Hepatocyte-Specific Ptpn6 Deletion Protects From Obesity-Linked Hepatic Insulin Resistance

Abstract

The protein-tyrosine phosphatase Shp1 negatively regulates insulin action on glucose homeostasis in liver and muscle, but its potential role in obesity-linked insulin resistance has not been examined. To investigate the role of Shp1 in hepatic insulin resistance, we generated hepatocyte-specific Shp1 knockout mice ( Ptpn6 H-KO ), which were subjected to extensive metabolic monitoring throughout an 8-week standard chow diet (SD) or high-fat diet (HFD) feeding. We report for the first time that Shp1 expression is upregulated in metabolic tissues of HFD-fed obese mice. When compared with their Shp1-expressing Ptpn6 f/f littermates, Ptpn6 H-KO mice exhibited significantly lowered fasting glycemia and heightened hepatic insulin sensitivity. After HFD feeding, Ptpn6 H-KO mice developed comparable levels of obesity as Ptpn6 f/f mice, but they were remarkably protected from liver insulin resistance, as revealed by euglycemic clamps and hepatic insulin signaling determinations. Although Ptpn6 H-KO mice still acquired diet-induced peripheral insulin resistance, they were less hyperinsulinemic during a glucose tolerance test because of reduced insulin secretion. Ptpn6 H-KO mice also exhibited increased insulin clearance in line with enhanced CC1 tyrosine phosphorylation in liver. These results show that hepatocyte Shp1 plays a critical role in the development of hepatic insulin resistance and represents a novel therapeutic target for obesity-linked diabetes.

Inhibition of Src homology 2 domain‐containing phosphatase 1 increases insulin sensitivity in high‐fat diet‐induced insulin‐resistant mice

“…After SHP‐1 inhibition, increased phosphorylation of the insulin receptor and the downstream kinase Akt, suggest that SHP‐1 may be a suitable drug target. This is consistent with the data recently received in mice with hepatocyte‐specific Ptpn6 deletion, resulting in lower fasting glucose and improved hepatic insulin sensitivity 8. To analyse the impact of a pharmacological PTP inhibition in vivo a commonly used model of insulin resistance induced by HFD feeding was applied in mice 8, 9, 26, 28, 29.…”

“…Moreover, elevated expression and activity of PTPs was detected in metabolic tissues in HFD‐induced insulin‐resistant mice earlier 8, 15, 27, including SHP‐1 8. Based on these data, SHP‐1 represents a potential therapeutic target for pharmacological intervention with sodium stibogluconate, a potent SHP‐1 inhibitor 22.…”

“…Besides other causes, obesity has been found being both associated with and promoting of insulin resistance. Strikingly, in insulin resistance upregulation and altered activity of PTPs have been detected 8, 9, 10.…”

Hyperinsulinemia induces insulin resistance and immune suppression via Ptpn6/Shp1 in zebrafish

“…In addition, it has been reported that PTPN6 may be involved in the development of insulin resistance and non-alcoholic fatty liver diseases in obesity (Xu et al 2012(Xu et al , 2014a. Pioneering studies performed by Dubois et al (2006) showed that PTPN6-deficient mice exhibited improved insulin sensitivity and glucose tolerance.…”

“…Pioneering studies performed by Dubois et al (2006) showed that PTPN6-deficient mice exhibited improved insulin sensitivity and glucose tolerance. Further studies by this group demonstrated that hepatocyte-specific Ptpn6 knockout (Ptpn6 H-KO ) mice were protected from hepatic insulin resistance and hepatocellular damage caused by diet-induced obesity (Xu et al 2012(Xu et al , 2014a.…”