Hepatocyte-Specific Ptpn6 Deletion Protects From Obesity-Linked Hepatic Insulin Resistance
- Elaine Xu1,2,
- Alexandre Charbonneau1,2,
- Yannève Rolland1,2,
- Kerstin Bellmann1,2,
- Lily Pao3,
- Katherine A. Siminovitch4,
- Benjamin G. Neel3,
- Nicole Beauchemin5,6 and
- André Marette1,2⇓
- 1Department of Medicine, Faculty of Medicine, Cardiology Axis of the Institut Universitaire de Cardiologie et de Pneumologie de Québec (Hôpital Laval), Québec, Québec, Canada
- 2Department of Metabolism, Vascular and Renal Health Axis, Laval University Hospital Research Center, Québec, Québec, Canada
- 3Campbell Family Cancer Research Institute, Ontario Cancer Institute, Princess Margaret Hospital and Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
- 4Department of Medicine, University of Toronto, Mount Sinai Hospital Samuel Lunenfeld Research Institute, Toronto, Ontario, Canada
- 5Goodman Cancer Research Centre, McGill University, Montréal, Québec, Canada
- 6Departments of Biochemistry, Medicine, and Oncology, McGill University, Montréal, Québec, Canada
- Corresponding author: André Marette, .
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 (Ptpn6H-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 Ptpn6f/f littermates, Ptpn6H-KO mice exhibited significantly lowered fasting glycemia and heightened hepatic insulin sensitivity. After HFD feeding, Ptpn6H-KO mice developed comparable levels of obesity as Ptpn6f/f mice, but they were remarkably protected from liver insulin resistance, as revealed by euglycemic clamps and hepatic insulin signaling determinations. Although Ptpn6H-KO mice still acquired diet-induced peripheral insulin resistance, they were less hyperinsulinemic during a glucose tolerance test because of reduced insulin secretion. Ptpn6H-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.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db11-1502/-/DC1.
L.P. is currently affiliated with Five Prime Therapeutics, South San Francisco, California.
- Received October 25, 2011.
- Accepted March 9, 2012.
- © 2012 by the American Diabetes Association.
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