APPEARANCE OF BROWN ADIPOCYTES IN WHITE ADIPOSE-TISSUE DURING CL-316,243-INDUCED REVERSAL OF OBESITY AND DIABETES IN ZUCKER FA FA RATS/

BACKGROUND: In our previous studies, chronic treatment of rats with a new beta(3)-adrenoceptor agonist, CL 316,243, retarded diet-induced ob esity and promoted thermogenesis in young animals and reversed establi shed diet-induced obesity in older animals that continued to eat a hig h fat diet. Reversal of obesity was associated with shrinking of enlar ged white adipocytes but the number of mature white adipocytes, which had not been increased by the diet, was not reduced. Drug-treatment in duced appearance of abundant brown adipocytes in white adipose tissue (WAT) depots as well as hypertrophy of brown adipose tissue (BAT) in b oth lean and diet-induced obese rats. OBJECTIVES: To find out whether the known hyperplasia of white adipocytes in the obese fa/fa rat could be reversed by CL 316,243-treatment and whether the grossly enlarged WAT depots of the obese fa/fa rat contain precursors to brown adipocyt es. RESULTS: CL 316,243 infusion (1 mg/kg/d) reduced abdominal fat. Th e loss of fat was due to a decrease in white adipocyte size, with no l oss of the markedly elevated number of adipocytes in the fa/fa rats. R esting metabolic rate increased by 40% in lean rats, by 70% in fa/fa r ats. Food intake decreased in the hyperphagic fa/fa rats but did not c hange in lean rats. In both lean and fa/fa rats, a marked increase in protein content of retroperitoneal WAT was associated with appearance of abundant densely-stained brown adipocytes expressing uncoupling pro tein (UCP) but total number of cells (from DNA content) actually decre ased. Hyperinsulinemia and hyperglycemia of fa/fa rats were reduced by treatment, indicating improved sensitivity to insulin. CONCLUSIONS: A bundant precursors to brown adipocytes are present in WAT depots of fa /fa rats and much of the exaggerated increase in resting metabolic rat e induced by CL 316,243 occurs in these cells. This beta(3)-adrenocept or agonist is an effective anti-obesity and anti-diabetic agent in fa/ fa rats. It does not bring about disappearance of mature white adipocy tes but does bring about a remodelling of WAT, with a marked change in cell composition.