Adipocyte ALK7 links nutrient overload to catecholamine resistance in obesity

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activin Receptors, Type I / antagonists & inhibitors
  • Activin Receptors, Type I / deficiency
  • Activin Receptors, Type I / genetics*
  • Adenosine Triphosphate / antagonists & inhibitors
  • Adenosine Triphosphate / metabolism
  • Adipocytes / metabolism
  • Adipocytes / pathology
  • Adipose Tissue / metabolism*
  • Adipose Tissue / pathology
  • Animals
  • Catecholamines / metabolism
  • Diet, High-Fat
  • Dietary Fats / adverse effects
  • Gene Expression Regulation
  • Humans
  • Lipid Peroxidation / drug effects
  • Lipolysis / drug effects
  • Mice
  • Mice, Knockout
  • Mitochondrial Turnover / drug effects
  • Obesity / etiology
  • Obesity / genetics*
  • Obesity / pathology
  • Obesity / prevention & control
  • Primary Cell Culture
  • Pyrazoles / pharmacology
  • Pyrimidines / pharmacology
  • Receptors, Adrenergic, beta / genetics*
  • Receptors, Adrenergic, beta / metabolism
  • Signal Transduction
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / metabolism

Substances

  • 1-tert-butyl-3-naphthalen-1-ylmethyl-1H-pyrazolo(3,4-d)pyrimidin-4-ylemine
  • Catecholamines
  • Dietary Fats
  • Pyrazoles
  • Pyrimidines
  • Receptors, Adrenergic, beta
  • Transforming Growth Factor beta
  • Adenosine Triphosphate
  • Activin Receptors, Type I
  • Acvr1c protein, mouse

Grants and funding

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.