Hepatic oxidative stress promotes insulin-STAT-5 signaling and obesity by inactivating protein tyrosine phosphatase N2

Gurzov, Esteban N., Tran, Melanie, Fernandez-Rojo, Manuel A., Merry, Troy L., Zhang, Xinmei, Xu, Yang, Fukushima, Atsushi, Waters, Michael J., Watt, Matthew J., Andrikopoulos, Sofianos, Neel, Benjamin G. and Tiganis, Tony (2014) Hepatic oxidative stress promotes insulin-STAT-5 signaling and obesity by inactivating protein tyrosine phosphatase N2. Cell Metabolism, 20 1: 85-102. doi:10.1016/j.cmet.2014.05.011


Author Gurzov, Esteban N.
Tran, Melanie
Fernandez-Rojo, Manuel A.
Merry, Troy L.
Zhang, Xinmei
Xu, Yang
Fukushima, Atsushi
Waters, Michael J.
Watt, Matthew J.
Andrikopoulos, Sofianos
Neel, Benjamin G.
Tiganis, Tony
Title Hepatic oxidative stress promotes insulin-STAT-5 signaling and obesity by inactivating protein tyrosine phosphatase N2
Journal name Cell Metabolism   Check publisher's open access policy
ISSN 1932-7420
1550-4131
Publication date 2014-07-01
Year available 2014
Sub-type Article (original research)
DOI 10.1016/j.cmet.2014.05.011
Open Access Status
Volume 20
Issue 1
Start page 85
End page 102
Total pages 18
Place of publication Cambridge, MA, United States
Publisher Cell Press
Language eng
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.
Keyword Hepatic insulin resistance
Obesity
Type 2 diabetes
Hepatic oxidative stress
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2015 Collection
Institute for Molecular Bioscience - Publications
 
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