Current awareness

The human β₃-adrenoceptor: the search for a physiological function

The β₃-adrenergic receptor (β₃-AR) is an important regulator of various physiological functions, such as thermogenesis in brown adipose tissue, lipolysis in white adipose tissue, negative inotropic effect in cardiomyocyte, and relaxation in blood vessel. The activation of β₃-AR by its agonists is shown to have metabolic (antiobesity and antidiabetic) and cardiovascular effects in animal models, highlighting β₃-AR as a potential therapeutic target in the treatment of several human diseases. Moreover, a substantial number of studies performed on different populations have identified some β₃-AR polymorphic variants associated with obesity, diabetes, cardiovascular diseases, and other disorders. The clinical phenotypes and functional characteristics of these variants provide insights into potential pathophysiological roles of β₃-AR in the development of these diseases.

Abdominal obesity, also termed visceral obesity, has been closely linked to a variety of metabolic disorders such as diabetes, cardiovascular diseases, and cancers, as well as total mortality. The most widely used measures of abdominal obesity are waist circumference (WC) and waist-hip ratio (WHR), which are determined by both environmental and genetic factors. Classic genetic studies such as twin studies and family studies have indicated that a high proportion of variance in WC or WHR is determined by genetic components. While linkage studies and candidate gene-based association studies have largely been unsuccessful in identifying genetic loci for abdominal obesity, genome-wide association studies have identified nearly 20 loci associated with WC or WHR, mostly in Caucasians. The genetic effects on abdominal obesity appear to be sex specific, with stronger effects observed in women. Recent evidence suggests that environmental factors such as lifestyle (e.g. physical activity vs. sedentary lifestyle) and diet (e.g. sugar sweetened beverages) may modify the genetic susceptibility to obesity, and other changes such as epigenetic alterations may also be involved in modulating the relation between genomic factors and abdominal obesity in humans.

Recent evidence supports a role for β₃-adrenoceptors in human non-pregnant and pregnant myometrium. The present study was designed to characterize the pharmacology of β-adrenoceptors involved in the function of non-pregnant rat myometrium by comparison of the activity of several β-adrenoceptor agonists and antagonists in isolated rat uterus and urinary bladder. Contractions of myometrial and detrusor strips were induced by adding 1 nM oxytocin and 15 mM KCl respectively. Cumulative concentration-response curves to the selective β₃-adrenoceptor agonists, CL 316243 and BRL 37344 and the selective β₂-adrenoceptor agonist ritodrine were obtained in the presence and absence of the selective β₂-adrenoceptor antagonist ICI 118551 and the non-selective β-adrenoceptor antagonist bupranolol. Both BRL 37344 (pD₂ = 6.79 ± 0.09) and ritodrine (pD₂ = 6.89 ± 0.19) produced potent inhibition of oxytocin-induced contractions in myometrial strips; CL 316243 was inactive at concentrations up to 10 μM. Concentration effect curves to both BRL 37344 and ritodrine were shifted (10 to 30-fold) to the right in the presence of ICI 118551 (10 nM). BRL 37344 (pD₂ = 8.51 ± 0.21) and CL 316243 (pD₂ = 8.61 ± 0.24) produced potent inhibition of detrusor strips, while ritodrine was almost 100-fold less potent (pD₂ = 5.83 ± 0.17). The response to all agonists was significantly attenuated by pretreatment with bupranolol (10 μM), but only ritodrine was affected by ICI 118551 (1 μM). These results demonstrate that relaxation of rat myometrium is mediated by β₂-adrenoceptors while, consistent with previous reports, the β₃-subtype is primarily responsible for relaxation of rat detrusor.

Gestational diabetes mellitus (GDM) is considered an important risk factor for the development of type 2 diabetes mellitus. We studied possible relations between GDM and both insulin receptor substrate 1 (IRS-1) (Gly972Arg) and β₃-adrenergic receptor (ADRB3 Trp64Arg, β₃-AR) gene mutations, considered potential modifying factors in the etiology of type 2 diabetes mellitus. We evaluated the 2 gene mutations in late gestation in 627 pregnant women, all studied using the glucose challenge test, followed (in positive tests) by the oral glucose tolerance test (100 g, Carpenter and Coustan [J Obstet Gynecol. 1982;144:768-773] criteria) We diagnosed 309 women with GDM, 41 with gestational impaired glucose tolerance and 277 normal pregnant women. Age, family history of diabetes, prepregnancy body mass index, weight gain during pregnancy, plasma glucose levels, hemoglobin A_1c, islet autoantibody levels, and insulin treatment during pregnancy were all evaluated. All pregnant women were genotyped for IRS-1 (Gly972Arg) and β₃-AR (ADRB3 Trp64Arg) polymorphisms. The frequency of IRS-1 gene polymorphism was significantly higher in women with GDM than in women with a normal glucose tolerance (NGT) (P = .039), and there was a significant trend (P = .032) in the increasing frequency of mutant allele Arg from NGT > gestational impaired glucose tolerance > GDM. The search for β₃-AR gene polymorphism showed no significant differences between women with GDM and women with NGT. The X-Arg genotype of IRS-1 was significantly associated with a positive family history of diabetes in NGT (P = .006) and neared significance in GDM (P = .057). Moreover, we found that NGT carriers of both polymorphisms had a higher prepregnancy body mass index than carriers of the IRS-1 variant alone (P = .0034), the β₃-AR variant alone (P = .039), or neither (P = .048), suggesting a possible synergistic effect of the 2 gene polymorphisms. These results suggest that the IRS-1 genetic polymorphism is involved in the occurrence of gestational diabetes, as well as type 2 diabetes mellitus.

The sympathetic nervous system is central for the neurohumoral regulation of the cardiovascular system and is largely involved in many cardiovascular diseases affecting millions of people around the world. It is classically admitted that β-adrenoceptors (β-AR) of the β₁ and β₂ subtypes mediate the effects of catecholamines on the force of contraction of cardiac muscle, and on the relaxation of vascular smooth muscle. However, the molecular characterization in 1989 of a third β-AR subtype, β₃, and later its identification in human heart has changed the classically admitted paradigm on the regulation of heart function by the β-adrenergic system. In blood vessels, β₃-AR, like β₁ and β₂, produced a relaxation. But at the present time, the physiological role of β₃-AR is not clearly identified. Thus, the purpose of this review is to summarize the pharmacological and molecular evidence supporting the functional roles of β₃-AR in cardiovascular tissues of various species, including humans. In addition, this review discusses the potential role of β₃-AR in several cardiovascular diseases and emphasizes their putative involvement as new therapeutic targets.

This study determined the effects of the lipophobic electron acceptor, nitroblue tetrazolium (5 μmol/kg, i.v.) on the vasoconstrictor responses elicited by the 5-hydroxytryptamine₂ (5-HT₂) receptor agonist, α-methyl-5-HT (5–50 μg/kg, i.v.) and the α₁-adrenoceptor agonist, phenylephrine (2.5–20 μg/kg, i.v.) in conscious Sprague–Dawley rats. The systemic injection of nitroblue tetrazolium elicited pronounced hemodynamic responses that subsided by 10–15 min. Prior to the administration of nitroblue tetrazolium, the injections of α-methyl-5-HT and phenylephrine elicited dose-dependent increases in mean arterial blood pressure and mesenteric, renal and hindquarter vascular resistances. After administration of nitroblue tetrazolium, the vasoconstrictor responses elicited by α-methyl-5-HT were augmented whereas those elicited by phenylephrine were diminished. These results are consistent with the possibility that nitroblue tetrazolium interacts with the extracellular ligand-binding domains of 5-HT₂ receptors and α₁-adrenoceptor and that this interaction has opposite effects on activities of these G protein coupled receptors.