抄録
Background
Dysregulation of insulin signaling in adipocytes is strongly associated with obesity-related metabolic disorders. However, its underlying molecular mechanism remains poorly understood. Here we report a novel gene that provides a previously unknown molecular mechanism in the regulation of adipocyte insulin signaling.
Methods
Through DNA microarray analysis using RNAs isolated from white adipose tissue (WAT) of lean and obese mice, we identified family with sequence similarity 13, member A (Fam13a) as a gene that is highly expressed in healthy WAT and down-regulated in obesity. Biological functions of Fam13a were analyzed using 3T3-L1 adipocytes and HEK293 cells in vitro. We also generated mice with targeted deletion or activation of Fam13a in adipocytes to assess Fam13a function in vivo. These mice were fed with either normal chow (NCD) or high-fat diet (HFD). Insulin sensitivity and glucose homeostasis were assessed by insulin tolerance and glucose tolerance test, respectively.
Results
Fam13a was highly expressed in mature adipocyte of WAT, and its expression in WAT was substantially reduced during obesity. We found that gene-silencing of Fam13a impaired insulin signaling in 3T3-L1 adipocytes, while overexpression of Fam13a accelerated it in HEK293 cells. We identified that Fam13a bound to insulin receptor substrate (IRS)-1 in its coiled-coil domain-dependent manner. Furthermore, Fam13a associated with protein phosphatase 2A (PP2A), and thus recruited PP2A to IRS1. This PP2A recruitment caused reduced Ser/Thr phosphorylation in IRS-1, which prevent the proteasomal degradation of IRS-1. Therefore, Fam13a increased IRS-1 expression and consequently accelerated insulin signaling. Targeted deletion of Fam13a exacerbated insulin resistance and worsened glucose tolerance in mice fed a high-fat diet due to impaired insulin signaling in WAT. Inversely, targeted activation of Fam13a in adipocytes enhanced insulin sensitivity even while consuming normal chow in association with augmented insulin signaling in WAT.
Conclusions
We revealed a novel mechanism regulating adipocyte insulin signaling by Fam13a. Since adipocyte insulin resistance is critically involved in the pathophysiology of obesity-related metabolic disorders, our data established Fam13a as a novel pharmacotherapeutic target for the treatment of metabolic disease.
