Desensitization of beta-adrenergic receptors in adipocytes causes increased insulin sensitivity of glucose transport

Green, Allan; Carroll, Richard; Dobias, Susan B.

doi:10.1152/ajpendo.1996.271.2.e271

Cited by 15 publications

(15 citation statements)

References 20 publications

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“…Similarly, in a recent study of ␤-adrenergic receptor down-regulation following isoproterenol infusion in vivo, we did not detect concomitant down-regulation of adipocyte G s (29). Therefore, it appears that the concentration of G s in adipocytes is not regulated in the same manner as are concentrations of G i .…”

Section: Discussionsupporting

confidence: 78%

Tumor Necrosis Factor α Stimulates Lipolysis in Adipocytes by Decreasing Gi Protein Concentrations

Gasic

Tian

Green

1999

Journal of Biological Chemistry

131

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Prolonged treatment (12-24 h) of adipocytes with tumor necrosis factor ␣ (TNF␣) stimulates lipolysis. We have investigated the hypothesis that TNF␣ stimulates lipolysis by blocking the action of endogenous adenosine. Adipocytes were incubated for 48 h with TNF␣, and lipolysis was measured in the absence or presence of adenosine deaminase. Without adenosine deaminase, the rate of glycerol release was 2-3-fold higher in the TNF␣-treated cells, but with adenosine deaminase lipolysis increased in the controls to approximately that in the TNF␣-treated cells. This suggests that TNF␣ blocks adenosine release or prevents its antilipolytic effect. Both N 6 -phenylisopropyl adenosine and nicotinic acid were less potent and efficacious inhibitors of lipolysis in treated cells. A decrease in the concentration of ␣-subunits of all three G i subtypes was detected by Western blotting without a change in G s proteins or ␤-subunits. G i2 ␣ was about 50% of control, whereas G i1 ␣ and G i3 ␣ were about 20 and 40% of control values, respectively. The time course of G i down-regulation correlated with the stimulation of lipolysis. Furthermore, down-regulation of G i by an alternative approach (prolonged incubation with N 6 -phenylisopropyl adenosine) stimulated lipolysis. These findings indicate that TNF␣ stimulates lipolysis by blunting endogenous inhibition of lipolysis. The mechanism appears to be a G i protein down-regulation.TNF␣ 1 is a multifunctional cytokine important in many pathological and physiological states (1). A series of recent reports has demonstrated that adipose tissue expresses TNF␣ mRNA and protein. Furthermore, adipose tissue from obese animals and humans expresses considerably more TNF␣ than does tissue from their lean counterparts (2, 3). This excess expression of TNF␣ in adipose tissue may form a link between obesity and development of insulin resistance, which often leads to type 2 diabetes in obese subjects (4). However, TNF␣ is not measurable in the circulation of obese subjects and is therefore considered an autocrine or paracrine regulator of adipose tissue metabolism.TNF␣ has several effects on adipocytes that may be related to the development of type 2 diabetes in obese subjects. It has been reported that TNF␣ induces insulin resistance possibly by inducing serine phosphorylation of insulin receptor substrate-1 and converting it to an inhibitor of the insulin receptor tyrosine kinase (5). In addition, TNF␣ causes a net depletion of the adipose tissue triglyceride. Initially, this was thought to be largely because of a decrease in the activity of lipoprotein lipase (6). However, we and others have reported that TNF␣ also stimulates lipolysis both in rat adipocytes maintained in primary culture (7) and in 3T3-L1 adipocytes (8 -10). We found that TNF␣-induced stimulation of lipolysis in primary adipocytes is chronic in nature, taking approximately 6 -12 h before a measurable effect is observed (7). Furthermore, neither the rate of isoproterenol-stimulated lipolysis nor the concentration of hormone-sens...

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Section: Discussionsupporting

confidence: 78%

Tumor Necrosis Factor α Stimulates Lipolysis in Adipocytes by Decreasing Gi Protein Concentrations

Gasic

Tian

Green

1999

Journal of Biological Chemistry

131

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“…The β-AR desensitization (including down-regulation of β 3 -ARs) induced by CL-treatment may therefore influence glucose transport capacity and the insulin sensitivity of adipocytes. Accordingly, Green and coworkers have reported that desensitization of β-ARs increases insulin effect on glucose uptake in WAT (15). Whether an increase in the capacity of adipose tissue to utilize glucose may occur in CL-treated rats or guinea pigs is further investigated in the second part of this study (12).…”

Section: Discussionmentioning

confidence: 91%

Prolonged treatment with the β3-adrenergic agonist CL 316243 induces adipose tissue remodeling in rat but not in guinea pig: 1) fat store depletion and desensitization of β-adrenergic responses

Ferrand

Redonnet

Prévot

et al. 2006

J. Physiol. Biochem.

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Beta3-adrenergic agonists have been considered as potent antiobesity and antidiabetic agents mainly on the basis of their beneficial actions discovered twenty years ago in obese and diabetic rodents. The aim of this work was to verify whether prolonged treatment with a beta3-adrenergic agonist known to stimulate lipid mobilisation, could promote desensitization of beta-adrenergic responses. Wistar rats and guinea pigs were treated during one week with CL 316243 (CL, 1 mg/kg/d) by implanted osmotic minipumps. In control animals, beta3-adrenergic agonists were lipolytic in rat but not in guinea pig adipocytes. CL-treatment did not alter body weight gain in both species, but reduced fat stores in rats. Lipolysis stimulation by forskolin was unmodified but responses to beta1-, beta2- and beta3-agonists were reduced in visceral or subcutaneous white adipose tissues of CL-treated rats. Similarly, the beta3-adrenergic-dependent impairment of insulin action on glucose transport and lipogenesis in rat adipocytes was diminished after CL-treatment. In rat adipocytes, [125I]ICYP binding and beta3-adrenoceptor mRNA levels were reduced after sustained CL administration. These findings show that CL 316243 exerts (beta3-adrenergic lipolytic and antilipogenic effects in rat adipocytes. These actions, which are likely involved in the fat depletion observed in rat, also lead to the desensitization of all beta-adrenergic responses. Therefore this desensitization, together with the lack of slimming action in guinea pig, seriously attenuates the usefulness of beta3-agonists as antiobesity agents, and may explain why such agonists have not been conducted to a widespread clinical use.

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“…Indeed, this hypothesis is consistent with several previous findings. (18). Moreover, the increase of glucose metabolism in fat cells can be considered, together with the β-AR down-regulation, as an adaptative phenomenom which limits the fat depletion promoted by continuous β-AR stimulation.…”

Section: Discussionmentioning

confidence: 99%

Prolonged treatment with the β3-adrenergic agonist CL 316243 induces adipose tissue remodeling in rat but not in guinea pig: 2) modulation of glucose uptake and monoamine oxidase activity

Duffaut

Bour

Prévot

et al. 2006

J. Physiol. Biochem.

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Beta3-adrenergic agonists are well-recognited to promote lipid mobilisation and adipose tissue remodeling in rodents, leading to multilocular fat cells enriched in mitochondria. However, effects of beta3-adrenergic agonists on glucose transport are still controversial. In this work, we studied in white adipose tissue (WAT) the influence of sustained beta3-adrenergic stimulation on the glucose transport and on the mitochondrial monoamine oxidase (MAO) activity. As one-week administration of CL 316243 (CL, 1 mg/kg/d) induces beta-adrenergic desensitization in rat but not in guinea pig adipocytes, attention was paid to compare these models. When expressing glucose uptake as nmoles of 2-deoxyglucose/100 mg cell lipids, maximally stimulated uptake was increased in adipocytes of WAT from treated rats but not from treated guinea pigs. However, basal hexose uptake was also increased in CL-treated rats and, as a consequence, the dose-dependent curves for insulin stimulation were similar in control and CL-treated rats when expressed as fold increase over basal. Insulin-induced lipogenesis was unchanged in rat or guinea pig adipocytes after CL-treatment. The glucose carriers GLUT4 and corresponding mRNA were increased in subcutaneous WAT or in brown adipose tissue (BAT) but not in visceral WAT or muscles of CL-treated rats. There was an increase of MAO activity in WAT and BAT, but not in liver, of CL-treated rats while no change was detected in guinea pigs. These findings show that only rat adipocytes, which are beta3-adrenergic-responsive, respond to chronic beta3-AR agonist by an increase of GLUT4 content and MAO activity, despite a desensitization of all beta-adrenoceptor subtypes.

show abstract

Desensitization of beta-adrenergic receptors in adipocytes causes increased insulin sensitivity of glucose transport

Cited by 15 publications

References 20 publications

Tumor Necrosis Factor α Stimulates Lipolysis in Adipocytes by Decreasing Gi Protein Concentrations

Tumor Necrosis Factor α Stimulates Lipolysis in Adipocytes by Decreasing Gi Protein Concentrations

Prolonged treatment with the β3-adrenergic agonist CL 316243 induces adipose tissue remodeling in rat but not in guinea pig: 1) fat store depletion and desensitization of β-adrenergic responses

Prolonged treatment with the β3-adrenergic agonist CL 316243 induces adipose tissue remodeling in rat but not in guinea pig: 2) modulation of glucose uptake and monoamine oxidase activity

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