STRAIN-SPECIFIC RESPONSE TO BETA(3)-ADRENERGIC RECEPTOR AGONIST TREATMENT OF DIET-INDUCED OBESITY IN MICE

Fat intake has long been associated with the development of obesity. T he studies described herein show that fat adversely affects adipocyte adrenergic receptor (AR) expression and function. As beta(3)AR agonist s have been shown to acutely reduce adipose tissue mass and improve th ermogenesis in genetically obese rodents, we examined whether chronic supplementation of a high fat diet with a highly selective beta(3)AR a gonist, CL316,243, could prevent diet-induced obesity, and whether the effect could be sustained over prolonged treatment. C57BL/6J and A/J mice were weaned onto one of three diets: low fat (10.5% calories from fat), high fat (58% calories from fat!, or high Eat supplemented with 0.001% CL316,243. B/6J mice gained more weight on the high fat diet t han A/J mice (at 16 weeks: B/6J, 36.6 +/- 1.4 g; A/J, 32.9 +/- 0.8 g; P < 0.002; n = 10), whereas weights on the low fat diets were similar (B/6J, 29.5 +/- 0.5 g; A/J, 28.8 +/- 0.6 g; P > 0.05; n = 10). CL316,2 43 prevented the development of diet-induced obesity in A/J animals, b ut not in B/6J animals. A/J mice weighed 26.0 +/- 0.5 g at 16 weeks, w hereas B/6J animals on the same diet weighed 34.1 +/- 0.8 g (P < 0.000 01; n = 10), but food intake was not different between the strains thr oughout the study. beta-Adrenergic stimulation of adenylyl cyclase in obese B/6J mice was decreased by more than 75% in white adipose tissue and by more than 90% in brown adipose tissue (BAT). In contrast, in f at-fed A/J mice, beta-agonist-stimulated adenylyl cyclase was decrease d in white adipose tissue by about 10%, whereas the activity in inters capular BAT was decreased by 50%, indicating significant retention of beta AR-stimulated activity in A/J mice compared to B/6J mice. High fa t feeding was associated with decreased expression of beta(3)AR and be ta(1)AR in white adipose tissue of both strains. However, chronic CL31 6,243 treatment prevented both the obesity and the decline in beta(3)A R and beta(1)AR messenger RNA levels in all adipose depots fi om A/J m ice, but not B/6J mice. As CL316,243-treated A/J mice, but not B/6J mi ce, also showed marked uncoupling protein expression in white adipose depots, the ability of chronic CL316,243 treatment to prevent diet-ind uced obesity is dependent upon the elaboration of functional BAT in th ese regions.