OBESITY AFTER GENETIC ABLATION OF BROWN ADIPOSE-TISSUE

Brown adipose tissue (BAT) has been proposed to play an important role in the regulation of energy balance. The unique presence of uncouplin g protein (UCP) permits BAT to expend calories unrelated to the perfor mance of work with the net result being the generation of heat. The ro le of BAT in mediating diet-induced thermogenesis had led to the sugge stion that BAT activity contributes to metabolic inefficiency and, as such, might provide a cellular and molecular explanation for protectio n from obesity. In order to directly test this hypothesis, we recently created mice with isolated BAT deficiency by using a suicide DNA tran sgenic vector in which regulatory elements of the UCP gene were used t o drive brown fat specific expression of diphteria toxin A-chain (DTA) . Transgenic mice are characterized by reduced energy expenditure and marked obesity, associated with insulin resistance and NIDDM with both receptor and post-receptor components. Feeding of a ''Western diet'' which derives 41% of its calories from fat leads to a synergistic effe ct on the development of obesity and its accompanying disorders in tra nsgenics. The results of our studies support a critical role for BAT i n the nutritional homeostasis of mice and suggest that the intact ther mogenic function of BAT is required for protection from diet induced o besity. Obese UCP-DTA mice have many features in common with obesity a s it appears in most humans, and should therefore be a useful model th at may aid studies of the pathogenesis and treatment of human obesity, NIDDM and their complications.