DECREASED BROWN FAT MARKEDLY ENHANCES SUSCEPTIBILITY TO DIET-INDUCED OBESITY, DIABETES, AND HYPERLIPIDEMIA

Previous studies have indicated that rodents are relatively resistant to diet-induced obesity and that this resistance may be mediated in pa rt by the capacity for diet-induced thermogenesis in brown adipose tis sue (BAT). To test this hypothesis, we fed UCP-DTA transgenic mice wit h toxigene-mediated ablation of BAT and their control littermates a '' Western diet'' [21% (wt/wt) fat] or normal mouse chow [6.5% (wt/wt) fa t]. The diets were begun at weaning (19 days old). At the age of 12 we eks, transgenic mice receiving the Western diet were markedly obese. T he increased body weight and total body lipid content were significant ly greater in transgenic mice receiving the Western diet than were the additive individual effects of Western diet (in control mice) and dec reased BAT (in chow-fed mice), suggesting a synergistic interaction be tween diminished BAT and diet. A synergistic effect of Western diet an d BAT ablation was also observed for morbid metabolic complications, s uch as insulin resistance, hyperglycemia, and hyperlipidemia. These me tabolic changes were accompanied by increased expression of tumor necr osis factor-alpha and decreased expression of GLUT4 and beta(3)-adrene rgic receptor messenger RNA levels in white adipose tissue of UCP-DTA transgenic mice receiving the Western diet compared to those in the ot her experimental groups. As previously described, transgenic mice with diminished brown fat are hyperphagic. Of note, the degree of hyperpha gia in transgenics compared to controls was similar whether the animal s were fed chow or a Western diet. Thus, the synergistic effect of Wes tern diet on obesity in transgenic mice was not mediated by a further stimulation of food intake. Overall, this study demonstrates the exist ence of a synergistic intel action between decreased BAT and Western d iet to cause marked obesity and its accompanying disorders, such as in sulin resistance and hyperlipidemia, and gives further support for the view that an important function of BAT is protection from diet-induce d obesity, diabetes, and insulin resistance.