Targeted gene disruption reveals a leptin-independent role for the mouse beta3-adrenoceptor in the regulation of body composition.

Revelli, Jean‐Pierre; Preitner, Frédéric; Samec, Sonia; Muniesa, Pedro; Kuehne, Françoise; Boss, Olivier; Vassalli, Jean‐Dominique; Dulloo, Abdul G.; Seydoux, Josiane; Giacobino, Jean‐Paul; Huarte, Joachim; Ody, Christiane

doi:10.1172/jci119620

Cited by 91 publications

(79 citation statements)

References 44 publications

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“…Furthermore, b1-AR mRNA but not b2-AR mRNA expression is decreased in the mutants, suggesting that b1-adrenergic receptor mRNA expression is up-regulated in white and brown adipose tissues of b3-AR mutant mice [109]. Body fat accumulation develops without hyperphagia at 21 weeks old [110]. These findings suggest that a disturbance of sympathetic neural action on adipose tissues by b3-AR results in an increased fat store without hyperphagia.…”

Section: Disturbances Of Sympathetic Effects On Glucose and Fat Metabmentioning

confidence: 85%

“…The effect of CL-316,243, which decreases food intake and increases oxygen consumption and plasma NEFA concentrations, are absent in b3-AR mutant mice [109,110]. Furthermore, b1-AR mRNA but not b2-AR mRNA expression is decreased in the mutants, suggesting that b1-adrenergic receptor mRNA expression is up-regulated in white and brown adipose tissues of b3-AR mutant mice [109].…”

Section: Disturbances Of Sympathetic Effects On Glucose and Fat Metabmentioning

confidence: 98%

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New insights into sympathetic regulation of glucose and fat metabolism

2000

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Since the observation by Claude Bernard in the 1850 s that puncture of the floor of the fourth ventricle in dogs results in the appearance of transient glucosuria, the central nervous system (CNS) has been implicated in the control of certain metabolic processes of energy homeostasis mainly through neuroendocrine systems. After its recent discovery, leptin, an adipocyte hormone, has been proposed to signal the CNS to modulate autonomic outflow and food intake, leading to alterations of energy metabolism [1,2]. Leptin has been suggested to increase sympathetic outflow and disturbances of leptin signalling lead to Diabetologia (2000) 43: 533±549 ReviewsNew insights into sympathetic regulation of glucose and fat metabolism AbstractThe autonomic nervous system modulates glucose and fat metabolism through both direct neural effects and hormonal effects. This review presents recent concepts on the sympathetic regulation of glucose and fat metabolism. Focally released norepinephrine from sympathetic nerves is likely to increase glucose uptake in skeletal muscle and adipose tissues independent of insulin but norepinephrine does not contribute so much as epinephrine to hepatic glucose production. Epinephrine increases hepatic glucose production and inhibits insulin secretion and the glucose uptake by tissues that is induced by insulin. Additionally, catecholamines can increase thermogenesis and lipolysis, leading to increased energy expenditure and decreased fat stores. It is likely that b-(b3)-adrenergic receptors mediate these responses. Alterations of central neurotransmission and environmental factors can change the relative contribution of sympathetic outflow to the pancreas, liver, adrenal medulla and adipose tissues, leading to the modulation of glucose and fat metabolism. Recent studies have proposed that leptin, an adipocyte hormone, affects the central nervous system to increase sympathetic outflow independent of feeding. The effects of leptin on glucose and fat metabolism could be in part mediated by the sympathetic nervous system. Studies using mice with a genetic disruption of serotonin 5-HT2 c receptor indicate that central neural mechanisms in the regulation of sympathetic outflow and satiety could be dissociated. Abnormalities of sympathetic effects, including disturbances of leptin and b3-adrenergic receptor signalling, are likely to cause obesity and impaired glucose tolerance in rodents and humans. These findings indicate that dysfunction of the sympathetic nervous system could predispose to obesity and Type II (non-insulin-dependent) diabetes mellitus. [Diabetologia (2000) 43: 533±549]

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Section: Disturbances Of Sympathetic Effects On Glucose and Fat Metabmentioning

confidence: 85%

Section: Disturbances Of Sympathetic Effects On Glucose and Fat Metabmentioning

confidence: 98%

New insights into sympathetic regulation of glucose and fat metabolism

2000

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“…For studies with the b 3 -adrenoceptor null mice, we used 10-week-old male FVB/NJ and aged-matched FVB/NJ male littermate mice with a targeted disruption of the b 3 adrenoceptor bred in Sanofi-Aventis care unit. They were generated as described by Revelli et al (1997). Preliminary experiments indicated that both b 3 -adrenoceptor null mice and their wild-type (WT) counterparts were not suitable for behavioral experiments, showing for example minimal defensive responses in the MDTB.…”

Section: Animalsmentioning

confidence: 99%

Stimulation of the β3-Adrenoceptor as a Novel Treatment Strategy for Anxiety and Depressive Disorders

Stemmelin

Cohen

Terranova

et al. 2007

Neuropsychopharmacol

109

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The characterization of the first selective orally active and brain-penetrant b 3 -adrenoceptor agonist, SR58611A (amibegron), has opened new possibilities for exploring the involvement of this receptor in stress-related disorders. By using a battery of tests measuring a wide range of anxiety-related behaviors in rodents, including the mouse defense test battery, the elevated plus-maze, social interaction, stressinduced hyperthermia, four-plate, and punished drinking tests, we demonstrated for the first time that the stimulation of the b 3 receptor by SR58611A resulted in robust anxiolytic-like effects, with minimal active doses ranging from 0.3 to 10 mg/kg p.o., depending on the procedure. These effects paralleled those obtained with the prototypical benzodiazepine anxiolytic diazepam or chlordiazepoxide.Moreover, when SR58611A was tested in acute or chronic models of depression in rodents, such as the forced-swimming and the chronic mild stress tests, it produced antidepressant-like effects, which were comparable in terms of the magnitude of the effects to those of the antidepressant fluoxetine or imipramine. Supporting these behavioral data, SR58611A modified spontaneous sleep parameters in a manner comparable to that observed with fluoxetine. Importantly, SR58611A was devoid of side effects related to cognition (as shown in the Morris water maze and object recognition tasks), motor activity (in the rotarod), alcohol interaction, or physical dependence. Antagonism studies using pharmacological tools targeting a variety of neurotransmitters involved in anxiety and depression and the use of mice lacking the b 3 adrenoceptor suggested that these effects of SR58611A are mediated by b 3 adrenoceptors. Taken as a whole, these findings indicate that the pharmacological stimulation of b 3 adrenoceptors may represent an innovative approach for the treatment of anxiety and depressive disorders.

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“…4 The b 3 AR recognizes most of the b 1 and b 2 AR antagonists as agonists 5 and reveals a lower affinity for catecholamines. 6 Thus, the primary function of this receptor may be to maintain signaling during periods of sustained sympathetic…”

Section: Introductionmentioning

confidence: 99%

β-Blockade and increased dyslipidemia in patients bearing Glu27 variant of β2 adrenergic receptor gene

et al. 2005

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In this study, the effects of polymorphisms of the b 2 and b 3 adrenergic receptor genes on the occurrence of dyslipidemia and diabetes mellitus in hypertensive patients treated with b-blockers (atenolol or metoprolol) were evaluated. Patients who gave written informed consent were asked to return for blood sampling for estimation of serum glucose, total cholesterol, HDL, triglycerides and for genotype determination. Genotyping analysis was performed by PCR-RFLP assay. In patients bearing b 2 AR Glu27 or the b 3 AR Arg64 variant there was a larger occurrence of hypertriglyceridemia, alone or in combination with elevated cholesterol levels. Furthermore, the b 2 AR Glu27 variant significantly associates with hypetriglyceridemia in a cumulative fashion. The risk to develop this side effect after b-blockade was four-fold higher in patients homozygous for the b 2 AR Glu27 variant as compared to b 2 AR27Gln allele. This result allows the identification of patients at high risk to develop metabolic complications to chronic b-blockade treatment.

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Targeted gene disruption reveals a leptin-independent role for the mouse beta3-adrenoceptor in the regulation of body composition.

Cited by 91 publications

References 44 publications

New insights into sympathetic regulation of glucose and fat metabolism

New insights into sympathetic regulation of glucose and fat metabolism

Stimulation of the β3-Adrenoceptor as a Novel Treatment Strategy for Anxiety and Depressive Disorders

β-Blockade and increased dyslipidemia in patients bearing Glu27 variant of β2 adrenergic receptor gene

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