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At least 19 recordsLinked to original sources
PubMed1992

The positive chronotropic effect induced by BRL 37344 and CGP 12177, two beta-3 adrenergic agonists, does not involve cardiac beta adrenoceptors but baroreflex mechanisms.

The presence of a beta-3 adrenoceptor (in addition to the classical beta-1 and beta-2 adrenoceptors) and its involvement in the control of heart rate was investigated in the dog. Experiments were carried out in conscious normal and sinoaortic denervated dogs (i.e. animals deprived of baroreceptor pathways). In normal dogs, infusion of isoproterenol, BRL 37344 (4-[-[(2-hydroxy-(3-chlorophenyl) ethyl)-amino]propyl]phenoxyacetate) (a beta-3 adrenergic agonist) or CGP 12177 (4-[3-t-butylamino-2-hydroxypropoxy]benzimidazol-2- one) (a beta-1 beta-2 adrenergic antagonist reported to act as an agonist for the beta-3 adrenergic receptor) increased heart rate with an order of potency: BRL 37344 > isoproterenol >> CGP 12177. [125I]Cyanopindolol binding (2-2000 pM) was saturable and Scatchard analysis indicated the presence of an homogenous population of binding sites. KD was 12.8 +/- 18.5 pM and maximum binding was 94.2 +/- 12.5 fmol/mg of protein. Competition binding studies on dog heart membranes using 150 pM [125I] cyanopindolol indicated an order of potency (CGP 12177 > isoproterenol > BRL 37344) different from that observed in cardiovascular studies. Isoproterenol stimulated adenylate cyclase activity in heart membranes from normal dogs, whereas CGP 12177 and BRL 37344 were without any stimulating action. The positive chronotropic effects of isoproterenol, BRL 37344 and CGP 12177 were accompanied with a reduction in arterial blood pressure. In sinoaortic denervated animals, isoproterenol infusion provoked tachycardia and hypotension. BRL 37344 and CGP 12177 were without any significant effect on heart rate but induced a rapid and dramatic hypotension.(ABSTRACT TRUNCATED AT 250 WORDS)

Adipose Tissue↗
PubMed1995

Beta 3-adrenergic activation of adenylyl cyclase in mouse white adipocytes: modulation by GTP and effect of obesity.

Lipolysis and adenylyl cyclase (AC) activation in response to beta-adrenergic agents are abnormally low in white epididymal adipose tissue (WAT) of the ob/ob mouse. The abundance of G-proteins (Gs alpha and Gi alpha) linked to AC is also abnormally low. By contrast, beta-adrenergic receptor (beta-AR) levels were previously found to be normal in WAT and elevated in liver. The relative importance of various forms of the beta-AR in mouse WAT was reassessed in view of the discovery of the beta 3-AR. The results show that (1) the beta 3-AR is mainly responsible for AC activation in lean-mouse WAT; (2) the beta 3-AR is only partly responsible for AC activation in obese mouse WAT; and (3) GTP modulates beta 3--but not beta 1--or beta 2-AR activation of AC in a biphasic manner. Therefore, the beta 3-AR appears responsible for the well-known bimodal effect of GTP on beta-adrenergic receptor-mediated AC activity in WAT.

Adenylate Cyclase Toxin↗
PubMed1995

Selective activation of brown adipocyte hormone-sensitive lipase and cAMP production in the mouse by beta 3-adrenoceptor agonists.

Acute injection of either noradrenaline or isoprenaline in mice activated both brown (BAT) and white (WAT) adipose tissue hormone-sensitive lipase activity (HSL). Dose-response studies indicated that isoprenaline (0.05-0.15 mg/kg) produced a dose-dependent activation of HSL in both BAT and WAT, whereas SR 58611A produced no change in HSL in WAT over a dose range (1-5 mg/kg) which, at the same time, dose-dependently increased HSL activity in BAT. The other beta 3-adrenoceptor agonists, ZD 7114 (10 mg/kg) and BRL 35135 A (5 mg/kg) also selectively increased HSL activity in BAT, these doses having previously been shown to stimulate lipogenesis in vivo. Higher doses of ZD 7114 and BRL 35135 produced no further increase in HSL activity and, in the case of BRL 35135, provoked symptoms of non-selective beta-adrenoceptor activation. The increase in HSL activity could be prevented by pretreating the mice with propranolol, 10 mg/kg, i.p., 30 min prior to the agonist. The activation of HSL activity by the beta 3-adrenoceptor agonists was associated with an increase in tissue cAMP production which was also prevented by pretreatment with propranolol. The degree of cAMP accumulation was least with BRL 35135 and greatest with ZD 7114. We conclude that, in the mouse adipocyte, the atypical beta-adrenoceptor (beta 3) is present in BAT, but is not present or functional in WAT.

Adipocytes↗
PubMed1995

Beta 2- but not beta 3-adrenoceptors mediate prejunctional inhibition of non-adrenergic non-cholinergic contraction of guinea pig main bronchi.

We studied the effects of selective beta-adrenoceptor agonists on the cholinergic and non-adrenergic non-cholinergic (excitatory NANC) contractions elicited by electrical field stimulation of guinea pig main bronchi in vitro. Addition of the selective beta 2-adrenoceptor agonists, fenoterol and salbutamol, and the selective beta 3-adrenoceptor agonist, BRL 37344 (4-[2-[(2-hydroxy-2-(3-chlor-phenyl)ethyl)amino]-propyl]-phenoxyac etic acid), induced a dose-dependent inhibition of the cholinergic contraction (pD2 7.89, 6.71 and 4.56, respectively) and the excitatory NANC response (pD2 9.11, 8.16 and 7.42, respectively). Fenoterol- and BRL 37344-induced inhibition of the excitatory NANC response was blocked with high potency (pKB 8.77 and 9.07, respectively) by the selective beta 2-adrenoceptor antagonist, ICI 118,511 (erythro-1-(7-methylindan-4-yloxy)-3-(isopropylamino)-but an-2-ol). A comparable contraction induced by neurokinin A (2 or 5 nM) was also inhibited by fenoterol, salbutamol and BRL 37344, but at significantly higher concentrations than for the inhibition of the excitatory NANC response (pD2 8.72, 7.56 and 6.66, respectively). Such a preferential inhibition of electrical field stimulation- versus agonist-induced effects was not observed for cholinergic contractions (pD2 versus methacholine-induced tone 7.86, 6.93 and 5.10, respectively). The results clearly exclude the involvement of beta 3-adrenoceptors in these responses. Furthermore they show that beta 2-adrenoceptors are involved in the prejunctional inhibition of excitatory NANC contractions, presumably via modulation of tachykinin release from sensory nerves, and solely in the postjunctional inhibition of cholinergic contractions.

Adrenergic beta-Agonists↗
PubMed1995

Control of beta 3-adrenergic receptor gene expression in brown adipocytes in culture.

Brown adipose tissue is a mammalian thermogenic tissue. Its ability to dissipate energy as heat is due to a unique mitochondrial protein, uncoupling protein (UCP). Activation and expression of UCP is under control of the sympathetic nervous system acting through beta -adrenergic receptors (AR). In this study we used Siberian hamster brown adipocytes differentiated in vitro to investigate the expression of the fat specific beta 3-AR. Binding studies using the new labelled beta 3 adrenergic ligand [3H]SB 206606 showed a density of beta 3-AR in brown adipocyte plasma membranes comparable to that measured in vivo. beta 3-AR mRNA expression was very high in mature brown adipocytes and was started to be expressed during differentiation before UCP mRNA. Its half-life was approximately 50 min. Treatment of cells with non-specific beta adrenergic agonists, specific beta 3-adrenergic agonists, and dibutyryl cyclic AMP resulted in a marked down regulation of beta 3-AR mRNA level within several hours.

Adipose Tissue, Brown↗
PubMed1995

Why do adipocytes make the beta 3 adrenergic receptor?

Adipocytes express a mixture of beta-adrenergic receptor subtypes, including the recently characterized beta 3 receptor. The co-expression of these subtypes by fat cells suggest they serve different signalling functions. In this review, the properties of recombinant and natively-expressed beta 3 receptors are detailed and contrasted with those of beta 1 and beta 2 receptors. The beta 3 receptor appears to differ from the other beta receptor subtypes with respect to receptor coupling efficiency, G-protein coupling specificity and regulation by agonist exposure. Lastly, the potential of the beta 3 receptor as a therapeutic target is discussed in view of new data regarding its tissue distribution in humans.

Adipocytes↗
PubMed1995

The M(r) 35,000 beta-adrenergic receptor mRNA-binding protein binds transcripts of G-protein-linked receptors which undergo agonist-induced destabilization.

The M(r) 35,000 beta-adrenergic receptor mRNA-binding protein, termed beta-ARB protein, is induced by beta-adrenergic agonists and binds to beta 2-receptor mRNAs that display agonist-induced destabilization. Recently a cognate sequence in the mRNA was identified that provides for recognition by beta-ARB protein. In the present work we test the ability of the beta-ARB to discriminate among G-protein-linked receptor mRNAs that either do or do not display agonist-induced destabilization and test the predictive value of the presence of the cognate sequence to identify receptors displaying post-transcriptional regulation. Transcripts of beta 2-, but not rat beta 1-, rat beta 3-, or human beta 3- adrenergic receptors bind beta-ARB protein, linking agonist-induced destabilization of mRNA to transcripts with the cognate sequence. Scanning GeneBank for G-protein-linked receptor transcripts with the cognate sequence revealed several candidates, including the thrombin receptor. We demonstrate that the thrombin receptor mRNA is recognized by beta-ARB protein and like the beta 2-receptor is regulated post-transcriptionally by agonist and cAMP. Thus, the domain of regulation by beta-ARB protein includes transcripts of G-protein-linked receptors other than beta 2-adrenergic receptors.

Adrenergic beta-Agonists↗
PubMed1995

Targeted disruption of the beta 3-adrenergic receptor gene.

beta 3-Adrenergic receptors (beta 3-ARs) are expressed predominantly in white and brown adipose tissue, and beta 3-selective agonists are potential anti-obesity drugs. However, the role of beta 3-ARs in normal physiology is unknown. To address this issue, homologous recombination was used to generate mice that lack beta 3-ARs. This was accomplished by direct injection of a DNA-targeting construct into mouse zygotes. Twenty-three transgenic mice were generated, of which two had targeted disruption of the beta 3-AR gene. Mice that were homozygous for the disrupted allele had undetectable levels of intact beta 3-AR mRNA, as assessed by RNase protection assay and Northern blotting, and lacked functional beta 3-ARs, as demonstrated by complete loss of beta 3-agonist (CL 316,243)-induced stimulation of adenylate cyclase activity and lipolysis. beta 3-AR-deficient mice had modestly increased fat stores (females more than males), indicating that beta 3-ARs play a role in regulating energy balance. 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. Finally, acute treatment of normal mice with CL 316,243 increased serum levels of free fatty acids (FFAs) (3.2-fold) and insulin (140-fold), increased energy expenditure (2-fold), and reduced food intake (by 45%). These effects were completely absent in beta 3-AR-deficient mice, proving that the actions of CL are mediated exclusively by beta 3-ARs. beta 3-AR-deficient mice should be useful as a means to a better understanding of the physiology and pharmacology of beta 3-ARs.

Adenylyl Cyclases↗
PubMed1995

Pharmacological characteristics and species-related variations of beta 3-adrenergic receptors.

Beta-adrenergic receptors (beta-AR) belong to the large multigenic family of receptors coupled to GTP-binding proteins. Three subtypes have been identified: beta 1-, beta 2- and beta 3-AR. Much of the work delineating the precise pharmacological comparison of the three beta-ARs has come from investigations with stably transfected Chinese hamster ovary cells (CHO cells). This review discusses the structure and function of beta 3-AR in various species and presents new findings on a number of beta 3-AR ligands including carazolol, tertatolol and CL 316,243 which were found to be selective and potent beta 3-AR agonists and ZD 2079 and salmeterol which appear to display full but non-subtype selective agonistic activity. Species-related variations of the beta 3-AR pharmacology have been shown for propranolol and bupranolol. With the ongoing characterization of the beta 3-AR at the molecular and cellular level, and with the advent of computer-assisted molecular modelling to aid in the determination of the three-dimensional structure of the receptor, it is thought that novel beta 3-AR compounds will become available with improved selectivity and potency.

Adrenergic beta-Agonists↗
PubMed1995

Beta 3-adrenoceptors in the cardiovascular system.

Behind the classic beta 1 and beta 2-adrenoceptors, recent molecular and pharmacological studies have described a new receptor, called the beta 3-adrenoceptor, in various mammalian tissues (brown and white adipose tissue, digestive smooth muscle). Few authors have investigated the putative existence of the beta 3-adrenoceptor in the cardiovascular system. This paper reviews the available data. In vitro studies show that beta 3-adrenoceptor agonists (BRL 37344, CGP 12177) induce a relaxation of fragments of rat carotid artery which is not antagonized by propranolol. In dogs, these drugs elicit a decrease in blood pressure due to peripheral vasodilation and an increase in heart rate which is of baroreflex origin. The vasodilating effects are mainly observed in cutaneous and adipose tissue vessels and cannot be explained by any known transductional mechanism. Activation of this vascular beta 3-adrenoceptor requires higher doses of catecholamines than for beta 1- or beta 2-adrenoceptors. In humans, the cardiovascular effects of beta 3-adrenoceptor agonists are explained by the activation of beta 1- or beta 2 (and not beta 3-)-adrenoceptors. These studies suggest the presence of vascular (but not cardiac) beta 3-adrenoceptors in dogs. In other species, including man, the presence of such cardiac beta 3-adrenoceptors remains to be resolved. Their physiological relevance remains unknown.

Adrenergic beta-Agonists↗
PubMed1995

Characterization of beta 1- and beta 3-adrenoceptors in intact brown adipocytes of the rat.

1. The binding properties of beta 1-, beta 2- and beta 3-adrenoceptors were determined in isolated brown adipocytes of the rat rather than in membrane preparations from tissue homogenates, because typical brown adipocytes represent only about 40% of the various cells present in brown adipose tissue. Binding characteristics were assessed with the hydrophilic beta-adrenoceptor radioligand, (-)-[3H]-CGP 12177. The potent beta-antagonist, bupranolol (100 microM) was used to determine nonspecific binding. Characterization was essentially performed by saturation and competition studies. 2. The saturation curve of (-)-[3H]-CGP 12177 was clearly biphasic (Hill coefficient, nH = 0.57 +/- 0.11, P < 0.01) indicating the presence of two different beta-adrenoceptor populations of high (KD = 0.24 +/- 0.04 nM) and low (KD = 80 +/- 7 nM) affinity. The low affinity sites were more numerous (Bmax = 121,000 +/- 30,000 sites/cell) than the high affinity sites (Bmax = 12,000 +/- 1,000 sites/cell). 3. (-)-[3H]-CGP 12177 (25 nM) was displaced by adrenaline (Ad), noradrenaline (NA), isoprenaline (Iso), phenylephrine (Phe) and by the new beta 3 agonist, CL 316,243 (CL) in a biphasic pattern. The order of potency for (-)-[3H]-CGP 12177 displacement from the small population of high affinity sites (Iso >> NA > Ad >> CL >> Phe was in agreement with a beta 1/beta 2-classification. In contrast, the potencies of the same agonists for displacing the radioligand from the low affinity binding sites (CL >> Iso > NA > Ad >> Phe) revealed the presence of a distinct population of adrenoceptors obeying a beta 3-classification. 5-HT did not displace (-)-[3H]-CGP 12177 (25 nM) when used at concentrations as high as 0.1 mM.4. The beta-adrenoceptor antagonist, (-)-bupranolol, was more effective than (-)-propranolol for displacing(- )-[3H]-CGP 12177 (25 nM) from the high (Ki= 0.029 =/- 0.011 and 0.19 +/- 0.07 nM, respectively and low (Ki= 0.27 +/- 0.04 microM and 1.6 +/- 0.2 lM, respectively) affinity binding sites. The selective beta 1 antagonist CGP 20712A efficiently displaced the radioligand from a small population (Ki = 65 +/- 19 pM)of binding sites, confirming the presence of beta 1-adrenoceptors.5. To evaluate whether beta 2-adrenoceptors could be identified in the population of high affinity binding sites, displacement studies were performed at a low concentration of (- )-[3H]-CGP 12177 (4 nM) that mainly labelled beta 1/beta 2-adrenoceptors. ICI 118 551 ( a selective beta 2-antagonist) and procaterol (a selective beta 2-agonist) displaced (- )-[3H]-CGP 12177 from its binding sites with very low affinity (Ki = 0.17 +/- 0.02 micro M and Ki = 11 +/- 2 micro M respectively).6. From these observations, we conclude that: (1) two kinds of binding sites with low and high affinities for (-)-[H]-CGP 12177 can be detected in intact brown adipocytes, (2) there are 10 times more low than high affinity beta-adrenoceptors, as determined by saturation or competition curve analysis, (3) the high affinity binding sites mainly correspond to beta1-adrenoceptors, whereas the low affinity sites represent beta 3-adrenoceptors, and (4) beta 2-adrenoceptors are undetectable.7. It is suggested that the low affinity beta 3-adrenoceptors represent the physiological receptors for noradrenaline secreted from sympathetic nerve endings when the concentration of the neurohormone in the synaptic cleft is very high and/or when the high affinity beta 1-adrenoceptors are desensitized by prolonged sympathetic stimulation such as chronic cold exposure.

Adipocytes↗
PubMed1995

Functional effects of long-term activation on human beta 2- and beta 3-adrenoceptor signalling.

The functional effects of long-term activation of beta-adrenoceptors were investigated by measuring adenylyl cyclase activity, cyclic AMP accumulation and cyclic AMP-dependent protein kinase activity in CHW and L cells expressing either human beta 2- or beta 3-adrenoceptors. Pre-incubation of CHW and L cells expressing beta 2-adrenoceptors with 10 microM isoprenaline for 24 h produced a marked reduction in the total receptor number and dramatically reduced the capacity of the receptor to stimulate adenylyl cyclase maximally. In contrast, the ability of beta 3-adrenoceptors number was observed in L but not in CHW cells. Maximal levels of intracellular cyclic AMP concentrations were reached during the first hour of receptor activation with isoprenaline in all four cell lines. In the absence of phosphodiesterase inhibitors, cyclic AMP decreased to basal levels within 24 h of continuous stimulation. This phenomenon occurred more rapidly in cells expressing the beta 2- than the beta 3-adrenoceptors. These results confirm that, at the level of adenylyl cyclase stimulation and cyclic AMP accumulation, the beta 3-adrenoceptor is more resistant than the beta 2-adrenoceptor to long-term desensitization. However, when cyclic AMP-dependent protein kinase activity was considered, a 24 h stimulation of beta 2- and when cyclic AMP-dependent protein kinase activity was considered, a 24 h stimulation of beta 2- and beta 3-adrenoceptor expressing cells led to the desensitization of the kinase in L but not in CHW cells. In conclusion, long-term desensitization may have distinct functional effects on cell signalling depending on the receptor subtype and the cell type considered. These findings might have practical implications for future strategies involving long-term therapies with receptor agonists.

Adenylyl Cyclases↗
PubMed1984

Catalase: an old enzyme with a new role?

Although animal catalase has been studied for decades, its physiological role has remained perplexing. It has two enzymatic functions, not only catalyzing the breakdown of H2O2 into O2 and H2O, but also in the presence of low concentrations of H2O2 catalyzing the oxidation of electron donors such as ethanol or phenols. In this article, I have summarized some well-known properties of the enzyme and have also described several recently discovered features. Of particular interest is the finding that, although catalase has been regarded as an intracellular enzyme, there is published evidence for its association with the plasma membrane of the erythrocyte. Moreover, recent work from my laboratory indicates that in vitro at alkaline pH in the presence of Mg2+, the biologically active diphenols (beta-3,4-dihydroxyphenylalanine and the beta-adrenergic agonists isoproterenol, norepinephrine, and epinephrine) appear to function as electron donor substrates for human erythrocyte catalase and inhibit the production of O2 from H2O2 at micromolar concentrations. The beta-adrenergic antagonist propranolol inhibits O2 production much less effectively and appears to competitively inhibit the reaction of catalase with epinephrine. These observations suggest an analogy between catalase and the beta-adrenergic hormone receptor and raise many questions of interest to basic science, health, and disease.

Animals↗
PubMed1993

Physiological desensitization of beta 3-adrenergic responses in brown fat cells: involvement of a postreceptor process.

To investigate a possible physiological desensitization process for beta 3-adrenergic responses, the effect of cold acclimation of hamsters on adrenergically stimulated oxygen consumption of isolated brown fat cells was investigated. Cells were prepared from control and from cold-acclimated hamsters. In agreement with earlier findings, cells isolated from cold-acclimated hamsters responded to norepinephrine addition with a decreased sensitivity (approximately 10 times higher 50% effective concentration) and a decreased maximal rate of oxygen consumption compared with cells from control hamsters. When cells were stimulated with the general beta-adrenergic agonist isoprenaline or with the beta 3-selective agonists BRL-37344 or CGP-12177, a similarly desensitized response was observed, demonstrating that it was indeed a beta 3-adrenergic response that was functionally desensitized. However, when the mitochondria within the cells were directly stimulated with exogenous free fatty acids (palmitate or octanoate), no difference between cells from control and cold-acclimated animals was seen, indicating that a mediatory step must be desensitized. When the cells were stimulated with forskolin (to activate adenylyl cyclase) or with 8-bromoadenosine 3',5'-cyclic monophosphate, the desensitized response was still observed. At post-adenosine 3',5'-cyclic monophosphate levels, a desensitization was not evident. Cyclic nucleotide phosphodiesterase activity was increased in cells from cold-acclimated animals. It is therefore suggested that this increased activity of phosphodiesterase could be (at least partly) responsible for the physiologically induced desensitized responses observed here.(ABSTRACT TRUNCATED AT 250 WORDS)

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1995

Apparent lack of beta 3-adrenoceptors and of insulin regulation of glucose transport in brown adipose tissue of guinea pigs.

Norepinephrine-induced thermogenesis was substantial in adipocytes from brown adipose tissue (BAT) of cold-acclimated guinea pigs but absent in adipocytes from BAT of warm-acclimated guinea pigs. There was no thermogenic response to any beta 3-adrenergic agonist (CL-316,243, ZD-7114, BRL-28410, CGP-12177). The receptor was characterized as a beta 1-adrenoceptor. Adrenergic agonists stimulated adenylate cyclase in membranes from BAT of both warm- and cold-acclimated guinea pigs also via a beta 1-adrenoceptor; beta 3-adrenergic agonists had no effect. Glucose transport by brown adipocytes from warm-acclimated guinea pigs was not stimulated by either norepinephrine or insulin. Cold acclimation induced the appearance of stimulation of glucose transport by norepinephrine in association with the appearance of a large capacity for thermogenesis, but there was little improvement in response to insulin. GLUT4 was present in membranes from BAT of both warm- and cold-acclimated guinea pigs. Insulin is known to have an antilipolytic effect on both BAT and white adipose tissue of guinea pigs. Thus there is a selective lack of insulin-regulated glucose transport that is not improved by cold acclimation. Guinea pigs may have a mutated component of the translocation mechanism for GLUT4. beta 3-Adrenoceptors appear to be absent in brown adipocytes of adult guinea pigs, as in white adipocytes of guinea pigs, yet are known to be present in the gut. Tissue-specific expression of beta 3-adrenergic receptors in guinea pigs may differ from that in rats, in which receptors are expressed in the adipose tissues and gut.

Acclimatization↗
PubMed1995

A pathogenic role of visceral fat beta 3-adrenoceptors in obesity.

Increased release of free fatty acids (FFA) from visceral fat cells to the portal venous system may cause several metabolic disturbances in obesity. However, this hypothesis and the underlying mechanism remain to be demonstrated. In this study catecholamine-induced lipid mobilization through lipolysis in omental adipose tissue was investigated in vitro in 25 markedly obese subjects (body mass index range 35-56 kg/m2) undergoing weight reduction surgery and in 19 nonobese subjects (body mass index range 20-28 kg/m2) undergoing cholecystectomy. Release of FFA and glycerol, induced by norepinephrine or adrenergic receptor subtype-specific agonists, were determined in isolated omental fat cells. The obese subjects had higher fat cell volume, blood pressure, plasma insulin levels, blood glucose, plasma triglycerides, and plasma cholesterol than the controls. There was evidence of upper-body fat distribution in the obese group. The rate of FFA and glycerol response to norepinephrine was increased twofold in the cells of obese subjects; no significant reutilization of FFA during catecholamine-induced lipolysis was observed in any of the groups (glycerol/FFA ratio near 1:3). There were no differences in the lipolytic sensitivity to beta 3- or beta 2-adrenoceptor specific agonists between the two groups. However, beta 3-adrenoceptor sensitivity was approximately 50 times enhanced (P = 0.0001), and the coupling efficiency of these receptors was increased from 37 to 56% (P = 0.01) in obesity. Furthermore, the obese subjects demonstrated a sixfold lower alpha 2-adrenoceptor sensitivity (P = 0.04). beta 3-Adrenoceptor sensitivity, but not alpha 2-, beta 1-, or beta 2-adrenoceptor sensitivity, correlated with norepinephrine-induced lipolysis (r = -0.67, P = 0.0001) and fat cell volume (r = -0.71, P = 0.0001). In conclusion, catecholamine-induced rate of FFA mobilization from omental fat cells is accelerated due to elevated rate of lipolysis in obesity, mainly because of an increased beta 3-adrenoceptor function, but partly also because of a decreased alpha 2-adrenoceptor function. This promotes an increased release of FFA to the portal system, which may contribute to the parallel metabolic disturbances observed in upper-body obesity.

Adipose Tissue↗
PubMed1995

Demonstration of an in vivo functional beta 3-adrenoceptor in man.

Although it is well established in several mammalian species that beta 3-adrenoceptors play a major role in regulating lipolysis and thermogenesis in adipose tissue, the functional existence and role of this receptor subtype in man has been controversial. We investigated whether the beta 3-adrenoceptor functionally co-exists with beta 1- and beta 2-adrenoceptors in vivo in human adipose tissue. Subcutaneous abdominal adipose tissue of healthy non-obese subjects was microdialyzed with equimolar concentrations of dobutamine (selective beta 1-adrenoceptor agonist), terbutaline (selective beta 2-adrenoceptor agonist), or CGP 12177 (selective beta 3-adrenoceptor agonist). All three agents caused a rapid, sustained, concentration-dependent and significant elevation of the glycerol level in the microdialysate (lipolysis index). However, only terbutaline stimulated the nutritive blood flow in adipose tissue, as measured by an ethanol escape technique. Dobutamine and CGP 12177 was equally effective in elevating the glycerol level (maximum effect 150% above baseline). Terbutaline was significantly more effective than the other two beta-agonists (maximum effect 200% above baseline). When adipose tissue was pretreated with the beta 1/beta 2-selective adrenoceptor blocker propranolol the glycerol increasing effect of dobutamine or terbutaline was inhibited by 80-85% but the glycerol response to CGP 12177 was not influenced. It is concluded that a functional beta 3-adrenoceptor is present in vivo in man. It co-exists with beta 1- and beta 2-adrenoceptors in adipose tissue and may therefore play a role in lipolysis regulation. It appears, however, that the beta 2-adrenoceptor is the most important beta-adrenoceptor subtype for the mobilization of lipids from abdominal subcutaneous adipose tissue because of its concomitant stimulatory effect on lipolysis and blood flow.

Adipose Tissue↗