SDF-1 Is an Autocrine Insulin-Desensitizing Factor in Adipocytes

Insulin desensitization occurs not only under the obese diabetic condition but also in the fasting state. However, little is known about the common secretory factor(s) that are regulated under these two insulin-desensitized conditions. Here, using database analysis and in vitro and in vivo experiments, we identified stromal derived factor-1 (SDF-1) as an insulin-desensitizing factor in adipocytes, overexpressed in both fasting and obese adipose tissues. Exogenously added SDF-1 induced extracellular signal–regulated kinase signal, which phosphorylated and degraded IRS-1 protein in adipocytes, decreasing insulin-mediated signaling and glucose uptake. In contrast, knockdown of endogenous SDF-1 or inhibition of its receptor in adipocytes markedly increased IRS-1 protein levels and enhanced insulin sensitivity, indicating the autocrine action of SDF-1. In agreement with these findings, adipocyte-specific ablation of SDF-1 enhanced insulin sensitivity in adipose tissues and in the whole body. These results point to a novel regulatory mechanism of insulin sensitivity mediated by adipose autocrine SDF-1 action and provide a new insight into the process of insulin desensitization in adipocytes.