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LTB4 promotes insulin resistance in obese mice by acting on macrophages, hepatocytes and myocytes

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Abstract

Insulin resistance results from several pathophysiologic mechanisms, including chronic tissue inflammation and defective insulin signaling. We found that liver, muscle and adipose tissue exhibit higher levels of the chemotactic eicosanoid LTB4 in obese high-fat diet (HFD)–fed mice. Inhibition of the LTB4 receptor Ltb4r1, through either genetic or pharmacologic loss of function, led to an anti-inflammatory phenotype with protection from insulin resistance and hepatic steatosis. In vitro treatment with LTB4 directly enhanced macrophage chemotaxis, stimulated inflammatory pathways, reduced insulin-stimulated glucose uptake in L6 myocytes, and impaired insulin-mediated suppression of hepatic glucose output in primary mouse hepatocytes. This was accompanied by lower insulin-stimulated Akt phosphorylation and higher Irs-1/2 serine phosphorylation, and all of these events were dependent on Gαi and Jnk1, two downstream mediators of Ltb4r1 signaling. These observations elucidate a novel role of the LTB4–Ltb4r1 signaling pathway in hepatocyte and myocyte insulin resistance, and they show that in vivo inhibition of Ltb4r1 leads to robust insulin-sensitizing effects.

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Figure 1: Inhibition of Ltb4r1 leads to an insulin-sensitive phenotype.
Figure 2: Ltb4r1 inhibitor blocks macrophage chemotaxis both in vitro and in vivo.
Figure 3: Ltb4r1 inhibitor improves epi-WAT inflammation in HFD mice.
Figure 4: Ltb4r1 inhibitor ameliorates inflammation.
Figure 5: LTB4 directly induces insulin resistance in myocytes and hepatocytes.
Figure 6: Ltb4r1 inhibitor improves hepatic steatosis.

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Acknowledgements

We thank A.D. Luster from Harvard Medical School for providing the Ltb4r1-KO mice. We thank A. Klip at The Hospital for Sick Children in Canada for providing L6 myocytes. This study was funded in part by grants to J.M. Olefsky from the US National Institute of Diabetes and Digestive and Kidney Diseases (DK033651, DK074868, DK063491, DK09062), the Eunice Kennedy Shriver National Institute of Child Health and Human Development/National Institutes of Health through a Cooperative Centers Program in Reproduction and Infertility Research (J.M. Olefsky), and a grant to J.M.Olefsky from Merck, Inc.

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P.L. designed the studies and performed most of the experiments; D.Y.O. performed macrophage signaling, chemotaxis, and FACS analysis; G.B. did glucose uptake and gluconeogenesis assay and western blot. W.S.L., M.L. and S. Talukdar assisted with hyperinsulinemic-euglycemic clamps; A.J., M.M., O.O. and R.M. assisted with collecting tissues and gene expression measurements; H.C. performed the GTT in female ovariectomized mice; J.M. Ofrecio and S. Taguchi assisted with genotyping; P.L. and J.M. Olefsky analyzed and interpreted the data, supervised the project, and co-wrote the manuscript.

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Correspondence to Pingping Li or Jerrold M Olefsky.

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Li, P., Oh, D., Bandyopadhyay, G. et al. LTB4 promotes insulin resistance in obese mice by acting on macrophages, hepatocytes and myocytes. Nat Med 21, 239–247 (2015). https://doi.org/10.1038/nm.3800

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