Defective metabolic effects of norepinephrine and insulin in obese Zucker rat brown adipose tissue

Abstract

The effects of insulin and norepinephrine on oxygen consumption, lipolysis, and glucose transport were investigated in adipocytes isolated from brown adipose tissue (BAT) of adult (4-5 mo) lean (Fa/?) and obese (fa/fa) Zucker rats. Total BAT protein content and cytochrome oxidase activity were similar in both phenotypes, suggesting that obese rats have a normal mitochondrial content. Light and electron micrographs revealed that brown adipocytes from obese rats contained very large multilocular triglyceride droplets, but their mitochondrial ultrastructure was normal. Norepinephrine, when added in excess (1 microM), stimulated brown adipocyte respiration 8-10 times above basal levels both in lean and obese animals. However, dose-response experiments disclosed that the 50% effective concentration (EC50) was significantly higher in cells isolated from obese rats compared with lean ones (EC50 115 vs. 43 nM, P less than 0.05). The lipolytic sensitivity to norepinephrine was also reduced in adipocytes isolated from obese animals (EC50 83 vs. 12 nM, P less than 0.05). Addition of dibutyryl adenosine 3',5'-cyclic monophosphate to respiring obese rat brown adipocytes restored to normal the defective response to norepinephrine, suggesting that the reduction in catecholamine sensitivity resulted from a deactivation of the receptor-adenylate cyclase complex. On the other hand, the antilipolytic and antithermogenic actions of physiological concentrations of insulin were significantly reduced in obese BAT cells. The sensitivity and responsiveness of obese rat brown adipocytes for insulin-stimulated glucose transport were also markedly decreased (EC50 1 vs. 0.3 nM, P less than 0.05; maximal velocity 3-fold vs. 7-fold).(ABSTRACT TRUNCATED AT 250 WORDS)