CXCL14 and insulin action.

CXCL14 is a member of CXC chemokine family. The physiological roles of CXCL14 and its receptor/signal transduction pathway remain largely unknown. In the human, CXCL14 exhibits chemoattractive activity for activated monocytes and dendritic precursor cells. Recruitment of dendritic precursor cells and inhibition of angiogenesis by CXCL14 suggest that this chemokine has a tumor suppressive function. However, analysis of CXCL14-deficient (CXCL14(-/-)) mice revealed that CXCL14 is dispensable for development and maintenance of tissue macrophages and dendritic cells. CXCL14(-/-) female mice, but not male mice, weigh significantly less than wild-type mice and are protected from obesity-induced hyperglycemia, hyperinsulinemia, hypoadiponectinemia, and insulin resistance. CXCL14 expression is elevated in white adipose tissue (WAT) of high-fat diet (HFD)-fed obese mice and leptin-system defective mutant mice. Phenotypes of HFD-fed CXCL14(-/-) female mice indicate that CXCL14 is involved in recruitment of macrophages into WAT, which causes chronic inflammation and contributes to insulin resistance. Transgenic overexpression of CXCL14 in skeletal muscle restores obesity-induced insulin resistance in CXCL14(-/-) female mice. In addition, CXCL14 attenuates insulin-stimulated glucose uptake in cultured myocytes. Based on these data, it is evident that CXCL14 is a novel regulator of glucose metabolism that acts by recruiting macrophages to WAT and interacting with insulin signaling pathways in skeletal muscle.