TREATMENT WITH CL-316,243, A BETA(3)-ADRENOCEPTOR AGONIST, REDUCES SERUM LEPTIN IN RATS WITH DIET-ASSOCIATED 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)-ad renoceptor agonist, CL 316,243 (CL) on serum leptin concentration in r ats with diet-induced obesity (DIO) or with genetic obesity (fa/fa Zuc ker). DESIGN: Leptin concentration was measured in serum of young cont rol 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 lep tin concentrations in young rats with DIO and in old mildly obese cont rol 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 c orrelated well with its effect to reduce white adipocyte size, except in fa/fa rats. In CL-treated fa/fa rats, despite reductions in body fa t mass and in white adipocyte size, and despite normalization of both hyperglycemia and hyperinsulinemia, the leptin concentration did not c hange. DISCUSSION: The reason for lack of change in leptin concentrati ons in fa/fa rats, despite shrinking of white adipocytes and partial r eversal of the obesity, may be due to another defect. The large increa se 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 f a/fa rats. Since leptin is rapidly excreted in urine and leptin recept ors (including a form known to be involved in leptin transport) are ex pressed in the kidney, we suggest that leptin excretion is impaired in the fa/fa rat. This impairment contributes to maintenance of an eleva ted concentration of leptin in its blood and prevents treatment with a beta(3)-adrenoceptor agonist from reducing this elevated concentratio n despite reversal of both obesity and diabetes. In addition, we sugge st that CL-induced suppression of hyperphagia in fa/fa rats is leptin- independent and due to the large increase in thermogenesis.