T-Cell Protein Tyrosine Phosphatase Attenuates STAT3 and Insulin Signaling in the Liver to Regulate Gluconeogenesis
- Atsushi Fukushima1,
- Kim Loh1,
- Sandra Galic1,
- Barbara Fam2,
- Ben Shields1,
- Florian Wiede1,
- Michel L. Tremblay3,
- Matthew J. Watt4,
- Sofianos Andrikopoulos2 and
- Tony Tiganis1
- 1Department of Biochemistry and Molecular Biology, Monash University, Victoria, Australia;
- 2Department of Medicine, Heidelberg Repatriation Hospital, The University of Melbourne, Victoria, Australia;
- 3Goodman Cancer Centre and the Department of Biochemistry, McGill University, Montreal, Quebec, Canada;
- 4Department of Physiology, Monash University, Victoria, Australia.
- Corresponding author: Tony Tiganis, Tony.Tiganis{at}med.monash.edu.au.
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 T-cell 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 analyzed insulin sensitivity and gluconeogenesis in chow versus high-fat–fed (HFF) Ptpn2+/− and Ptpn2+/+ mice and insulin and IL-6 signaling and gluconeogenic gene expression in Ptpn2+/− and Ptpn2+/+ hepatocytes.
RESULTS HFF Ptpn2+/− mice exhibited lower fasted blood glucose and decreased hepatic glucose output as determined in hyperinsulinemic euglycemic 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-β–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.
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- © 2010 by the American Diabetes Association.
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