Identification of IRS-1 Ser-1101 as a target of S6K1 in nutrient- and obesity-induced insulin resistance.
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.
Tremblay
Frédéric
F
Department of Anatomy and Physiology, Laval University Hospital Research Center, Ste-Foy, QC, Canada G1V 4G2.
Brûlé
Sophie
S
Hee Um
Sung
S
Li
Yu
Y
Masuda
Kohei
K
Roden
Michael
M
Sun
Xiao Jian
XJ
Krebs
Michael
M
Polakiewicz
Roberto D
RD
Thomas
George
G
Marette
André
A
D000818:Animals; D006801:Humans; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance / Q000502:physiology*; D051379:Mice; D009752:Nutritional Status; D009765:Obesity / Q000503:physiopathology*; D010750:Phosphoproteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D010766:Phosphorylation; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D012694:Serine; D020123:Sirolimus / Q000494:pharmacology
C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D010750:Phosphoproteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D012694:Serine; D020123:Sirolimus
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