Lipocalin-13 Regulates Glucose Metabolism by both Insulin-Dependent and Insulin-Independent Mechanisms

Abstract

Insulin sensitivity is impaired in obesity, and insulin resistance is the primary risk factor for type 2 diabetes. Here we show that lipocalin-13 (LCN13), a lipocalin superfamily member, is a novel insulin sensitizer. LCN13 was secreted by multiple cell types. Circulating LCN13 was markedly reduced in mice with obesity and type 2 diabetes. Three distinct approaches were used to increase LCN13 levels: LCN13 transgenic mice, LCN13 adenoviral infection, and recombinant LCN13 administration. Restoration of LCN13 significantly ameliorated hyperglycemia, insulin resistance, and glucose intolerance in mice with obesity. LCN13 enhanced insulin signaling not only in animals but also in cultured adipocytes. Recombinant LCN13 increased the ability of insulin to stimulate glucose uptake in adipocytes and to suppress hepatic glucose production (HGP) in primary hepatocyte cultures. Additionally, LCN13 alone was able to suppress HGP, whereas neutralization of LCN13 increased HGP in primary hepatocyte cultures. These data suggest that LCN13 regulates glucose metabolism by both insulin-dependent and insulin-independent mechanisms. LCN13 and LCN13-related molecules may be used to treat insulin resistance and type 2 diabetes.

ACKNOWLEDGMENTS

This study was supported by grants DK065122 and DK073601 from the National Institutes of Health and by research award 1-09-RA-156 from the American Diabetes Association. This work utilized the cores supported by the Michigan Diabetes Research and Training Center (funded by NIH 5P60 DK20572), the University of Michigan's Cancer Center (funded by NIH 5P30 CA46592), the University of Michigan Nathan Shock Center (funded by NIH P30AG013283), and the University of Michigan Gut Peptide Research Center (funded by NIH DK34933).

We thank Hong Shen and Lin Jiang for their technical support and for helpful discussions.