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

• Published in: The Journal of biological chemistry 2007-10, Vol.282 (42), p.30423-30433
• Main Authors: Ruffolo, Salvatore C., Forsell, Pontus K.A., Yuan, Xiling, Desmarais, Sylvie, Himms-Hagen, Jean, Cromlish, Wanda, Wong, Kenny K., Kennedy, Brian P.
• Format: Article
• Language: English
• Subjects: Adenoviridae; Adipocytes - enzymology; Adipocytes - pathology; Adipose Tissue - enzymology; Adipose Tissue - pathology; Animals; Antibiotics, Antineoplastic - pharmacology; Enzyme Activation - drug effects; Enzyme Activation - genetics; Glucose - metabolism; Humans; Insulin Resistance - genetics; Medicin och hälsovetenskap; Mice; Mice, Inbred BALB C; Mice, Knockout; Organ Specificity - genetics; Phosphorylation; Protein Kinases - metabolism; Protein Tyrosine Phosphatase, Non-Receptor Type 1 - deficiency; Proto-Oncogene Proteins c-akt - metabolism; Receptor, Insulin - metabolism; Ribosomal Protein S6 Kinases, 70-kDa - metabolism; Sirolimus - pharmacology; TOR Serine-Threonine Kinases
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M700697200

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.