Synergy of sibutramine and low-dose leptin in treatment of diet-induced obesity in rats

Tachyphylaxis to the effects of anorexigenic agents, such as sibutramine (S ), may be due, in part, to counterregulatory decreases in energy expenditur e (EE) and increases in hunger that result from reduced circulating leptin (L) due to loss of body fat and lowered L production/adipocyte. The present study was conducted to test the hypothesis that L administered at low dose s sufficient to restore ambient L to preweight loss concentrations would en hance the intercurrent efficacy of S by reducing the strength of physiologi c counterregulation to weight loss. Forty male Sprague-Dawley rats were fed a high-fat (HF) diet (45% energy) to induce obesity. After 8 weeks, the ob ese rats (600 +/- 58 g) were weight-matched into 4 groups (N = 8/group) and implanted subcutaneously (SC) with 2 mL, 7-day Alzet mini-pumps that provi ded: vehicle (V, saline), L (0.5 mg/kg/d), S (3 mg/kg/d), or L+S. Food inta ke (FI) on the HF diet was measured daily. On day 7,24-hour EE was measured by indirect calorimetry, and the animals then killed for body composition analysis. Compared with vehicle, treatment with S alone, but not L alone, p roduced significant weight loss (-23 +/- 26 v -6 +/- 16 g, P <.01). L alone , or with S, increased fat oxidation (decreased respiratory quotient [RQ]) compared with V (P <.05). The lack of decline in EE with S may be due to it s documented effect to stimulate thermogenesis. Administration of L with S synergistically decreased FI and increased weight loss and fractional fat l oss. A reduction in plasma L concentration may contribute to the "plateau p henomenon" observed in studies of weight loss therapies. Replacement doses of L during S administration increased weight loss and fractional fat loss by (1) decreasing food intake and (2) by increasing fat oxidation. Such dru g combinations may be useful in the treatment of human obesity. Copyright ( C) 2001 by W.B. Saunders Company.