NR4A1 Counteracts Insulin Resistance Via Preserving The IRS1 Availability

Insulin resistance is the essential event for most type 2 diabetes formation.So far,to explore the the initiation of insulin resistance has become the bottle neck for diabetes research.Previously,we found NR4A1 alleviated JNK activation incurred by cellular stresses(ER-stress and oxidative stress)in pancreatic β cells via reducing MKK4(the kinase for JNK)level and/or via enhancing MKP7(a phosphotase for p-JNK)expression.It has been proved that activated JNK is an important player for insulin resistance.Whether NR4A1 is able to diminish insulin resistance via alleviating JNK activation in adipocytes or muscle cells remains unknown.NR4A1 KO mice exhibited metabolic abnormality and insulin resistance compared with the WT mice,such as increased body weight,increased adipose mass and decreased insulin sensitivity or response.To explore the underlie mechanisms,3T3 L1 adipocytes and C2C12 skeleton muscle cells were exploited to over-express NR4A1,thereafter,we found overexpression NR4A1 resulted in reduced JNK activation level,pS307IRS1 level and increased AKT activation level upon insulin stimulation;we further found the increased pS307IRS 1 level was JNK activation associated.Our data showed that NR4A1 over-expression in adipocytes or muscle cells led to increased cblb expression and decreased MKK4 level.We figured out that NR4A1 reduced pS307IRS1 level and increased insulin sensitivity via cblb/MKK4/p-JNK pathway in adipocytes and muscle cells.Our animal study further confirmed that the cblb protein expression level was reduced,p-JNK level and the pS307IRS1 level were increased in the adipose tissue or muscle tissue from NR4A1 KO mice compared with that from WT mice.We also found the expression of cblb was correlated with NR4A1 in adipose tissue and muscle tissue from WT mice rather than from NR4A1 KO mice.We conclude that the inducible molecule NR4A1 in adipocytes or muscle resists IRS1 phosphorylation at S307 via alleviating JNK activation pathway to ensure the availability of IRS1 for insulin signaling;conversely,the abortive NR4A1 expression results in increased JNK activation,subsequently increased pS307IRS1 level and consequently decreased availability of IRS 1 for insulin signaling,eventually results in insulin resistance.Our research provides a new view for insulin resistance initiation.