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Effect of the (C825T) Gß₃ Polymorphism on Adrenoceptor-Mediated Lipolysis in Human Fat Cells

From the Department of Medicine, Karolinska Institutet and Clinical Research Center at the Center of Metabolism and Endocrinology, Huddinge Hospital, Huddinge, Sweden

A common Gß₃ 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 Gß₃ protein content was markedly decreased in adipocytes of TT carriers, but the alternatively spliced short form of Gß₃ 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 ß₁- and ß₂-adrenoceptors as well as for the antilipolytic ₂A-adrenoceptor. In TT carriers, maximum ß-adrenoceptor agonist-stimulated lipolysis was decreased, but the maximum antilipolytic effect of ₂-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 ₂A-adrenoceptors, ß₂-adrenoceptors, G_i, or G_s. In conclusion, the C825T variant of Gß₃ influences lipolysis. Adipocytes of TT carriers have a lower Gß₃ protein content and a decreased function of native G_s- as well as G_i-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 Gß₃ 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.

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