Mfge8 promotes obesity by mediating the uptake of dietary fats and serum fatty acids.
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 αvβ3 integrin- and αvβ5 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.
1] Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California, USA. [2] Lung Biology Center, University of California, San Francisco, San Francisco, California, USA. [3] Department of Medicine, University of California, San Francisco, San Francisco, California, USA.
Amin
A
Khalifeh-Soltani
1] Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California, USA. [2] Lung Biology Center, University of California, San Francisco, San Francisco, California, USA. [3] Department of Medicine, University of California, San Francisco, San Francisco, California, USA.
William
W
McKleroy
1] Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California, USA. [2] Lung Biology Center, University of California, San Francisco, San Francisco, California, USA. [3] Department of Medicine, University of California, San Francisco, San Francisco, California, USA.
Stephen
S
Sakuma
1] Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California, USA. [2] Department of Medicine, University of California, San Francisco, San Francisco, California, USA.
Yuk Yin
YY
Cheung
1] Metabolic Biology, University of California, Berkeley, Berkeley, California, USA. [2] Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, California, USA.
Kevin
K
Tharp
Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California, USA.
Yifu
Y
Qiu
KineMed Inc., Emeryville, California, USA.
Scott M
SM
Turner
1] Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California, USA. [2] Department of Medicine, University of California, San Francisco, San Francisco, California, USA. [3] Department of Physiology, University of California, San Francisco, San Francisco, California, USA.
Ajay
A
Chawla
1] Metabolic Biology, University of California, Berkeley, Berkeley, California, USA. [2] Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, California, USA.
Andreas
A
Stahl
1] Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California, USA. [2] Lung Biology Center, University of California, San Francisco, San Francisco, California, USA. [3] Department of Medicine, University of California, San Francisco, San Francisco, California, USA.
Kamran
K
Atabai
D041721:3T3-L1 Cells; D000704:Analysis of Variance; D000818:Animals; D000954:Antigens, Surface / Q000235:genetics / Q000378:metabolism*; D001786:Blood Glucose / Q000378:metabolism; D015153:Blotting, Western; D001823:Body Composition / Q000502:physiology; D002250:Carbon Radioisotopes / Q000378:metabolism; D002458:Cell Fractionation; D017931:DNA Primers / Q000235:genetics; D004041:Dietary Fats / Q000378:metabolism / Q000493:pharmacokinetics*; D005227:Fatty Acids / Q000097:blood / Q000493:pharmacokinetics*; D005434:Flow Cytometry; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D018345:Mice, Knockout; D046228:Microarray Analysis; D018613:Microscopy, Confocal; D008894:Milk Proteins / Q000235:genetics / Q000378:metabolism*; D046912:Multiprotein Complexes / Q000378:metabolism; D009765:Obesity / Q000235:genetics* / Q000378:metabolism; D019301:Oleic Acid / Q000378:metabolism; D051058:Oncogene Protein v-akt / Q000378:metabolism; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D010766:Phosphorylation; D060888:Real-Time Polymerase Chain Reaction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism
D000954:Antigens, Surface; D001786:Blood Glucose; D002250:Carbon Radioisotopes; D017931:DNA Primers; D004041:Dietary Fats; D005227:Fatty Acids; C490919:Mfge8 protein, mouse; D008894:Milk Proteins; D046912:Multiprotein Complexes; D014280:Triglycerides; D019301:Oleic Acid; D058539:Phosphatidylinositol 3-Kinase; D000076225:Mechanistic Target of Rapamycin Complex 2; D051058:Oncogene Protein v-akt; D058570:TOR Serine-Threonine Kinases