LIVER BETA-ADRENERGIC RECEPTORS, G-PROTEINS, AND ADENYLYL-CYCLASE ACTIVITY IN OBESITY-DIABETES SYNDROMES

The ob and db genes produce similar hormonal anomalies in mice. Althou gh the expression of the syndromes diverges with age, at 8-12 wk both ob/ob and db/db mice are hyperglycemic and hyperinsulinemic and show e vidence of hypercorticoidism. Nevertheless, membranes isolated from li vers of ob/ob and db/db mice behave differently in terms of adenylyl c yclase activity and beta-adrenergic receptor function. There are three times as many beta(2)-adrenergic receptor binding sites and a threefo ld increase in the response to catecholamines in ob/ob mouse liver mem branes than in comparable preparations from normal controls or db/db m ice. By contrast, the two main G proteins of liver membranes (G(s) alp ha and G(i) alpha 2) are less abundant in the mutants, ob/ob and db/db , than in their respective lean controls. Adrenalectomy normalizes the exaggerated response to beta-adrenergic agonists and the number of be ta-adrenergic binding sites in the ob/ob mouse. This shows that the en hanced beta-adrenergic receptor response is linked to hypercorticoidis m. Cellular maturation and differentiation (D. C. Watkins, J. K. North rup, and C. C. Malbon, J. Biol. Chem. 262: 10651-10657, 1987) and dise ases such as obesity and diabetes (cf. N. McFarlane-Anderson, J. Baill y, and N. BeginHeick, Biochem. J. 282: 15-23, 1992) have been associat ed with modifications in the complement of G proteins detected in cell s. However, the relationship among levels, types, and intracellular lo calization of G proteins in tissues and their influence on the transdu ction of the message to an effector system, such as adenylyl cyclase, are not yet well understood.