We have previously shown that Sam68-deficient mice have a lean phenotype and are protected against dietary-induced obesity due to defects in mTOR and S6K1 alternative splicing.
The increased levels of S6K1 in obesity and its positive association with insulin resistance and inflammation suggest a role for this protein in the changes that take place in VAT in obesity establishing a link between inflammation and a higher risk for the development of metabolic diseases.
Earlier, we reported that S6K1(-/-) mice have reduced body fat mass, have elevated rates of lipolysis, have severely decreased adipocyte size, and are resistant to high fat diet (HFD)-induced obesity.
Time-course studies also revealed that mTOR and S6K1 activation by insulin was accelerated in tissues of obese rats, in association with increased inhibitory phosphorylation of insulin receptor substrate-1 (IRS-1) on Ser636/Ser639 and impaired Akt activation.
In vitro studies with rapamycin suggest that mTOR/S6K1 overactivation contributes to elevated serine phosphorylation of IRS-1, leading to impaired insulin signaling to Akt in liver and muscle of this dietary model of obesity.