Strain-Specific Response to 3-Adrenergic Receptor Agonist Treatment of Diet-Induced Obesity in Mice

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Abstract
Fat intake has long been associated with the development of obe- sity. The studies described herein show that fat adversely affects adipocyte adrenergic receptor (AR) expression and function. As b3AR agonists have been shown to acutely reduce adipose tissue mass and improve thermogenesis in genetically obese rodents, we examined whether chronic supplementation of a high fat diet with a highly selective b3AR agonist, CL316,243, could prevent diet-induced obe- sity, and whether the effect could be sustained over prolonged treat- ment. 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 fat supplemented with 0.001% CL316,243. B/6J mice gained more weight on the high fat diet than A/J mice (at 16 weeks: B/6J, 36.6 6 1.4 g; A/J, 32.9 6 0.8 g; P , 0.002; n 5 10), whereas weights on the low fat diets were similar (B/6J, 29.5 60.5 g; A/J, 28.8 60.6 g; P. 0.05; n 5 10). CL316,243 prevented the development of diet- induced obesity in A/J animals, but not in B/6J animals. A/J mice weighed 26.0 60.5 g at 16 weeks, whereas B/6J animals on the same diet weighed 34.1 6 0.8 g( P ,0.00001; n 5 10), but food intake was not different between the strains throughout the study. b-Adrenergic stimulation of adenylyl cyclase in obese B/6J mice was decreased by morethan75%inwhiteadiposetissueandbymorethan90%inbrown adipose tissue (BAT). In contrast, in fat-fed A/J mice, b-agonist-stim- ulated adenylyl cyclase was decreased in white adipose tissue by about 10%, whereas the activity in interscapular BAT was decreased by 50%, indicating significant retention of bAR-stimulated activity in A/J mice compared to B/6J mice. High fat feeding was associated with decreasedexpressionof b3ARand b1ARinwhiteadiposetissueofboth strains. However, chronic CL316,243 treatment prevented both the obesity and the decline in b3AR and b1AR messenger RNA levels in all adipose depots from A/J mice, but not B/6J mice. As CL316,243- treated A/J mice, but not B/6J mice, also showed marked uncoupling protein expression in white adipose depots, the ability of chronic CL316,243 treatment to prevent diet-induced obesity is dependent upon the elaboration of functional BAT in these regions. (Endocri- nology 138: 405-413, 1997)

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