Editors' ChoiceMetabolism

Trapped in Fat

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Science Signaling  29 Apr 2014:
Vol. 7, Issue 323, pp. ec113
DOI: 10.1126/scisignal.2005424

Obesity triggers the accumulation of macrophages in adipose tissue, which triggers chronic inflammation that contributes to insulin resistance. Ramkhelawon et al. found that this obesity-induced accumulation of macrophages in adipose tissue required netrin-1, initially characterized as a guidance cue for axonal growth cones, and its chemorepulsive receptor UNC5B. Mice fed a high-fat diet showed increased expression of Ntn1 (which encodes netrin-1) and increased netrin-1 abundance, as well as increased mRNA and protein abundance for Unc5b (but not those for the chemoattractive receptors for netrin-1) in visceral adipose tissue compared with mice fed standard chow. Adipose tissue from obese individuals showed increased expression of NTN1 and UNC5H2 (an Unc5b human homolog) compared with that from lean individuals. A high-fat diet increases the serum concentrations of free fatty acids, which evoke inflammatory responses in macrophages. Application of the saturated free fatty acid palmitate to bone marrow–derived macrophages increased the expression of Ntn1 and Unc5b and the release of netrin-1 from macrophages in an NF-κB (nuclear factor κB)–dependent manner. Furthermore, application of medium conditioned by palmitate-treated differentiated 3T3-L1 cells to bone marrow-derived macrophages increased the expression of Ntn1 and Unc5b in a manner that partially required the cytokines TNF-α (tumor necrosis factor–α) and IL-6 (interleukin-6). Compared with adipose tissue macrophages from mice on a standard diet, those from mice fed a high-fat diet showed reduced migration in response to the chemokine CCL19, a defect that was rescued by a blocking antibody to Unc5b. Moreover, palmitate-treated peritoneal macrophages migrated to a lesser extent in response to CCL19 compared with untreated counterparts, and the defect in migration was attenuated by a competitive peptide inhibitor of netrin-1. Mice reconstituted with bone marrow from Ntn1–/– mice fed a high-fat diet showed fewer signs of adipose tissue inflammation and increased emigration of macrophages from adipose tissue, as well as improved glucose tolerance and insulin sensitivity. Thus, targeting the netrin-Unc5b signaling pathway in macrophages could improve metabolic parameters by diminishing the inflammation associated with obesity.

B. Ramkhelawon, E. J. Hennessy, M. Ménager, T. D. Ray, F. J. Sheedy, S. Hutchison, A. Wanschel, S. Oldebeken, M. Geoffrion, W. Spiro, G. Miller, R. McPherson, K. J. Rayner, K. J. Moore, Netrin-1 promotes adipose tissue macrophage retention and insulin resistance in obesity. Nat. Med. 20, 377–384 (2014). [PubMed]