Hepatic Oxidative Stress Promotes Insulin-STAT-5 Signaling and Obesity by Inactivating Protein Tyrosine Phosphatase N2

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, contribut...

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Veröffentlicht in:Cell metabolism 2014-07, Vol.20 (1), p.85-102
Hauptverfasser: 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
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Sprache:eng
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Zusammenfassung: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. [Display omitted] •Reactive oxygen species oxidize and inactivate hepatic PTPs in obesity•PTPN2 (TCPTP) inactivation in the liver promotes insulin-STAT-5 signaling•PTPN2 inactivation and STAT-5 signaling in the liver promotes obesity•PTPN2 inactivation in the liver promotes steatosis and insulin resistance Oxidative stress occurs in a wide variety of human diseases, including obesity and diabetes. Gurzov et al. elucidate a pathway whereby oxidative stress inactivates protein tyrosine phosphatase N2 (also known as TCPTP) in the liver to selectively promote lipogenesis and insulin-induced STAT-5 signaling, leading to obesity.
ISSN:1550-4131
1932-7420
DOI:10.1016/j.cmet.2014.05.011