T-cell protein tyrosine phosphatase attenuates STAT3 and insulin signaling in the liver to regulate gluconeogenesis

Atsushi Fukushima, Kim Loh, Sandra Galic, Barbara Fam, Benjamin Shields, Florian Wiede, Michel L Tremblay, Matthew J Watt, Sofianos Andrikopoulos, Tony Tiganis

Research output: Contribution to journalArticleResearchpeer-review

60 Citations (Scopus)

Abstract

Abstract Objective - Insulin-induced phosphatidylinositol 3-kinase (PI3K)/Akt signaling and interleukin-6 (IL-6)-instigated JAK/STAT3 signaling pathways in the liver inhibit the expression of gluconeogenic genes to decrease hepatic glucose output. The insulin receptor (IR) and JAK1 tyrosine kinases and STAT3 can serve as direct substrates for the protein tyrosine phosphatase TCPTP. Homozygous TCPTP-deficiency results in perinatal lethality prohibiting any informative assessment of TCPTP s role in glucose homeostasis. Here we have used Ptpn2+/- mice to investigate TCPTP s function in glucose homeostasis. Research design and methods - We analysed insulin sensitivity and gluconeogenesis in chow versus high fat fed Ptpn2+/- and Ptpn2+/+ mice and insulin and IL-6 signaling and gluconeogenic gene expression in Ptpn2+/- and Ptpn2+/+ hepatocytes. Results - High fat fed Ptpn2+/- mice exhibited lower fasted blood glucose and decreased hepatic glucose output as determined in hyperinsulinaemic euglycaemic clamps and by the decreased blood glucose levels in pyruvate tolerance tests. The reduced hepatic glucose output coincided with decreased expression of the gluconeogenic genes G6pc and Pck1 and enhanced hepatic STAT3 phosphorylation and PI3K/Akt signaling in the fasted state. Insulin-induced IR b-subunit Y1162/Y1163 phosphorylation and PI3K/Akt signaling and IL-6-induced STAT3 phosphorylation were also enhanced in isolated Ptpn2+/- hepatocytes. The increased insulin and IL-6 signaling resulted in enhanced suppression of G6pc and Pck1 mRNA. Conclusions - Liver TCPTP antagonises both insulin and STAT3 signaling pathways to regulate gluconeogenic gene expression and hepatic glucose output.
Original languageEnglish
Pages (from-to)1906 - 1914
Number of pages9
JournalDiabetes
Volume59
Issue number8
DOIs
Publication statusPublished - 2010

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