Identification of IRS-1 Ser-1101 as a target of S6K1 in nutrient- and obesity-induced insulin resistance

• Published in: Proceedings of the National Academy of Sciences - PNAS 2007-08, Vol.104 (35), p.14056-14061
• Main Authors: Tremblay, Frédéric, Brûlé, Sophie, Hee Um, Sung, Li, Yu, Masuda, Kohei, Roden, Michael, Sun, Xiao Jian, Krebs, Michael, Polakiewicz, Roberto D, Thomas, George, Marette, André
• Format: Article
• Language: English
• Subjects: Adipocytes; Amino acids; animal proteins; Animals; Biological Sciences; free amino acids; HeLa cells; high fat diet; Humans; Insulin; Insulin Receptor Substrate Proteins; insulin receptor substrate-1; Insulin resistance; Insulin Resistance - physiology; Liver; Mice; mutants; Mutation; nutrient availability; nutrient excess; nutrient overload; nutrient sensing; Nutritional Status; Obesity; Obesity - physiopathology; Phosphoproteins - chemistry; Phosphoproteins - genetics; Phosphoproteins - metabolism; Phosphoproteins - physiology; Phosphorylation; protein kinases; protein phosphorylation; Proteins; RNA, Messenger - genetics; RNA, Small Interfering - genetics; Serine; Sirolimus - pharmacology; Skeletal muscle
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0706517104

S6K1 has emerged as a critical signaling component in the development of insulin resistance through phosphorylation and inhibition of IRS-1 function. This effect can be triggered directly by nutrients such as amino acids or by insulin through a homeostatic negative-feedback loop. However, the role of S6K1 in mediating IRS-1 phosphorylation in a physiological setting of nutrient overload is unresolved. Here we show that S6K1 directly phosphorylates IRS-1 Ser-1101 in vitro in the C-terminal domain of the protein and that mutation of this site largely blocks the ability of amino acids to suppress IRS-1 tyrosine and Akt phosphorylation. Consistent with this finding, phosphorylation of IRS-1 Ser-1101 is increased in the liver of obese db/db and wild-type, but not S6K1⁻/⁻, mice maintained on a high-fat diet and is blocked by siRNA knockdown of S6K1 protein. Finally, infusion of amino acids in humans leads to the concomitant activation of S6K1, phosphorylation of IRS-1 Ser-1101, a reduction in IRS-1 function, and insulin resistance in skeletal muscle. These findings indicate that nutrient- and hormonal-dependent activation of S6K1 causes insulin resistance in mice and humans, in part, by mediating IRS-1 Ser-1101 phosphorylation.