title: Adipocyte ALK7 links nutrient overload to catecholamine resistance in obesity.
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.
authors.affiliation: Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden Department of Physiology, National University of Singapore, Singapore, Singapore.
authors.forename: Tingqing
authors.initials: T
authors.lastname: Guo
authors.affiliation: Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Patricia
authors.initials: P
authors.lastname: Marmol
authors.affiliation: Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden Life Sciences Institute, National University of Singapore, Singapore, Singapore.
authors.forename: Annalena
authors.initials: A
authors.lastname: Moliner
authors.affiliation: Department of Molecular Medicine and Surgery, Section for Integrative Physiology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Marie
authors.initials: M
authors.lastname: Björnholm
authors.affiliation: Department of Cellular and Molecular Pharmacology, Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, United States.
authors.forename: Chao
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Cellular and Molecular Pharmacology, Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, United States.
authors.forename: Kevan M
authors.initials: KM
authors.lastname: Shokat
authors.affiliation: 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 carlos.ibanez@ki.se.
authors.forename: Carlos F
authors.initials: CF
authors.lastname: Ibanez
mesh_terms: D030201:Activin Receptors, Type I / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics*; D000255:Adenosine Triphosphate / Q000037:antagonists & inhibitors / Q000378:metabolism; D017667:Adipocytes / Q000378:metabolism / Q000473:pathology; D000273:Adipose Tissue / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D002395:Catecholamines / Q000378:metabolism; D059305:Diet, High-Fat; D004041:Dietary Fats / Q000009:adverse effects; D005786:Gene Expression Regulation; D006801:Humans; D015227:Lipid Peroxidation / Q000187:drug effects; D008066:Lipolysis / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D063269:Mitochondrial Turnover / Q000187:drug effects; D009765:Obesity / Q000209:etiology / Q000235:genetics* / Q000473:pathology / Q000517:prevention & control; D061251:Primary Cell Culture; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D011943:Receptors, Adrenergic, beta / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism
chemical_list: C479693:1-tert-butyl-3-naphthalen-1-ylmethyl-1H-pyrazolo(3,4-d)pyrimidin-4-ylemine; D002395:Catecholamines; D004041:Dietary Fats; D011720:Pyrazoles; D011743:Pyrimidines; D011943:Receptors, Adrenergic, beta; D016212:Transforming Growth Factor beta; D000255:Adenosine Triphosphate; D030201:Activin Receptors, Type I; C515277:Acvr1c protein, mouse
keywords: TGF-beta; adipose tissue; beta-adrenergic; chemical-genetic; lipolysis; obesity