleted and pair-fed ob lob animals. ob lob animals had greater mass, less lean body mass, and a 10% higher metabolic rate when (V) over dot o(2) was referenced to lean mass. Dietary manipulation achieved identical body weight in ob/ob and C57BL/6J animals; however, despite weight gain in C57BL/6J animals, percent fat mass remained higher in ob/ob animals (55 vs. 30%). Exogenous leptin increased (V) over dot o(2) in ob/ob but not control animals. Weight loss in leptin-repleted ob lob mice was greater than in pair-fed animals (45 vs. 17%). We conclude, on the basis of the observed increase in (V) over dot o(2) and accelerated weight loss seen with leptin repletion, that leptin deficiency causes a reduction in metabolic rate in ob lob mice. In contrast, these physiological studies suggest that comparison of (V) over dot o(2) in obese and lean animals does not produce useful information on the contribution of leptin to metabolism.