Major thermogenic defect associated with insulin resistance in brown adipose tissue of obese diabetic SHR/N-cp rats

Abstract

The effects of norepinephrine and insulin on thermogenesis were investigated in adipocytes isolated from brown adipose tissue (BAT) of obese non-diabetic LA/N-cp rats (obese LA), obese diabetic SHR/N-cp rats (obese SHR), and their corresponding lean controls. The maximal calorigenic response (Vmax) and the sensitivity [50% effective concentration (EC50)] to norepinephrine (1 microM) were markedly reduced in brown adipocytes from obese SHR rats compared with their lean controls (3- to 4-fold decrease in the Vmax and 50% increase in the EC50 value). In the same cells, there was a similar decrease in the respiratory response to dibutyryl adenosine 3',5'-cyclic monophosphate, indicating the presence of a major postreceptor defect. Remarkably, total BAT cytochrome oxidase activity (an index of cellular mitochondrial content) was also diminished three to four times in obese SHR rats, suggesting that a reduced BAT mitochondrial content is responsible for the decreased thermogenesis. Ultrastructural studies revealed that the cytoplasm of brown adipocytes from obese SHR rats contained a large lipid droplet, numerous tiny droplets, and few atypical mitochondria with loosely packed cristae. Adipocytes from obese SHR rats were also characterized by a significant resistance to the antithermogenic effect of insulin but not to that of the nonmetabolizable adenosine analogue N6-phenylisopropyl adenosine. In contrast, all the above biochemical parameters were normal in obese LA rats. These results demonstrate that the marked insulin resistance in BAT of obese SHR rats is associated with a decreased responsiveness and sensitivity to norepinephrine, indicating the presence of receptor and postreceptor defects. It is suggested that insulin resistance and/or diabetes in SHR/N-cp rats lead to a decreased mitochondriogenesis in BAT, which results in a reduced thermogenic capacity, thereby contributing to the development of obesity.