title: Hepatic oxidative stress promotes insulin-STAT-5 signaling and obesity by inactivating protein tyrosine phosphatase N2.
abstract: Hepatic insulin resistance is a key contributor to the pathogenesis of obesity and type 2 diabetes (T2D). Paradoxically, the development of insulin resistance in the liver is not universal, but pathway selective, such that insulin fails to suppress gluconeogenesis but promotes lipogenesis, contributing to the hyperglycemia, steatosis, and hypertriglyceridemia that underpin the deteriorating glucose control and microvascular complications in T2D. The molecular basis for the pathway-specific insulin resistance remains unknown. Here we report that oxidative stress accompanying obesity inactivates protein-tyrosine phosphatases (PTPs) in the liver to activate select signaling pathways that exacerbate disease progression. In obese mice, hepatic PTPN2 (TCPTP) inactivation promoted lipogenesis and steatosis and insulin-STAT-5 signaling. The enhanced STAT-5 signaling increased hepatic IGF-1 production, which suppressed central growth hormone release and exacerbated the development of obesity and T2D. Our studies define a mechanism for the development of selective insulin resistance with wide-ranging implications for diseases characterized by oxidative stress.
authors: Department of Biochemistry and Molecular Biology, Monash University, Wellington Road, Clayton, VIC 3800, Australia.
authors: Esteban N
authors: EN
authors: Gurzov
authors: Department of Biochemistry and Molecular Biology, Monash University, Wellington Road, Clayton, VIC 3800, Australia.
authors: Melanie
authors: M
authors: Tran
authors: Department of Biochemistry and Molecular Biology, Monash University, Wellington Road, Clayton, VIC 3800, Australia.
authors: Manuel A
authors: MA
authors: Fernandez-Rojo
authors: Department of Biochemistry and Molecular Biology, Monash University, Wellington Road, Clayton, VIC 3800, Australia.
authors: Troy L
authors: TL
authors: Merry
authors: Department of Biochemistry and Molecular Biology, Monash University, Wellington Road, Clayton, VIC 3800, Australia.
authors: Xinmei
authors: X
authors: Zhang
authors: Princess Margaret Cancer Center, University Health Network, 101 College Street, Toronto Medical Discovery Tower, University of Toronto, Toronto, ON M5G 1L7, Canada; Department of Medical Biophysics, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada.
authors: Yang
authors: Y
authors: Xu
authors: Department of Biochemistry and Molecular Biology, Monash University, Wellington Road, Clayton, VIC 3800, Australia.
authors: Atsushi
authors: A
authors: Fukushima
authors: Institute for Molecular Bioscience, Services Road, University of Queensland, St. Lucia, QLD 4072, Australia.
authors: Michael J
authors: MJ
authors: Waters
authors: Department of Physiology, Monash University, Wellington Road, Clayton, VIC 3800, Australia.
authors: Matthew J
authors: MJ
authors: Watt
authors: Department of Medicine Heidelberg Repatriation Hospital, 300 Waterdale Road, Heidelberg West, The University of Melbourne, VIC 3081, Australia.
authors: Sofianos
authors: S
authors: Andrikopoulos
authors: Princess Margaret Cancer Center, University Health Network, 101 College Street, Toronto Medical Discovery Tower, University of Toronto, Toronto, ON M5G 1L7, Canada; Department of Medical Biophysics, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada.
authors: Benjamin G
authors: BG
authors: Neel
authors: Department of Biochemistry and Molecular Biology, Monash University, Wellington Road, Clayton, VIC 3800, Australia. Electronic address: tony.tiganis@monash.edu.
authors: Tony
authors: T
authors: Tiganis
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D059305:Diet, High-Fat; D005260:Female; D005979:Glutathione Peroxidase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D013006:Growth Hormone / Q000378:metabolism; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D007328:Insulin / Q000378:metabolism* / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008099:Liver / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009765:Obesity / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D000094765:Glutathione Peroxidase GPX1
chemical_list: D007328:Insulin; D017382:Reactive Oxygen Species; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; C494080:Stat1 protein, mouse; C494087:Stat3 protein, mouse; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone; D005979:Glutathione Peroxidase; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2; D000094765:Glutathione Peroxidase GPX1; C000722068:Gpx1 protein, mouse