Journal
NATURE MEDICINE
Volume 20, Issue 2, Pages 175-183Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nm.3450
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Funding
- US National Institutes of Health [P30 DK 063-7202]
- University of California, San Francisco (UCSF) Diabetes and Endocrinology Research Center
- UCSF Cardiovascular Research Institute
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Fatty acids are integral mediators of energy storage, membrane formation and cell signaling. The pathways that orchestrate uptake of fatty acids remain incompletely understood. Expression of the integrin ligand Mfge8 is increased in human obesity and in mice on a high-fat diet, but its role in obesity is unknown. We show here that Mfge8 promotes the absorption of dietary triglycerides and the cellular uptake of fatty acid and that Mfge8-deficient (Mfge8(-/-)) mice are protected from diet-induced obesity, steatohepatitis and insulin resistance. Mechanistically, we found that Mfge8 coordinates fatty acid uptake through alpha(v)beta(3) integrin- and alpha(v)beta(5) integrin-dependent phosphorylation of Akt by phosphatidylinositide-3 kinase and mTOR complex 2, leading to translocation of Cd36 and Fatp1 from cytoplasmic vesicles to the cell surface. Collectively, our results imply a role for Mfge8 in regulating the absorption and storage of dietary fats, as well as in the development of obesity and its complications.
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