Abstract
Obesity is associated with blunted β-adrenoreceptor (β-AR)-mediated lipolysis and lipid oxidation in adipose tissue, but the mechanisms linking nutrient overload to catecholamine resistance are poorly understood. We report that targeted disruption of TGF-β superfamily receptor ALK7 alleviates diet-induced catecholamine resistance in adipose tissue, thereby reducing obesity in mice. Global and fat-specific Alk7 knock-out enhanced adipose β-AR expression, β-adrenergic signaling, mitochondrial biogenesis, lipid oxidation, and lipolysis under a high fat diet, leading to elevated energy expenditure, decreased fat mass, and resistance to diet-induced obesity. Conversely, activation of ALK7 reduced β-AR-mediated signaling and lipolysis cell-autonomously in both mouse and human adipocytes. Acute inhibition of ALK7 in adult mice by a chemical-genetic approach reduced diet-induced weight gain, fat accumulation, and adipocyte size, and enhanced adipocyte lipolysis and β-adrenergic signaling. We propose that ALK7 signaling contributes to diet-induced catecholamine resistance in adipose tissue, and suggest that ALK7 inhibitors may have therapeutic value in human obesity.
Keywords:
TGF-beta; adipose tissue; beta-adrenergic; chemical-genetic; lipolysis; obesity.
Copyright © 2014, Guo et al.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Activin Receptors, Type I / antagonists & inhibitors
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Activin Receptors, Type I / deficiency
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Activin Receptors, Type I / genetics*
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Adenosine Triphosphate / antagonists & inhibitors
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Adenosine Triphosphate / metabolism
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Adipocytes / metabolism
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Adipocytes / pathology
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Adipose Tissue / metabolism*
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Adipose Tissue / pathology
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Animals
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Catecholamines / metabolism
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Diet, High-Fat
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Dietary Fats / adverse effects
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Gene Expression Regulation
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Humans
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Lipid Peroxidation / drug effects
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Lipolysis / drug effects
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Mice
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Mice, Knockout
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Mitochondrial Turnover / drug effects
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Obesity / etiology
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Obesity / genetics*
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Obesity / pathology
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Obesity / prevention & control
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Primary Cell Culture
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Pyrazoles / pharmacology
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Pyrimidines / pharmacology
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Receptors, Adrenergic, beta / genetics*
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Receptors, Adrenergic, beta / metabolism
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Signal Transduction
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Transforming Growth Factor beta / genetics
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Transforming Growth Factor beta / metabolism
Substances
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1-tert-butyl-3-naphthalen-1-ylmethyl-1H-pyrazolo(3,4-d)pyrimidin-4-ylemine
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Catecholamines
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Dietary Fats
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Pyrazoles
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Pyrimidines
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Receptors, Adrenergic, beta
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Transforming Growth Factor beta
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Adenosine Triphosphate
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Activin Receptors, Type I
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Acvr1c protein, mouse
Grants and funding
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.