Myostatin induces insulin resistance via Cblb-mediated degradation of IRS1 in response to high calorie diet intake [Gene Regulation]

January 22nd, 2014 by Bonala, S., Lokireddy, S., McFarlane, C., Patnam, S., Sharma, M., Kambadur, R.

To date a plethora of evidence has clearly demonstrated that continued high calorie intake leads to insulin resistance and T2D with or without obesity. However, the necessary signals that initiate insulin resistance during high calorie intake remain largely unknown. Our results here show that in response to a regimen of high fat or high glucose diets, Mstn levels were induced in muscle and liver of mice. High glucose or fat mediated induction of Mstn was controlled at the level of transcription, since highly conserved carbohydrate response (ChoRE) and sterol responsive (E-box) elements were present in the Mstn promoter and were revealed to be critical for ChREBP or SREBP1c regulation of Mstn expression. Further molecular analysis suggested that the increased Mstn levels (due to high glucose or fatty acid loading) resulted in increased expression of Cblb in a Smad3-dependent manner. Cblb is an ubiquitin E3 ligase that has been shown to specifically degrade IRS1 protein. Consistent with this, our results revealed that elevated Mstn levels specifically up regulated Cblb, resulting in enhanced ubiquitin proteasome-mediated degradation of IRS1. In addition, over expression or knock down of Cblb had a major impact on IRS1 and pAkt levels in the presence or absence of insulin. Collectively, these observations strongly suggest that increased glucose levels and high fat diet both result in increased circulatory Mstn levels. The increased Mstn in turn, is a potent inducer of insulin resistance by degrading IRS1 protein via the E3 ligase, Cblb in a Smad3-dependent manner.