Mfge8 promotes obesity by mediating the uptake of dietary fats and serum fatty acids

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Abstract

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.

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Figure 1: Mfge8 mediates fatty acid uptake.
Figure 2: Mfge8 mediates absorption of dietary fats.
Figure 3: Mfge8 mediates fatty acid clearance from serum and deposition in peripheral organs.
Figure 4: Mfge8 increases fatty acid uptake through PI3K.
Figure 5: Mfge8 induces cell surface translocation of Cd36 and Fatp1.
Figure 6: Mfge8−/− mice are protected from DIO.

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Acknowledgements

This research was supported by US National Institutes of Health grant P30 DK 063-7202 and the University of California, San Francisco (UCSF) Diabetes and Endocrinology Research Center and UCSF Cardiovascular Research Institute startup funds (K.A.). We would like to thank K. Nguyen for help with flow cytometry studies, A. Atakilit and D. Sheppard (UCSF Lung Biology Center) for providing integrin-blocking antibodies, R. Silverstein for providing Cd36−/− mice (Cleveland Clinic Research Institute) and K. Ashrafi for thoughtful review of the manuscript.

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A.K.-S. and W.M. designed and performed in vivo and in vitro experiments and aided in writing the manuscript. S.S. carried out in vivo experiments with obese mice, isolated recombinant protein constructs and performed flow cytometry. Y.Y.C. carried out in vivo insulin sensitivity studies. K.T. aided with isolation of primary and pre-adipocytes and measured fecal energy content. Y.Q. aided with metabolic cage studies. S.M.T., A.S. and A.C. aided in the design of experiments and interpretation of results. K.A. designed the study, analyzed the data and wrote the manuscript.

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Correspondence to Kamran Atabai.

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The authors declare no competing financial interests.

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Khalifeh-Soltani, A., McKleroy, W., Sakuma, S. et al. Mfge8 promotes obesity by mediating the uptake of dietary fats and serum fatty acids. Nat Med 20, 175–183 (2014). https://doi.org/10.1038/nm.3450

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