The extracellular matrix protein MAGP1 supports thermogenesis and protects against obesity and diabetes through regulation of TGF-β.
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.
Department of Cell Biology & Physiology, Washington University School of Medicine, St. Louis, MO clarissa.craft@wustl.edu.
Clarissa S
CS
Craft
Department of Medicine, Center for Human Nutrition, Washington University School of Medicine, St. Louis, MO.
Terri A
TA
Pietka
Department of Medicine, Center for Human Nutrition, Washington University School of Medicine, St. Louis, MO.
Timothy
T
Schappe
Department of Medicine, Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, St. Louis, MO.
Trey
T
Coleman
Department of Cell Biology & Physiology, Washington University School of Medicine, St. Louis, MO.
Michelle D
MD
Combs
Department of Cell Biology & Physiology, Washington University School of Medicine, St. Louis, MODepartment of Medicine, Center for Human Nutrition, Washington University School of Medicine, St. Louis, MO.
Samuel
S
Klein
Department of Cell Biology & Physiology, Washington University School of Medicine, St. Louis, MODepartment of Medicine, Center for Human Nutrition, Washington University School of Medicine, St. Louis, MO.
Nada A
NA
Abumrad
Department of Cell Biology & Physiology, Washington University School of Medicine, St. Louis, MO.
Robert P
RP
Mecham
D017667:Adipocytes / Q000378:metabolism*; D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D003285:Contractile Proteins / Q000172:deficiency / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism*; D016326:Extracellular Matrix Proteins / Q000172:deficiency / Q000378:metabolism*; D058685:Genetic Pleiotropy; D020022:Genetic Predisposition to Disease; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D000072260:RNA Splicing Factors; D015398:Signal Transduction; D022722:Thermogenesis / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D003285:Contractile Proteins; D016326:Extracellular Matrix Proteins; D000072260:RNA Splicing Factors; D016212:Transforming Growth Factor beta; C016598:microfibrillar protein