Adipocyte ALK7 links nutrient overload to catecholamine resistance in obesity
Copyright policy )Adipocyte ALK7 links nutrient overload to catecholamine resistance in obesity
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.
- National University of Singapore Libraries Singapore
- National University of Singapore Singapore
- University of California, San Francisco United States
- Howard Hughes Medical Institute United States
- Karolinska Institute Sweden
obesity, Activin Receptors, beta-adrenergic, pyrimidine derivative, Type I, Cardiovascular, Oral and gastrointestinal, Mice, Adenosine Triphosphate, Catecholamines, Transforming Growth Factor beta, Receptors, Adipocytes, 2.1 Biological and endogenous factors, animal, genetics, TGF-beta, Aetiology, Biology (General), pyrazole derivative, Cancer, transforming growth factor beta, Mice, Knockout, Diabetes, Q, R, lipid peroxidation, deficiency, gene expression regulation, Mitochondrial Turnover, 1-tert-butyl-3-naphthalen-1-ylmethyl-1H-pyrazolo(3,4-d)pyrimidin-4-ylemine, adipose tissue, Stroke, fat intake, Adipose Tissue, catecholamine, 5.1 Pharmaceuticals, Adrenergic, Medicine, Acvr1c protein, Development of treatments and therapeutic interventions, lipid diet, signal transduction, Signal Transduction, QH301-705.5, Knockout, Science, Lipolysis, adenosine triphosphate, beta adrenergic receptor, Primary Cell Culture, 610, adipocyte, Diet, High-Fat, activin receptor 1, Receptors, Adrenergic, beta, Animals, Humans, human, Obesity, chemical-genetic, Human Biology and Medicine, mouse, antagonists and inhibitors, Metabolic and endocrine, Nutrition, Prevention, 500, Dietary Fats, mitochondrial dynamics, Diet, High-Fat, Pyrimidines, Gene Expression Regulation, drug effects, adverse effects, lipolysis, Pyrazoles, pathology, beta, Biochemistry and Cell Biology, Lipid Peroxidation, knockout mouse, metabolism, Activin Receptors, Type I, primary cell culture
obesity, Activin Receptors, beta-adrenergic, pyrimidine derivative, Type I, Cardiovascular, Oral and gastrointestinal, Mice, Adenosine Triphosphate, Catecholamines, Transforming Growth Factor beta, Receptors, Adipocytes, 2.1 Biological and endogenous factors, animal, genetics, TGF-beta, Aetiology, Biology (General), pyrazole derivative, Cancer, transforming growth factor beta, Mice, Knockout, Diabetes, Q, R, lipid peroxidation, deficiency, gene expression regulation, Mitochondrial Turnover, 1-tert-butyl-3-naphthalen-1-ylmethyl-1H-pyrazolo(3,4-d)pyrimidin-4-ylemine, adipose tissue, Stroke, fat intake, Adipose Tissue, catecholamine, 5.1 Pharmaceuticals, Adrenergic, Medicine, Acvr1c protein, Development of treatments and therapeutic interventions, lipid diet, signal transduction, Signal Transduction, QH301-705.5, Knockout, Science, Lipolysis, adenosine triphosphate, beta adrenergic receptor, Primary Cell Culture, 610, adipocyte, Diet, High-Fat, activin receptor 1, Receptors, Adrenergic, beta, Animals, Humans, human, Obesity, chemical-genetic, Human Biology and Medicine, mouse, antagonists and inhibitors, Metabolic and endocrine, Nutrition, Prevention, 500, Dietary Fats, mitochondrial dynamics, Diet, High-Fat, Pyrimidines, Gene Expression Regulation, drug effects, adverse effects, lipolysis, Pyrazoles, pathology, beta, Biochemistry and Cell Biology, Lipid Peroxidation, knockout mouse, metabolism, Activin Receptors, Type I, primary cell culture
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