EFFECT OF CL-316,243, A THERMOGENIC BETA-3-AGONIST, ON ENERGY-BALANCEAND BROWN AND WHITE ADIPOSE TISSUES IN RATS

The objective was to assess the effect of a new, highly selective beta (3)-adrenergic agonist, CL-316,243 (CL) (J. D. Bloom, M. D. Dutia, B. D. Johnson, A. Wissner, M. G. Burns, E. E. Largis, J. A. Dolan, and T. H. Claus., J. Med. Chem. 35: 3081, 1992), on energy balance and brown and white adipose tissues (BAT and WAT, respectively) in young rats e ating a high-fat diet to induce obesity. Chronic treatment with CL inc reased body temperature and 24-h energy expenditure, mainly by increas ing resting metabolic rate. Food intake was not altered but carcass fa t was reduced. Interscapular BAT was markedly hypertrophied, with thre e- to fourfold increases in the content of uncoupling protein (UCP) an d cytochrome oxidase. Quantitative immunoelectron microscopy of inters capular BAT of CL-treated rats showed smaller mitochondria with an unc hanged total amount of UCP per mitochondrion. The relative frequency o f the four major cell types in BAT (mature brown adipocytes, preadipoc ytes, interstitial cells, endothelial cells) was not altered. The CL-i nduced hypertrophy differed from that induced by chronic stimulation b y endogenous norepinephrine (as in cold-adaptation) in absence of hype rplasia (there was a slightly reduced DNA content), absence of an incr ease in the thyroxine (T-4) 5'-deiodinase activity, and absence of a s elective increase in UCP concentration. WAT depots weighed less and ha d fewer cells (lower DNA. content) in the CL-treated rats. Some multil ocular adipocytes appeared in these normally almost exclusively uniloc ular WAT depots (mesenteric, inguinal, epididymal, retroperitoneal). W e conclude that CL not only promotes BAT mitochondrial proliferation a nd thermogenesis and overall energy expenditure and leanness, but also retards the development of WAT hyperplasia during the early stage of diet-induced obesity.