Journal Article

Liver-Specific Deletion of Protein-Tyrosine Phosphatase 1B (PTP1B) Improves Metabolic Syndrome and Attenuates Diet-Induced Endoplasmic Reticulum Stress

Jason K. Kim, Benjamin G. Neel, You-Ree Cho, Barbara B. Kahn, Mirela Delibegovic, Derek Zimmer, Eun-Gyoung Hong, Kendra K. Bence, Caitlin Kauffman, Kimberly Rak

2009

Overview

Liver-Specific Deletion of Protein-Tyrosine Phosphatase 1B (PTP1B) Improves Metabolic Syndrome and Attenuates Diet-Induced Endoplasmic Reticulum Stress Mirela Delibegovic 1 6 , Derek Zimmer 2 , Caitlin Kauffman 2 , Kimberly Rak 2 , Eun-Gyoung Hong 3 4 , You-Ree Cho 4 , Jason K. Kim 3 4 , Barbara B. Kahn 5 , Benjamin G. Neel 1 7 and Kendra K. Bence 2 1 Cancer Biology Program, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 2 Department of Animal Biology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 3 Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 4 Department of Internal Medicine, Section of Endocrinology and Metabolism, Yale University School of Medicine, New Haven, Connecticut 5 Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 6 School of Biological Sciences, University of Aberdeen, Aberdeen, U.K 7 Division of Stem Cell and Developmental Biology, Ontario Cancer Institute, Toronto, Canada Corresponding authors: Kendra Bence, kbence{at}vet.upenn.edu , and Mirela Delibegovic, m.delibegovic{at}abdn.ac.uk Abstract OBJECTIVE— The protein tyrosine phosphatase PTP1B is a negative regulator of insulin signaling; consequently, mice deficient in PTP1B are hypersensitive to insulin. Because PTP1B −/− mice have diminished fat stores, the extent to which PTP1B directly regulates glucose homeostasis is unclear. Previously, we showed that brain-specific PTP1B −/− mice are protected against high-fat diet–induced obesity and glucose intolerance, whereas muscle-specific PTP1B −/− mice have increased insulin sensitivity independent of changes in adiposity. Here we studied the role of liver PTP1B in glucose homeostasis and lipid metabolism. RESEARCH DESIGN AND METHODS— We analyzed body mass/adiposity, insulin sensitivity, glucose tolerance, and lipid metabolism in liver-specific PTP1B −/− and PTP1Bfl/fl control mice, fed a chow or high-fat diet. RESULTS— Compared with normal littermates, liver-specific PTP1B −/− mice exhibit improved glucose homeostasis and lipid profiles, independent of changes in adiposity. Liver-specific PTP1B −/− mice have increased hepatic insulin signaling, decreased expression of gluconeogenic genes PEPCK and G-6-Pase, enhanced insulin-induced suppression of hepatic glucose production, and improved glucose tolerance. Liver-specific PTP1B −/− mice exhibit decreased triglyceride and cholesterol levels and diminished expression of lipogenic genes SREBPs, FAS, and ACC. Liver-specific PTP1B deletion also protects against high-fat diet–induced endoplasmic reticulum stress response in vivo, as evidenced by decreased phosphorylation of p38MAPK, JNK, PERK, and eIF2α and lower expression of the transcription factors C/EBP homologous protein and spliced X box-binding protein 1. CONCLUSIONS— Liver PTP1B plays an important role in glucose and lipid metabolism, independent of alterations in adiposity. Inhibition of PTP1B in peripheral tissues may be useful for the treatment of metabolic syndrome and reduction of cardiovascular risk in addition to diabetes. Footnotes Published ahead of print at http://diabetes.diabetesjournals.org on 15 December 2008. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C Section 1734 solely to indicate this fact. Accepted December 8, 2008. Received July 9, 2008. DIABETES

• Publisher: American Diabetes Association
• Subject: Animals / Biological and medical sciences / Blood Glucose - metabolism / Body Composition / Control / Diabetes. Impaired glucose tolerance / Dietary Fats - adverse effects / Endocrine pancreas. Apud cells (diseases) / Endocrinopathies / Endoplasmic reticulum / Endoplasmic Reticulum - physiology / Etiopathogenesis. Screening. Investigations. Target tissue resistance / Gene Amplification / Gene Deletion / Gene Expression Regulation / Genetic aspects / Glucose metabolism / Homeostasis / Insulin - pharmacology / Insulin - physiology / Liver - enzymology / Medical sciences / Metabolic diseases / Metabolic Syndrome - blood / Metabolic Syndrome - etiology / Metabolic Syndrome - prevention & control / Metabolic syndrome X / Metabolism / Mice / Mice, Inbred C57BL / Mice, Knockout / Miscellaneous / Other metabolic disorders / Physiological aspects / Protein tyrosine kinase / Protein Tyrosine Phosphatase, Non-Receptor Type 1 - deficiency / Protein Tyrosine Phosphatase, Non-Receptor Type 1 - genetics / Reference Values / Reverse Transcriptase Polymerase Chain Reaction / Risk factors / Signal Transduction - genetics / Signal Transduction - physiology