Brown Adipose Tissue in Lean and Obese Mice: Insulin-Receptor Binding and Tyrosine Kinase Activity

Insulin-receptor binding and tyrosine kinase activity have been studied in brown adipose tissue from lean and obese mice. Brown adipose tissue carries functional insulin receptors comparable with those of conventional insulin target tissues. The α-subunit (M_r 130,000) was labeled with photoreactive insulin; the βsubunit (M_r, 95,000) was phosphorylated in a cell-free system, and its level of phosphorylation was increased in a dose-dependent manner by insulin. Two types of obese mice, mice rendered obese by gold thioglucose injection (GTG obese) and genetically obese ob/ob mice, were used. Insulin-receptor number was decreased by 60–70% in obese mice, when expressed per milligram of plasma membrane protein or per microgram of glycoprotein, whereas only a 30–40% diminution was observed in skeletal muscle, indicating that insulin receptors from brown adipose tissue are greatly affected by the downregulation process. Insulin-stimulated autophosphorylation of the insulin-receptor β-subunit was decreased by 60–70% in preparations of obese mice compared with lean mice in direct proportion to the diminished level of insulin-receptor number. Similarly, the ability of receptors to catalyze the phosphorylation of a synthetic substrate (copolymer glutamate-tyrosine) was reduced. These results suggest that the decrease in insulin-receptor number and in associated tyrosine kinase activity could explain the insulinresistant glucose uptake and the alteration in diet-induced thermogenesis described in obese animals.