Adipocyte ALK7 links nutrient overload to catecholamine resistance in obesity
Tingqing Guo,
Patricia Marmol,
Annalena Moliner,
Marie Björnholm,
Chao Zhang,
Kevan M Shokat,
Carlos F Ibanez
Affiliations
Tingqing Guo
Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden; Department of Physiology, National University of Singapore, Singapore, Singapore
Patricia Marmol
Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden
Annalena Moliner
Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden; Life Sciences Institute, National University of Singapore, Singapore, Singapore
Marie Björnholm
Department of Molecular Medicine and Surgery, Section for Integrative Physiology, Karolinska Institutet, Stockholm, Sweden
Chao Zhang
Department of Cellular and Molecular Pharmacology, Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, United States
Kevan M Shokat
Department of Cellular and Molecular Pharmacology, Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, United States
Carlos F Ibanez
Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden; Department of Physiology, National University of Singapore, Singapore, Singapore; Life Sciences Institute, National University of Singapore, Singapore, Singapore
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.
