The Extracellular Matrix Protein MAGP1 Supports Thermogenesis and Protects Against Obesity and Diabetes Through Regulation of TGF-β
- Clarissa S. Craft1⇑,
- Terri A. Pietka2,
- Timothy Schappe2,
- Trey Coleman3,
- Michelle D. Combs1,
- Samuel Klein1,2,
- Nada A. Abumrad1,2 and
- Robert P. Mecham1
- 1Department of Cell Biology & Physiology, Washington University School of Medicine, St. Louis, MO
- 2Department of Medicine, Center for Human Nutrition, Washington University School of Medicine, St. Louis, MO
- 3Department of Medicine, Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, St. Louis, MO
- Corresponding author: Clarissa S. Craft, .
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.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db13-1604/-/DC1.
See accompanying article, p. 1858.
- Received October 17, 2013.
- Accepted January 19, 2014.
- © 2014 by the American Diabetes Association.
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