Obesity after genetic ablation of brown adipose tissue

Abstract

Brown adipose tissue (BAT) has been proposed to play an important role in the regulation of energy balance. The unique presence of uncoupling protein (UCP) permits BAT to expend calories unrelated to the performance of work with the net result being the generation of heat. The role of BAT in mediating diet-induced thermogenesis had led to the suggestion that BAT activity contributes to metabolic inefficiency and, as such, might provide a cellular and molecular explanation for protection from obesity. In order to directly test this hypothesis, we recently created mice with isolated BAT deficiency by using a suicide DNA transgenic vector in which regulatory elements of the UCP gene were used to drive brown fat specific expression of diptheria 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 effect on the development of obesity and its accompanying disorders in transgenics. The results of our studies support a critical role for BAT in the nutritional homeostasis of mice and suggest that the intact thermogenic function of BAT is required for protection from diet induced obesity. Obese UCP-DTA mice have many features in common with obesity as it appears in most humans, and should therefore be a useful model that may aid studies of the pathogenesis and treatment of human obesity, NIDDM and their complications.