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

Pingping Li, Dayoung Oh, Gautam Bandyopadhyay, William S. Lagakos, Saswata Talukdar, Olivia Osborn, Andrew Johnson, Heekyung Chung, Rafael Mayoral, Michael Maris, Jachelle M. Ofrecio, Sayaka Taguchi, Min Lu, Jerrold M. Olefsky

Research output: Contribution to journalArticle

132 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)239-247
Number of pages9
JournalNature medicine
Volume21
Issue number3
DOIs
StatePublished - Mar 2015

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Li, P., Oh, D., Bandyopadhyay, G., Lagakos, W. S., Talukdar, S., Osborn, O., Johnson, A., Chung, H., Mayoral, R., Maris, M., Ofrecio, J. M., Taguchi, S., Lu, M., & Olefsky, J. M. (2015). LTB4 promotes insulin resistance in obese mice by acting on macrophages, hepatocytes and myocytes. Nature medicine, 21(3), 239-247. https://doi.org/10.1038/nm.3800