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Departments of Psychiatry and Behavioral Sciences, and Pharmacology (S.C.), and The Sarah W. Stedman Center for Nutritional Studies, Duke University Medical Center, Durham, North Carolina 27710
Address all correspondence and requests for reprints to: Dr. Sheila Collins, Box 3557, Duke University Medical Center, Durham, North Carolina 27710. E-mail: sco{at}galactose.mc.duke.edu
Fat intake has long been associated with the development of obesity. The studies described herein show that fat adversely affects adipocyte adrenergic receptor (AR) expression and function. As ß3AR 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 ß3AR agonist, 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 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 ± 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). CL316,243 prevented the development of diet-induced obesity in A/J animals, but not in B/6J animals. A/J mice weighed 26.0 ± 0.5 g at 16 weeks, whereas B/6J animals on the same diet weighed 34.1 ± 0.8 g (P < 0.00001; n = 10), but food intake was not different between the strains throughout the study. ß-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 fat-fed A/J mice, ß-agonist-stimulated 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 ßAR-stimulated activity in A/J mice compared to B/6J mice. High fat feeding was associated with decreased expression of ß3AR and ß1AR in white adipose tissue of both strains. However, chronic CL316,243 treatment prevented both the obesity and the decline in ß3AR and ß1AR 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.
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T. M. Dixon, K. W. Daniel, S. R. Farmer, and S. Collins CCAAT/Enhancer-binding Protein alpha Is Required for Transcription of the beta 3-Adrenergic Receptor Gene during Adipogenesis J. Biol. Chem., January 5, 2001; 276(1): 722 - 728. [Abstract] [Full Text] [PDF]
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