Treatment with CL 316,243, a beta 3-adrenoceptor agonist, reduces serum leptin in rats with diet- or aging-associated obesity, but not in Zucker rats with genetic (fa/fa) obesity.

Objective: To assess the effect of chronic treatment with a beta 3-adrenoceptor agonist, CL 316,243 (CL) on serum leptin concentration in rats with diet-induced obesity (DIO) or with genetic obesity (fa/fa Zucker).

Design: Leptin concentration was measured in serum of young control rats, young rats with DIO and old control or genetically obese fa/fa Zucker rats, that were treated chronically with CL for 2-4 weeks in our previous studies.

Results: Treatment with CL reduced elevated leptin concentrations in young rats with DIO and in old mildly obese control rats to the low concentration of young lean rats. It did not alter the grossly elevated concentration in fa/fa rats. This effect of CL correlated well with its effect to reduce white adipocyte size, except in fa/fa rats. In CL-treated fa/fa rats, despite reductions in body fat mass and in white adipocyte size, and despite normalization of both hyperglycemia and hyperinsulinemia, the leptin concentration did not change.

Discussion: The reason for lack of change in leptin concentrations in fa/fa rats, despite shrinking of white adipocytes and partial reversal of the obesity, may be due to another defect. The large increase in white adipocyte number in these animals was not reversed by the treatment and might have contributed to elevated leptin production. In addition, all forms of leptin receptor are known to be defective in fa/fa rats. Since leptin is rapidly excreted in urine and leptin receptors (including a form known to be involved in leptin transport) are expressed in the kidney, we suggest that leptin excretion is impaired in the fa/fa rat. This impairment contributes to maintenance of an elevated concentration of leptin in its blood and prevents treatment with a beta 3-adrenoceptor agonist from reducing this elevated concentration despite reversal of both obesity and diabetes. In addition, we suggest that CL-induced suppression of hyperphagia in fa/fa rats is leptin-independent and due to the large increase in thermogenesis.