SH2B1 enhances insulin sensitivity by both stimulating the insulin receptor and inhibiting tyrosine dephosphorylation of insulin receptor substrate proteins.
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.


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 catalytic activity and insulin receptor substrate (IRS)-1/IRS-2 dephosphorylation was examined using in vitro kinase assays and in vitro dephosphorylation assays, respectively. SH2B1 was coexpressed with PTP1B, and insulin receptor-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 insulin receptor autophosphorylation and tyrosine phosphorylation of IRSs. Purified SH2B1 stimulated insulin receptor catalytic activity in vitro. The SH2 domain of SH2B1 was both required and sufficient to promote insulin receptor 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 phosphatidylinositol 3-kinase pathway.


CONCLUSIONS
SH2B1 is an endogenous insulin sensitizer. It directly binds to insulin receptors, IRS-1 and IRS-2, and enhances insulin sensitivity by promoting insulin receptor catalytic activity and by inhibiting tyrosine dephosphorylation of IRS proteins.
Morris
David L
DL
Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
Cho
Kae Won
KW
Zhou
Yingjiang
Y
Rui
Liangyou
L
D000273:Adipose Tissue / Q000502:physiology; D000818:Animals; D001921:Brain / Q000502:physiology; D019556:COS Cells; D002522:Chlorocebus aethiops; D004041:Dietary Fats / Q000494:pharmacology; D005260:Female; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology*; D007668:Kidney / Q000166:cytology; D008099:Liver / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000502:physiology; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism*; D010750:Phosphoproteins / Q000235:genetics* / Q000378:metabolism*; D010766:Phosphorylation / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D014157:Transcription Factors; D014443:Tyrosine / Q000378:metabolism
D004041:Dietary Fats; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; C526298:Irs2 protein, mouse; D009687:Nuclear Proteins; D010750:Phosphoproteins; C099550:Sh2bp1 protein, mouse; D014157:Transcription Factors; D014443:Tyrosine; D005947:Glucose