Phenotypic characterization of the Trp64Arg polymorphism in the beta 3-adrenergic receptor gene in normal weight and obese subjects.

The beta 3-adrenergic receptor, located mainly in fat cells of visceral adipose tissue, is involved in the regulation of lipolysis and thermogenesis. Recently, a mutation in the corresponding gene resulting in the replacement of tryptophan by arginine in position 64 (Trp64Arg) has been demonstrated, which associated with obesity and metabolic complications of obesity. We have investigated whether this polymorphism is associated with changes in beta 3-adrenergic receptor function or clinical characteristics in 40 non-obese and 43 obese non-diabetic subjects who underwent elective abdominal surgery. The beta-adrenergic receptor gene polymorphism was examined by restriction-enzyme cleavage conformation. Beta 3-adrenergic receptor function was investigated by measuring lipolysis in isolated visceral white fat cells incubated with noradrenaline (natural ligand) or (CGP) 12,177 (selective beta 3-agonist). No homozygotes for the mutation were found. The allelic frequency of Trp64Arg was similar in obese and non-obese subjects (9.4 and 12.5%, respectively). In obese and non-obese subjects there was no change in body mass index, body fat distribution, fat cell size, fasting circulating levels of insulin, glucose or lipids, blood pressure or adipocyte lipolysis induced by noradrenaline or CGP 12,177 when Trp64Arg heterozygotes were compared with Trp64A homozygotes. Our results suggest that the Trp64Arg mutation in its heterozygous form is not a major determinant of beta 3-adrenergic receptor function (when assessed by lipolysis in white adipose tissue) or of the pathophysiology of obesity.