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Elife. 2014 Aug 25;3:e03245. doi: 10.7554/eLife.03245.

Adipocyte ALK7 links nutrient overload to catecholamine resistance in obesity.

Author information

1
Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden Department of Physiology, National University of Singapore, Singapore, Singapore.
2
Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
3
Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden Life Sciences Institute, National University of Singapore, Singapore, Singapore.
4
Department of Molecular Medicine and Surgery, Section for Integrative Physiology, Karolinska Institutet, Stockholm, Sweden.
5
Department of Cellular and Molecular Pharmacology, Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, United States.
6
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.

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

PMID:
25161195
PMCID:
PMC4139062
DOI:
10.7554/eLife.03245
[Indexed for MEDLINE]
Free PMC Article

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