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Netrin-1 promotes adipose tissue macrophage retention and insulin resistance in obesity

Nature Medicine volume 20, pages 377–384 (2014)Cite this article

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Abstract

During obesity, macrophage accumulation in adipose tissue propagates the chronic inflammation and insulin resistance associated with type 2 diabetes. The factors, however, that regulate the accrual of macrophages in adipose tissue are not well understood. Here we show that the neuroimmune guidance cue netrin-1 is highly expressed in obese but not lean adipose tissue of humans and mice, where it directs the retention of macrophages. Netrin-1, whose expression is induced in macrophages by the saturated fatty acid palmitate, acts via its receptor Unc5b to block their migration. In a mouse model of diet-induced obesity, we show that adipose tissue macrophages exhibit reduced migratory capacity, which can be restored by blocking netrin-1. Furthermore, hematopoietic deletion of Ntn1 facilitates adipose tissue macrophage emigration, reduces inflammation and improves insulin sensitivity. Collectively, these findings identify netrin-1 as a macrophage retention signal in adipose tissue during obesity that promotes chronic inflammation and insulin resistance.

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Figure 1: Netrin-1 and Unc5b are upregulated in adipose tissue of obese mice.
Figure 2: Netrin-1 is expressed by adipose tissue macrophages in obese human VAT.
Figure 3: Palmitate upregulates Ntn1 and Unc5b expression in macrophages.
Figure 4: Netrin-1 blocks chemokine-induced migration of ATMs and promotes ATM accumulation during HFD feeding.
Figure 5: Netrin-1 promotes macrophage retention in adipose tissue during obesity.
Figure 6: Netrin-1 expression by ATMs promotes metabolic dysfunction.

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  • 14 March 2014

    In the version of this article initially published online, the corresponding author’s e-mail address was incorrect. The correct address is kathryn.moore@nyumc.org. The error has been corrected for all versions of this article.

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Acknowledgements

Support for this work came from the US National Institutes of Health (RC1HL100815 to K.J.M. and T32HL098129 to E.J.H.), the American Heart Association (13POST14490016 to B.R.) and the Canadian Institutes of Health Research (MOP-2390941 to R.M.).

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Authors and Affiliations

  1. Department of Medicine, The Leon H. Charney Division of Cardiology, Marc and Ruti Bell Program for Vascular Biology and Disease, New York University School of Medicine, New York, New York, USA

    Bhama Ramkhelawon, Elizabeth J Hennessy, Tathagat Dutta Ray, Frederick J Sheedy, Susan Hutchison, Amarylis Wanschel, Scott Oldebeken, Westley Spiro & Kathryn J Moore

  2. Molecular Pathogenesis Program, The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, New York, USA

    Mickaël Ménager

  3. University of Ottawa Heart Institute, Ottawa, Ontario, Canada

    Michele Geoffrion

  4. Department of Surgery, New York University School of Medicine, New York, New York, USA

    George Miller, Ruth McPherson & Katey J Rayner

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  1. Bhama Ramkhelawon
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Contributions

B.R., K.J.R. and K.J.M. conceived of the study; B.R. performed the in vivo studies and data analyses, and assisted in the preparation of the manuscript; E.J.H., W.S. and S.H. assisted with mouse studies; F.J.S. performed ELISA assays; M.M. assisted with flow cytometry studies, S.O. performed RT-PCR; G.M. and R.M. collected human samples; K.J.R. and M.G. performed serum netrin-1 ELISA; T.D.R. performed western blotting; A.W. performed migration assays; and K.J.M. designed, analyzed and interpreted the studies, and wrote the manuscript.

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Correspondence to Kathryn J Moore.

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Ramkhelawon, B., Hennessy, E., Ménager, M. et al. Netrin-1 promotes adipose tissue macrophage retention and insulin resistance in obesity. Nat Med 20, 377–384 (2014). https://doi.org/10.1038/nm.3467

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