Basal Activation of p70S6K Results in Adipose-specific Insulin Resistance in Protein-tyrosine Phosphatase 1B–/– Mice

Although protein-tyrosine phosphatase 1B (PTP-1B) is a negative regulator of insulin action, adipose tissue from PTP-1B–/– mice does not show enhanced insulin-stimulated insulin receptor phosphorylation. Investigation of glucose uptake in isolated adipocytes revealed that the adipocytes from PTP-1B–/– mice have a significantly attenuated insulin response as compared with PTP-1B+/+ adipocytes. This insulin resistance manifests in PTP-1B–/– animals older than 16 weeks of age and could be partially rescued by adenoviral expression of PTP-1B in null adipocytes. Examination of adipose signaling pathways found that the basal p70S6K activity was at least 50% higher in adipose from PTP-1B–/– mice compared with wild type animals. The increased basal activity of p70S6K in PTP-1B–/– adipose correlated with decreases in IR substrate-1 protein levels and insulin-stimulated Akt/protein kinase B activity, explaining the decrease in insulin sensitivity even as insulin receptor phosphorylation was unaffected. The insulin resistance of the of the PTP-1B–/– adipocytes could also be rescued by treatment with rapamycin, suggesting that in adipose the loss of PTP-1B results in basal activation of mTOR (mammalian target of rapamycin) complex 1 leading to a tissue-specific insulin resistance. Although protein-tyrosine phosphatase 1B (PTP-1B) is a negative regulator of insulin action, adipose tissue from PTP-1B–/– mice does not show enhanced insulin-stimulated insulin receptor phosphorylation. Investigation of glucose uptake in isolated adipocytes revealed that the adipocytes from PTP-1B–/– mice have a significantly attenuated insulin response as compared with PTP-1B+/+ adipocytes. This insulin resistance manifests in PTP-1B–/– animals older than 16 weeks of age and could be partially rescued by adenoviral expression of PTP-1B in null adipocytes. Examination of adipose signaling pathways found that the basal p70S6K activity was at least 50% higher in adipose from PTP-1B–/– mice compared with wild type animals. The increased basal activity of p70S6K in PTP-1B–/– adipose correlated with decreases in IR substrate-1 protein levels and insulin-stimulated Akt/protein kinase B activity, explaining the decrease in insulin sensitivity even as insulin receptor phosphorylation was unaffected. The insulin resistance of the of the PTP-1B–/– adipocytes could also be rescued by treatment with rapamycin, suggesting that in adipose the loss of PTP-1B results in basal activation of mTOR (mammalian target of rapamycin) complex 1 leading to a tissue-specific insulin resistance. The binding of insulin to the insulin receptor (IR) 3The abbreviations used are: IR, insulin receptor; IRS, IR substrate; PTP-1B, protein-tyrosine phosphatase 1B; p70S6K, p70 S6 kinase; mTOR, mammalian target of rapamycin; TORC, mTOR complex; IWAT, inguinal white adipose tissue; IBAT, interscapular brown adipose tissue; PKA, protein kinase A; CREB, cyclic-AMP responsive element-binding protein; PTEN, phosphatase and tensin homolog; TSC, tuberous sclerosis complex; BSA, bovine serum albumin; siRNA, small interfering RNA; PBS, phosphate-buffered saline; MOPS, 4-morpholinepropanesulfonic acid; WT, wild type. induces autophosphorylation of the IR on several key tyrosine residues. Tyrosine phosphorylation of the receptor leads to the recruitment of adaptor proteins and further propagation of the insulin signal in the cell. Protein-tyrosine phosphatase 1B (PTP-1B) has been shown to be a negative regulator of insulin signaling by interacting with (1Boute N. Boubekeur S. Lacasa D. Issad T. 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Full Text Full Text PDF PubMed Scopus Google Scholar). of insulin sensitivity, of the insulin signaling as well as in insulin signaling in the adipose of PTP-1B–/– The that adipocytes from PTP-1B–/– mice decrease in insulin that is attributable to a in protein The reduced protein levels the of in the activity of p70S6K in PTP-1B–/– adipocytes. This that PTP-1B in adipose of p70S6K resulting in tissue-specific insulin resistance. of PTP-1B–/– mice has been and on (5Elchebly M. Payette P. Michaliszyn E. Cromlish W. Collins S. Loy A.L. Normandin D. Cheng A. Himms-Hagen J. Chan C.C. Ramachandran C. Gresser M.J. Tremblay M.L. Kennedy B.P. 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Biol. Chem. Full Text PDF PubMed Google Scholar). at in with and insulin the and and at the insulin was and and the as the and the of used was with and at with and in in 1 of insulin at with and in 1 of at by with PBS, with of and uptake was in the of B and from to activity in was the kinase from with adipocytes and with with with of and as the p70S6K with adipocytes and with with with of 1 1 of and with to with of 1 of at with MOPS, 1 1 and with in of of complex was with of of in at The was by of to a and with and with and The was p70S6K phosphorylation by in PTP-1B have shown that of PTP-1B in mice to in the insulin sensitivity of partially attributable to increased insulin-stimulated tyrosine phosphorylation of the IR in muscle and liver (5Elchebly M. Payette P. Michaliszyn E. Cromlish W. Collins S. Loy A.L. Normandin D. Cheng A. Himms-Hagen J. Chan C.C. Ramachandran C. Gresser M.J. Tremblay M.L. Kennedy B.P. 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