Letter | Published:

Fatty acid synthesis configures the plasma membrane for inflammation in diabetes

Nature volume 539, pages 294298 (10 November 2016) | Download Citation

Abstract

Dietary fat promotes pathological insulin resistance through chronic inflammation1,2,3. The inactivation of inflammatory proteins produced by macrophages improves diet-induced diabetes4, but how nutrient-dense diets induce diabetes is unknown5. Membrane lipids affect the innate immune response6, which requires domains7 that influence high-fat-diet-induced chronic inflammation8,9 and alter cell function based on phospholipid composition10. Endogenous fatty acid synthesis, mediated by fatty acid synthase (FAS)11, affects membrane composition. Here we show that macrophage FAS is indispensable for diet-induced inflammation. Deleting Fasn in macrophages prevents diet-induced insulin resistance, recruitment of macrophages to adipose tissue and chronic inflammation in mice. We found that FAS deficiency alters membrane order and composition, impairing the retention of plasma membrane cholesterol and disrupting Rho GTPase trafficking—a process required for cell adhesion, migration and activation. Expression of a constitutively active Rho GTPase, however, restored inflammatory signalling. Exogenous palmitate was partitioned to different pools from endogenous lipids and did not rescue inflammatory signalling. However, exogenous cholesterol, as well as other planar sterols, did rescue signalling, with cholesterol restoring FAS-induced perturbations in membrane order. Our results show that the production of endogenous fat in macrophages is necessary for the development of exogenous-fat-induced insulin resistance through the creation of a receptive environment at the plasma membrane for the assembly of cholesterol-dependent signalling networks.

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Acknowledgements

This work was supported by NIH grants DK101392, DK076729, DK088083, DK20579, DK56341, RR00954, HL067773 and the Taylor Family Institute for Innovative Psychiatric Research. S. Teitelbaum provided the constitutively active Rac construct, T. Pryse performed confocal microscopy, L. Yang and M. Miller assisted with imaging and L. Mydock-McGrane prepared the cholesterol alkyne.

Author information

Affiliations

  1. Division of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, St. Louis, Missouri 63110, USA

    • Xiaochao Wei
    • , Haowei Song
    • , Li Yin
    • , Michael G. Rizzo
    •  & Clay F. Semenkovich
  2. Diabetic Cardiovascular Disease Center, Washington University School of Medicine, St. Louis, Missouri 63110, USA

    • Rohini Sidhu
    •  & Daniel S. Ory
  3. Department of Developmental Biology, Washington University School of Medicine, St. Louis, Missouri 63110, USA

    • Douglas F. Covey
  4. Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri 63110, USA

    • Clay F. Semenkovich

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Contributions

X.W., H.S., L.Y., M.G.R., and R.S. performed the experiments. H.S. performed lipidomic and proteomic analyses. R.S. and D.S.O. designed and performed the analysis for oxysterols. D.F.C. designed experiments using sterol analogues. X.W. and C.F.S. designed the experiments, analysed all data, and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Clay F. Semenkovich.

Reviewer Information Nature thanks A. Chawla, A. Tall and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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    Supplementary Information

    This file contains Supplementary Tables 1-2 and uncropped blots for Figures 1-4 and Extended Data Figures 1, 2, 6, 7 and 9.

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https://doi.org/10.1038/nature20117

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