Activation of Nogo‐B receptor expression ameliorates type 2 diabetes in mice by improving insulin sensitivity

Abstract

Reduction of insulin resistance/improvement of insulin sensitivity is the most effective treatment for type 2 diabetes (T2D). We previously reported Nogo‐B receptor (NGBR) is a specific negative regulator for liver X receptor alpha (LXRα)‐dependent hepatic lipogenesis, indicating NGBR may play an important role in hepatic lipid metabolism. However, it remains unknown if NGBR is involved in glucose metabolism and insulin sensitivity. Herein, we report the role of NGBR expression in insulin resistance and T2D development.In vitro, the role of NGBR in insulin sensitivity was analyzed by NGBR knockdown/overexpression in hepatic cell line. The pathophysiological role of NGBR in insulin sensitivity was analyzed in high‐fat diet (HFD)/streptozotocin (STZ)‐induced diabetic mice infected with recombinant adenovirus expressing NGBR by tail vein injection. We found inhibition of NGBR expression by siRNA decreased insulin sensitivity, and attenuated adiponectin‐activated AMPKa phosphorylation in hepatocytes. Reciprocally, NGBR overexpression enhanced insulin response. In vivo, NGBR overexpression was observed in mouse liver after infection of recombinant adenovirus expressing NGBR. Associated with NGBR overexpression, blood glucose was reduced while insulin sensitivity/glucose homeostasis was enhanced. NGBR overexpression also decreased triglyceride and NEFA levels in both liver and serum, and attenuated the injury in pancreatic islets. Furthermore, genes related to ER stress and mitochondrial functions in skeletal muscles and inflammation in adipose tissues were improved by hepatic NGBR overexpression. In conclusion, our study implicates the importance of understanding the role of hepatic NGBR in insulin sensitivity and treatment of T2D.