Hypertrophy of brown adipocytes in brown and white adipose tissues and reversal of diet-induced obesity in rats treated with a beta3-adrenoceptor agonist.

In a previous study, we demonstrated that chronic treatment with a new beta3-adrenoceptor agonist, CL 316,243 [disodium (R,R)-5-[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]-amino]propyl]-1,3-ben zodioxazole-2,2-dicarboxylate], promoted thermogenesis, caused the appearance of multilocular adipocytes in white adipose tissue (WAT), and retarded development of obesity in young rats eating a high-fat diet (Himms-Hagen et al., Am J Physiol 266: R1371-R1382, 1994). Objectives of the present study were to find out whether CL 316,243 could reverse established diet-induced obesity in rats and to identify the multilocular adipocytes that appeared in WAT. Infusion of CL 316,243 (1 mg/kg/day) reduced abdominal fat, with a decrease in enlarged adipocyte size but no loss of white adipocytes. The resting metabolic rate increased by 40-45%, but food intake was not altered. Abundant densely stained multilocular brown adipocytes expressing uncoupling protein (UCP) appeared in retroperitoneal WAT, in which a marked increase in protein content occurred. UCP content of interscapular brown adipose tissue (BAT) was also increased markedly. We suggest that the substantial increase in the resting metabolic rate induced by CL 316,243 occurs in brown adipocytes in both BAT and WAT. The origin of the brown adipocytes that appeared in WAT is uncertain. They may have been small brown preadipocytes, expressing beta3-adrenoceptors but with few mitochondria and little or no UCP, that were induced to hypertrophy by the beta3-agonist.