β2-Adrenergic Receptor Polymorphisms and Salbutamol-Stimulated Energy Expenditure

Abstract

The beta-adrenergic system is involved in the control of energy metabolism and expenditure. The beta2-adrenergic receptor (beta2-AR) gene shows polymorphisms that have been associated with obesity in several studies. In vitro and in vivo studies suggest differences in beta2-AR-mediated function between these polymorphisms. The aim of this study was to investigate the influence of genetic variation in codon 16 of the beta2-AR gene on energy metabolism in humans. Thirty-four subjects were recruited [Gly16Gly (n = 13), Gly16Arg (n = 16), or Arg16Arg (n = 5)]. The beta2-AR was stimulated with two doses of salbutamol (50 and 100 ng/kg fat-free mass per minute) after blockade of the beta1-adrenergic receptors with atenolol. Energy expenditure and plasma substrate and hormone concentrations were measured. The increase in energy expenditure (DeltaEE) was significantly different among groups in which the Arg16Arg group showed the lowest increase (P < 0.05 vs. Gly carriers). In a multiple regression model, variations in the increase in nonesterified fatty acid concentration during salbutamol infusion (partial r = 0.51) and the polymorphism contributed significantly to the variation in DeltaEE. Thirty-five percent of the variation in DeltaEE was explained by these two factors. We conclude that subjects with the Arg16Arg polymorphism of the beta2-AR gene have a reduced thermogenic response to beta2-adrenergic stimulation. Although this relatively small study needs confirmation, the findings support a role for this polymorphism in the development and maintenance of overweight and obesity.

Thermogenic responsiveness to nonspecific β-adrenergic stimulation is not related to genetic variation in codon 16 of the β2-adrenergic receptor

“…This investigation extends and clarifies the physiological significance of recent findings that adults with the Arg16Arg variant of the ␤ 2 -AR demonstrate a reduced thermogenic response to selective ␤ 2 -AR activation (iv salbutamol) (25). Because ␤-AR modulation of EE occurs as a result of stimulation of all three ␤-AR subtypes (30,31), our findings are consistent with the concept that this polymorphism likely does not play an important role in determining metabolic responsiveness to endogenous physiological activa- Data are means Ϯ SE.…”

“…On the basis of recent observations that the Arg16Arg ␤ 2 -AR polymorphism is associated with reduced sensitivity to selective ␤ 2 -AR stimulation (25), it could have been hypothesized that tonic peripheral sympathetic nervous system activity is greater in adults with that gene variant, causing greater norepinephrine release and agonist-promoted downregulation. Thus an additional novel finding of the present investigation is that genetic variation in codon 16 of the ␤ 2 -AR is not associated with basal MSNA.…”

“…Recent evidence in humans suggests that a single nucleotide polymorphism in codon 16 of the ␤ 2 -AR gene influences regulation of multiple physiological systems and responses (11,(13)(14)(15)21) including the increase in EE in response to selective ␤ 2 -AR activation (25). However, with respect to the latter observation (25), in vivo physiological activation of the peripheral ␤-AR system and consequent increases in EE occur as a result of activation of all three ␤-AR subtypes (30,31). It is unknown whether this ␤ 2 -AR gene variant modulates the increase in EE in response to nonspecific ␤-AR activation.…”

“…On the basis of the recent work using selective ␤ 2 -AR activation (25), we hypothesized that adults with the Arg16Arg polymorphism would demonstrate reduced responsiveness to nonspecific ␤-AR stimulation. A secondary goal was to determine whether any group differences observed in nonselective ␤-AR responsiveness were related to differences in tonic peripheral sympathetic nervous system activity.…”

Association of a beta-2 adrenoceptor (ADRB2) gene variant with a blunted in vivo lipolysis and fat oxidation

“…11 Previous studies have reported associations between codons 16 and 27 polymorphisms and obesity, insulin resistance and hypertension. [12][13][14][15][16][17][18][19][20][21][22] Finally, the substitution of isoleucine for threonine at codon 164 (Thr164Ile), in the receptor transmembrane-spanning domains, alters agonist binding and decreases coupling of the G s protein to the receptor. 23,24 There is evidence from in vitro studies that some of these receptor variants might be important for catecholamine-induced adipocyte lipolysis in humans.…”