Effect of the (C825T) Gβ3 polymorphism on adrenoceptor-mediated lipolysis in human fat cells

Abstract

A common Gβ3 gene polymorphism (C825T) influences G protein receptor-mediated signal transduction. We investigated whether this polymorphism influences lipolysis in isolated subcutaneous fat cells from 114 healthy obese subjects. The Gβ3 protein content was markedly decreased in adipocytes of TT carriers, but the alternatively spliced short form of Gβ3 previously shown in platelets of 825T carriers was not detected. Fat cells of TT carriers showed a significant 10-fold decrease in the half-maximum effective concentration of agonists selective for lipolytic β1- and β2-adrenoceptors as well as for the antilipolytic α2A-adrenoceptor. In TT carriers, maximum β-adrenoceptor agonist-stimulated lipolysis was decreased, but the maximum antilipolytic effect of α2-adrenoceptors was less marked. Norepinephrine induced adipocyte lipolysis and circulating fasting levels of free fatty acids and glycerol were reduced by half in TT carriers. The polymorphism did not influence the adipocyte content of α2A-adrenoceptors, β2-adrenoceptors, Gαi, or Gαs. In conclusion, the C825T variant of Gβ3 influences lipolysis. Adipocytes of TT carriers have a lower Gβ3 protein content and a decreased function of native Gs- as well as Gi-coupled adrenoceptors, which reduces the lipolytic effect of catecholamines. These data differ from those obtained in other cell systems that have shown increased expression of an alternative spliced Gβ3 variant and enhanced G protein signaling in 825T carriers, indicating that the polymorphism has cell type-specific effects that may be of importance for type 2 diabetes and other insulin-resistant conditions.