βAR Signaling Required for Diet-Induced Thermogenesis and Obesity Resistance

Bachman, Eric; Dhillon, Harveen; Zhang, Chen Yu; Cinti, Saverio; Bianco, Antonio C.; Kobilka, Brian K.; Lowell, Bradford B.

doi:10.1126/science.1073160

Cited by 741 publications

(627 citation statements)

References 18 publications

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“…Mice lacking BAT due to the production of diphtheria toxin in this tissue are obese and insulin-resistant [17], indicating the importance of BAT in the control of body weight. Administration of β-adrenergic receptor (AR) agonists increases the metabolic rate [18][19][20], and mice lacking all three β-AR genes become markedly obese when reared on a HFD [21]. In contrast, transgenic overexpression of human β1-AR (also known as ADRB1) in WAT resulted in lean mice and an abundance of brown adipocytes in WAT [22].…”

Section: Introductionmentioning

confidence: 99%

Increased fat:carbohydrate oxidation ratio in Il1ra −/− mice on a high-fat diet is associated with increased sympathetic tone

et al. 2008

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Aims/hypothesis Proinflammatory cytokines, including IL-1, exert pleiotropic effects on the neuro-immuno-endocrine system. Previously, we showed that mice with knockout of the gene encoding IL-1 receptor antagonist (Il1ra −/− , also known as Il1rn −/− ) have a lean phenotype. The present study was designed to analyse the mechanisms leading to this lean phenotype.Methods Il1ra −/− mice were fed a high-fat diet following weaning. Energy expenditure, body temperature, heart rate, blood parameters, urinary catecholamines and adipose tissue were analysed. Results Il1ra −/− mice exhibited resistance to obesity induced by a high-fat diet; this resistance was associated with increased energy expenditure and a decreased respiratory quotient, indicating that the ratio of fat:carbohydrate metabolism in Il1ra −/− mice is greater than in controls. Activity level in Il1ra −/− mice was significantly decreased and body temperature was significantly increased, compared with wild-type (WT) mice. Inguinal white adipose tissues in Il1ra −/− mice express increased levels of Ucp1 and mitochondrial respiratory chain genes compared with WT mice. Histological analysis of adipose tissue in Il1ra −/− mice revealed that brown adipose tissue is hyperactive and inguinal white adipose tissue contains smaller cells, which exhibit the distinctive multilocular appearance of brown adipocytes. Urinary epinephrine and norepinephrine excretion in Il1ra −/− mice was significantly increased compared with WT mice, suggesting that Il1ra −/− mice have increased sympathetic tone. Consistent with this, heart rate in Il1ra −/− mice was also significantly increased. Conclusions/interpretation Our results show that Il1ra −/− mice have increased energy expenditure, fat:carbohydrate oxidation ratio, body temperature, heart rate and catecholamine production. All of these observations are consistent with an enhanced sympathetic tone.

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Section: Introductionmentioning

confidence: 99%

Increased fat:carbohydrate oxidation ratio in Il1ra −/− mice on a high-fat diet is associated with increased sympathetic tone

et al. 2008

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“…ADRB3 agonists in rodents show an increase in lipolysis and energy expenditure and mice lacking ADRB3s develop obesity. 47,48 Human cardiac tissue and blood vessels contain ADRB3s and upregulation of ADRB3s in failing hearts has been demonstrated. 49 ADRB3 may be clinically important in the cardiovascular system as there is evidence for activation by beta-agonists and inhibition by beta-blockers, but the overall significance of cardiac ADRB3s remains uncertain.…”

Section: Adrb3 Polymorphismsmentioning

confidence: 99%

Pharmacogenetics of the human beta-adrenergic receptors

Taylor

2006

Pharmacogenomics J

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The beta-adrenergic receptors (ADRBs) are cell surface receptors that play central roles in the sympathetic nervous system. Pharmacological targeting of two of these receptors, ADRB1 and ADRB2, represents a widely used therapeutic approach for common and important diseases including asthma, hypertension and heart failure. Genetic variation in both ADRB1 and ADRB2 has been linked to both in vitro and clinical disease phenotypes. More recently, interest has shifted to studies that explore potential interaction between variation in ADRBs and medications directed at these important receptors. This paper reviews the current state of knowledge and understanding of ADRB genetic variation and explores the likely direction of future studies in this area.

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“…The b-less mice exhibited normophagic obesity and a defective cold-induced thermogenesis. 19,20 Furthermore, they did not respond to a high-fat diet by an increase in oxygen consumption, suggesting a failure in their diet-induced thermogenesis. 19 The b-less mouse model would be an invaluable tool to test in vivo the respective contributions of the b-adrenergic system and of putative direct peripheral effects of leptin on thermogenesis and oxidative substrate utilization.…”

Section: Introductionmentioning

confidence: 99%

“…19,20 Furthermore, they did not respond to a high-fat diet by an increase in oxygen consumption, suggesting a failure in their diet-induced thermogenesis. 19 The b-less mouse model would be an invaluable tool to test in vivo the respective contributions of the b-adrenergic system and of putative direct peripheral effects of leptin on thermogenesis and oxidative substrate utilization. Therefore, leptin was infused subcutaneously through osmotic minipumps in wild-type (WT) and b-less mice and its effects on food intake, body weight, energy expenditure, glucose and lipid utilization, as well as BAT thermogenic gene expression were determined.…”

Section: Introductionmentioning

confidence: 99%

Effects of leptin on energy metabolism in β-less mice

Asensio¹,

Arsenijevic²,

Lehr³

et al. 2008

Int J Obes

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Objective: To investigate the impact of b-adrenoceptor deficiency on the metabolic effects of leptin. Measurements: Leptin was infused subcutaneously through an osmotic minipump in wild-type (WT) and b 1 /b 2 /b 3 -adrenoceptor knockout (b-less) mice and its effects on food intake, energy expenditure, carbohydrate and lipid utilization as well as on the levels of expression of the brown adipose tissue (BAT), thermogenic marker uncoupling protein-1 (UCP1) and type II deiodinase (D2) mRNAs were compared. Results: Leptin treatment decreased food intake by 23% in both the WT and the b-less mice. In pair-fed animals being used as controls, leptin treatment was found to increase energy expenditure in WT, but not in b-less mice. No difference was observed in carbohydrate or fat utilization between leptin-treated WT and b-less mice. Leptin increased UCP1 and D2 mRNA levels in WT mouse BAT 1.7-and 3-fold, respectively, but had no effect on the expression of these genes in b-less mouse BAT. Conclusion: The stimulatory effects of leptin on oxygen consumption, BAT UCP1 and D2 expression require functional b-adrenoceptors, but its inhibitory effect on food intake and its stimulatory effect on fat utilization is independent of the b-adrenoceptor signalling.

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βAR Signaling Required for Diet-Induced Thermogenesis and Obesity Resistance

Cited by 741 publications

References 18 publications

Increased fat:carbohydrate oxidation ratio in Il1ra −/− mice on a high-fat diet is associated with increased sympathetic tone

Increased fat:carbohydrate oxidation ratio in Il1ra −/− mice on a high-fat diet is associated with increased sympathetic tone

Pharmacogenetics of the human beta-adrenergic receptors

Effects of leptin on energy metabolism in β-less mice

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