The Extracellular Matrix Protein MAGP1 Supports Thermogenesis and Protects Against Obesity and Diabetes Through Regulation of TGF-β

  1. Robert P. Mecham1
  1. 1Department of Cell Biology & Physiology, Washington University School of Medicine, St. Louis, MO
  2. 2Department of Medicine, Center for Human Nutrition, Washington University School of Medicine, St. Louis, MO
  3. 3Department of Medicine, Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, St. Louis, MO
  1. Corresponding author: Clarissa S. Craft, clarissa.craft{at}wustl.edu.

Abstract

Microfibril-associated glycoprotein 1 (MAGP1) is a component of extracellular matrix microfibrils. Here we show that MAGP1 expression is significantly altered in obese humans, and inactivation of the MAGP1 gene (Mfap2−/−) in mice results in adipocyte hypertrophy and predisposition to metabolic dysfunction. Impaired thermoregulation was evident in Mfap2−/− mice prior to changes in adiposity, suggesting a causative role for MAGP1 in the increased adiposity and predisposition to diabetes. By 5 weeks of age, Mfap2−/− mice were maladaptive to cold challenge, uncoupling protein-1 expression was attenuated in the brown adipose tissue, and there was reduced browning of the subcutaneous white adipose tissue. Levels of transforming growth factor-β (TGF-β) activity were elevated in Mfap2/ adipose tissue, and the treatment of Mfap2/ mice with a TGF-β–neutralizing antibody improved their body temperature and prevented the increased adiposity phenotype. Together, these findings indicate that the regulation of TGF-β by MAGP1 is protective against the effects of metabolic stress, and its absence predisposes individuals to metabolic dysfunction.

Footnotes

  • Received October 17, 2013.
  • Accepted January 19, 2014.

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  1. Diabetes vol. 63 no. 6 1920-1932
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