Disease relevance of Adrb3

• To examine potential interactions between leptin and the beta3 adrenergic system in the regulation of food intake, we determined the effects of treatment with a selective beta3 adrenergic receptor (AR) agonist (CL 316,243 [1 mg/kg]) on body weight, food intake, and leptin expression [1].
• Immortalized brown adipocyte cell lines derived from a mouse hibernoma express all three beta-adrenergic receptor subtypes, including beta 3-adrenergic receptor (AR) [2].
• Both isoproterenol and another beta 3AR-selective agonist, BRL 37344, increased RNA synthesis which was inhibited by pertussis toxin (PTX) [3].
• Taken together, these studies demonstrate that beta3-adrenoceptor disruption creates conditions which predispose to the development of obesity [4].
• Pharmacological studies have revealed a non-beta1, beta2 or beta3 adrenergic receptor that mediates tachycardia in rat and human atria [5].

Psychiatry related information on Adrb3

• Phenotypic linkage between single-nucleotide polymorphisms of beta3-adrenergic receptor gene and NADH dehydrogenase subunit-2 gene, with special reference to eating behavior [6].

High impact information on Adrb3

• We find that UCP-deficient mice consume less oxygen after treatment with a beta3-adrenergic-receptor agonist and that they are sensitive to cold, indicating that their thermoregulation is defective [7].
• Taken together, these results now provide a consistent picture of an important role of the beta 3-adrenoceptor in the regulation of lipid metabolism and as an obvious target for drugs to treat some forms of obesity [8].
• Targeted gene disruption reveals a leptin-independent role for the mouse beta3-adrenoceptor in the regulation of body composition [4].
• Targeted disruption of mouse beta3-adrenoceptor was generated by homologous recombination, and validated by an acute in vivo study showing a complete lack of effect of the beta3-adrenoceptor agonist CL 316,243 on the metabolic rate of homozygous null (-/-) mice [4].
• Thus, chronic stimulation of the beta 3-adrenergic receptor induces ectopic expression of UCP in adipose tissues conventionally considered as white fat and even in skeletal muscle, which probably contributes to the potent anti-obesity effect of the beta 3-adrenergic agonist [9].

Chemical compound and disease context of Adrb3

• The beta3-adrenergic receptor in the obesity and diabetes prone rhesus monkey is very similar to human and contains arginine at codon 64 [10].
• The beta3-adrenoceptor-selective agonist BRL 37344 (1 micromol/l), in the presence of (-)-propranolol (200 nmol/l), did not cause positive or negative inotropic effects in control and pertussis toxin-treated atria [11].
• Pertussis toxin suppresses carbachol-evoked cardiodepression but does not modify cardiostimulation mediated through beta1- and putative beta4-adrenoceptors in mouse left atria: no evidence for beta2- and beta3-adrenoreceptor function [11].
• Recently, the incidence of a naturally occurring variant of the human beta 3-adrenergic receptor was shown to correlate with hereditary obesity in Pima Indians and Japanese individuals [12].
• Diazoxide restores beta3-adrenergic receptor function in diet-induced obesity and diabetes [13].

Biological context of Adrb3

• Transcriptional down-regulation by insulin of the beta 3-adrenergic receptor expression in 3T3-F442A adipocytes: a mechanism for repressing the cAMP signaling pathway [14].
• Importantly, beta 1 but not beta 2-AR mRNA levels up-regulated in white and brown adipose tissue of beta 3-AR-deficient mice (brown more than white), strongly implying that beta 3-ARs mediate physiologically relevant signaling under normal conditions and that "cross-talk" exists between beta 3-ARs and beta 1-AR gene expression [15].
• Thus, beta3 AR agonists via beta3 ARs suppress leptin levels acutely and simultaneously suppress food intake via a mechanism that operates downstream of leptin and two of its putative central targets [1].
• Mechanism of amelioration of insulin resistance by beta3-adrenoceptor agonist AJ-9677 in the KK-Ay/Ta diabetic obese mouse model [16].
• Noradrenaline-dependent brown adipose tissue (BAT) thermogenesis is activated by the cold and excess energy intake, largely depends on the activity of the uncoupling protein 1 (UCP1), and is mediated mainly through the beta3-adrenoceptor (beta3-AR) [17].

Anatomical context of Adrb3

• Incubation of membranes from cultured cells or brown adipocytes from tissue with CL316,243 at an optimal concentration (5 microM) did not prevent norepinephrine from further stimulating adenylyl cyclase activity, suggesting that the combined activation of beta 1AR/beta 2AR, plus beta 3AR, together produced an additive cAMP response [2].
• Three beta 3AR transcripts of 2.1, 2.6, and 3.5 kilobases were identified in adipose tissue from lean mice by Northern blotting [18].
• The beta 3AR-selective agonist BRL37344 stimulated adenylyl cyclase activity in lean membranes to a slightly lesser extent than epinephrine, but was more potent (73% high affinity component; K(act) = 3.61 x 10(-8) M) [18].
• The functional consequences of these changes in beta 3AR and beta 1AR expression were assessed by measuring beta-agonist-stimulated adenylyl cyclase activity in adipocyte plasma membranes with subtype-selective beta-adrenergic agonists and antagonists [18].
• RESULTS: Western blots of rat heart nuclear fractions and confocal immunofluorescent analysis of adult rat and mouse ventricular cardiomyocytes displayed the presence of beta 1AR and beta 3AR but, surprisingly, not the beta 2AR on nuclear membranes [3].

Associations of Adrb3 with chemical compounds

• This correlated with a lower potency of the beta 3-AR-selective agonists CGP12177, ICI201651, and BRL37344 in stimulating adenylate cyclase [14].
• No effect of the CL 316,243 compound was seen in mice with targeted disruption of the beta3 AR gene [1].
• Transcriptional modulation by n-butyric acid of beta 1-, beta 2-, and beta 3-adrenergic receptor balance in 3T3-F442A adipocytes [19].
• Anti-obesity and anti-diabetic activities of a new beta3 adrenergic receptor agonist, (S)-(Z)-[4-[[1-[2-[(2-hydroxy-3-phenoxypropyl)]amino]ethyl]-1-propenyl] phenoxy] acetic acid ethanedioic acid (SWR-0342SA), in KK-Ay mice [20].
• In these cells, beta 3AR mRNA increased in response to exposure to the beta 3AR agonist isoproterenol and remained elevated during exposures of up to 24-30 hr [21].

Regulatory relationships of Adrb3

• (-)-[125I]Iodocyanopindolol saturation and competition binding experiments indicated that TNF-alpha induced a 2-fold decrease in beta3-adrenoreceptor number, a nonsignificant reduction in beta1-subtype population, and a approximately 4.5-fold increase in beta2-adrenoreceptor density [22].
• These results indicate that a mutation of 5-HT(2C) receptor gene leads to a secondary decrease in beta 3-AR gene expression that is related to enhanced adiposity [23].
• The vigorous expression of luciferase driven by the beta3-AR gene sequence was inhibited by TZDs in a PPAR-gamma2-dependent manner [24].
• These results suggest that the increased plasma adiponectin levels seen in db/db mice treated with this beta3-adrenoceptor agonist induce a down-regulation of adiponectin receptor 2 mRNA expression specifically in the liver [25].
• We conclude that beta 3-adrenoceptor agonist stimulates insulin secretion via beta 3-action in the perfused mouse pancreas [26].

Other interactions of Adrb3

• Differential regulation by tumor necrosis factor-alpha of beta1-, beta2-, and beta3-adrenoreceptor gene expression in 3T3-F442A adipocytes [22].
• Beta-3 adrenoceptor (beta-3AR) expression in leptin treated OB/OB mice [27].
• Regulation of the uncoupling protein gene (Ucp) by beta 1, beta 2, and beta 3-adrenergic receptor subtypes in immortalized brown adipose cell lines [2].
• All cell lines responded to the highly selective beta 3-adrenergic receptor agonist CL316,243 by stimulating adenylyl cyclase activity (3-10-fold over basal). beta 1-, beta 2-, and beta 3-adrenergic receptor mRNA was detected by Northern blotting and/or reverse transcriptase-polymerase chain reaction [2].
• Chronic stimulation of the beta3-adrenergic receptor (AR) in obese animals resulted in a reduced adiposity associated with an increased expression of thermogenic uncoupling protein (UCP)1 in adipose tissues [28].

Analytical, diagnostic and therapeutic context of Adrb3

• Northern blotting analysis indicated that insulin induced a rapid and sharp decrease in beta 3-AR mRNA levels [14].
• In control adipocytes, beta 1-, beta 2-, and beta 3-AR transcripts (quantitated by a polymerase chain reaction assay) represented 6.5, 0.5, and 93% of total beta-AR mRNA, respectively [19].
• In Southern blot experiments, a probe derived from the murine beta 3AR gene hybridizes to a unique restriction fragment in the murine and human genomes [29].
• The regulation of the expression of the beta3 adrenoreceptor gene was examined in the brown adipose tissue of intact mice and in murine brown fat primary cell cultures [30].
• Acute activation of beta3-AR doubled metabolic rate in wild-type mice and sharply elevated body temperature and BAT blood flow, as determined by laser Doppler flowmetry [31].

References