Regulation of diet induced brown adipose tissue thermogenesis in the genetically obese (fa/fa) Zucker rat

The obesity of the fa/fa rat is thought to result from an inability to activate the sympathetic drive to brown adipose tissue (BAT) in response to dietary signals, which may be related to an imbalance in the autonomic nervous system and a hypersensitivity to corticosterone. The role of central glucose metabolism in the control of diet induced BAT thermogenesis (as assessed by measurements of [3 H]GDP binding to BAT mitochondria) was investigated in lean and obese Zucker rats by use of 2 deoxy-D-glucose (2DG), an inhibitor of glucose metabolism. 2DG inhibited BAT GDP binding in lean, but not obese, Zucker rats. 2DG had no effect on GDP binding in animals of either phenotype exposed to cold, but decreased BAT function in lean overfed rats, suggesting that 2DG was preferentially inhibiting diet-induced thermogenesis. Adrenalectomy restored the ability of fa/fa rats to respond to 2DG with an inhibition of BAT GDP binding. This restoration was abolished by corticosterone replacement and lean animals treated with corticosterone were unable to respond to 2DG. BAT denervation, but not subdiaphragmatic vagotomy abolished the response of BAT to 2DG. Intracarotid infusion of 2DG depressed BAT and rectal temperatures and tended to reduce BAT GDP binding effects not seen after intrahepatic portal infusion of 2DG it is suggested that 2DG acts centrally to inhibit BAT mitochondrial GDP binding through depression of efferent nerve activity to BAT, and the effects of 2DG on BAT are inhibited by corticosterone. Adrenalectomy was shown to be equally effective at restoring energy balance and BAT function in obese rats fed either a high fat or high carbohydrate diet and normalised 32K protein levels in BAT mitochondria of obese animals. 32K protein concentration in BAT mitochondria was unaffected by diet but the molar binding ration of GDP:32K protein was consistently higher on the high carbohydrate diet. The role of brain opioids in the hyperphagia of obese rats was examined by opiate blockade by naloxone. Acute naloxone injection depressed food intake in young obese, but not lean rats, and increased BAT GDP binding in lean but not obese animals. Adrenalectomy abolished this increase in GDP binding in lean rats. Chronic naloxone treatment of adult Zucker rats had no effects on food intake, body weight gain or BAT function in rats of either phenotype. The hypothesis that the obesity of the fa/fa rat arises from an imbalance in the autonomic nervous system due to gluco-corticoid hypersensitivity in the hypothalmic glucose sensing areas is discussed. (D75607/87)