Abstract

Objective- SH2B1 is a SH2 domain-containing adaptor protein expressed in both the central nervous system and peripheral tissues. Neuronal SH2B1 controls body weight; however, the functions of peripheral SH2B1 remain unknown. Here we studied peripheral SH2B1 regulation of insulin sensitivity and glucose metabolism.

Research Design and Methods- We generated TgKO mice expressing SH2B1 in the brain but not peripheral tissues. Various metabolic parameters and insulin signaling were examined in TgKO mice fed a high fat diet (HFD). The effect of SH2B1 on the insulin receptor (IR) catalytic activity and IRS-1/IRS-2 dephosphorylation was examined using in vitro kinase assays and in vitro dephosphorylation assays, respectively. SH2B1 was coexpressed with PTP1B, and IR-mediated phosphorylation of IRS-1 was examined.

Results- Deletion of peripheral SH2B1 markedly exacerbated HFD-induced hyperglycemia, hyperinsulinemia and glucose intolerance in TgKO mice. Insulin signaling was dramatically impaired in muscle, liver and adipose tissue in TgKO mice. Deletion of SH2B1 impaired insulin signaling in primary hepatocytes, whereas SH2B1 overexpression stimulated IR autophosphorylation and tyrosine phosphorylation of IR substrates. Purified SH2B1 stimulated IR catalytic activity in vitro. The SH2 domain of SH2B1 was both required and sufficient to promote IR activation. Insulin stimulated the binding of SH2B1 to IRS-1 or IRS-2. This physical interaction inhibited tyrosine dephosphorylation of IRS-1 or IRS-2 and increased the ability of IRS proteins to activate the PI 3-kinase pathway.

Conclusions- SH2B1 is an endogenous insulin sensitizer. It directly binds to IR, IRS-1 and IRS-2, and enhances insulin sensitivity by promoting IR catalytic activity and by inhibiting tyrosine dephosphorylation of IRS proteins.