Human beta-2 adrenoceptor gene polymorphisms are highly frequent in obesity and associate with altered adipocyte beta-2 adrenoceptor function.

Abstract

Catecholamines play a central role in the regulation of energy expenditure, in part by stimulating lipid mobilization through lipolysis in fat cells. The beta-2 adrenoceptor (BAR-2) is a major lipolytic receptor in human fat cells. To determine whether known polymorphisms in codons 16, 27, and 164 of this receptor play a role in obesity and subcutaneous adipocyte BAR-2 lipolytic function, we investigated a group of 140 women with a large variation in body fat mass. Only the polymorphisms in codons 16 and 27 were common in the study population. The Gln27Glu polymorphism was markedly associated with obesity with a relative risk for obesity of approximately 7 and an odds ratio of approximately 10. Homozygotes for Glu27 had an average fat mass excess of 20 kg and approximately 50% larger fat cells than controls. However, no significant association with changes in BAR-2 function was observed. The Arg16Gly polymorphism was associated with altered BAR-2 function with Gly16 carriers showing a fivefold increased agonist sensitivity and without any change in BAR-2 expression. However, it was not significantly linked with obesity. These findings suggest that genetic variability in the human BAR-2 gene could be of major importance for obesity, energy expenditure, and lipolytic BAR-2 function in adipose tissue, at least in women.

Studies of the associations between functional β2-adrenergic receptor variants and obesity, hypertension and type 2 diabetes in 7,808 white subjects

“…The present case-control study, quantitative trait analysis and meta-analysis did not provide evidence of an impact of the variant on obesity, which is consistent with previously performed case-control studies [2,[4][5][6][7][8][9]. Previous studies have suggested sex differences [16].…”

“…The Arg allele frequency of the ADRB2 Arg16Gly variant (38%) was similar to previously identified allele frequencies [2,4,5]. The present case-control study, quantitative trait analysis and meta-analysis did not provide evidence of an impact of the variant on obesity, which is consistent with previously performed case-control studies [2,[4][5][6][7][8][9].…”

“…The same ambiguity is observed when the two variants are examined in relation to hypertension [9,10,[12][13][14][15] and type 2 diabetes [2,5,9,14,[16][17][18].…”

“…Polymorphisms have been identified in this receptor, of which the Arg16Gly and Gln27Glu variants are the most frequent [1]. The Arg16Gly variant has shown increased agonist binding in human fat cells [2] and in Chinese hamster fibroblasts. Furthermore, both polymorphisms have altered agonist-induced downregulation [3].…”

Pharmacogenetics of the human beta-adrenergic receptors

“…6 The importance of the ADRB system in cardiovascular physiology has been explored on multiple levels and led to the discovery of multiple polymorphic variants in this system ( Figure 1). 14,[20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39] ADRB1 polymorphisms Twenty-three polymorphisms of ADRB1 have been described and 13 of these predict amino-acid changes in the ADRB1 protein. 14,40 As ADRB1 does not have a recognized role in the pathogenesis of asthma, the majority of genetic association studies have focused on cardiovascular phenotypes.…”