Adipocyte ALK7 links nutrient overload to catecholamine resistance in obesity

• Published in: eLife 2014-08, Vol.3, p.e03245
• Main Authors: Guo, Tingqing, Marmol, Patricia, Moliner, Annalena, Björnholm, Marie, Zhang, Chao, Shokat, Kevan M, Ibanez, Carlos F
• Format: Article
• Language: English
• Subjects: Activin Receptors, Type I - antagonists & inhibitors; Activin Receptors, Type I - deficiency; Activin Receptors, Type I - genetics; Adenosine Triphosphate - antagonists & inhibitors; Adenosine Triphosphate - metabolism; Adipocytes; Adipocytes - metabolism; Adipocytes - pathology; Adipose tissue; Adipose Tissue - metabolism; Adipose Tissue - pathology; Adrenergic receptors; Animals; beta-adrenergic; Body fat; Body weight gain; Catecholamines; Catecholamines - metabolism; chemical-genetic; Diet, High-Fat; Dietary Fats - adverse effects; Energy expenditure; Gene Expression Regulation; High fat diet; Human Biology and Medicine; Humans; Insulin; Kinases; Lipid peroxidation; Lipid Peroxidation - drug effects; Lipolysis; Lipolysis - drug effects; Medicin och hälsovetenskap; Mice; Mice, Knockout; Mitochondria; Mitochondrial Turnover - drug effects; Nervous system; NMR; Nuclear magnetic resonance; Obesity; Obesity - etiology; Obesity - genetics; Obesity - pathology; Obesity - prevention & control; Oxidation; Physiology; Plasmids; Primary Cell Culture; Pyrazoles - pharmacology; Pyrimidines - pharmacology; Receptors, Adrenergic, beta - genetics; Receptors, Adrenergic, beta - metabolism; Rodents; Signal Transduction; Sodium; TGF-beta; Transforming Growth Factor beta - genetics; Transforming Growth Factor beta - metabolism
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/elife.03245

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.