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

  1. André Marette1,2
  1. 1Department of Medicine, Faculty of Medicine, Cardiology Axis of the Institut Universitaire de Cardiologie et de Pneumologie de Québec (Hôpital Laval), Québec, Québec, Canada
  2. 2Department of Metabolism, Vascular and Renal Health Axis, Laval University Hospital Research Center, Québec, Québec, Canada
  3. 3Campbell Family Cancer Research Institute, Ontario Cancer Institute, Princess Margaret Hospital and Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
  4. 4Department of Medicine, University of Toronto, Mount Sinai Hospital Samuel Lunenfeld Research Institute, Toronto, Ontario, Canada
  5. 5Goodman Cancer Research Centre, McGill University, Montréal, Québec, Canada
  6. 6Departments of Biochemistry, Medicine, and Oncology, McGill University, Montréal, Québec, Canada
  1. Corresponding author: André Marette, andre.marette{at}criucpq.ulaval.ca.

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 (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.

Footnotes

  • Received October 25, 2011.
  • Accepted March 9, 2012.

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  1. Diabetes vol. 61 no. 8 1949-1958
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