Progress 01/01/08 to 09/30/08
Outputs
OUTPUTS: The results of this USDA-funded project have been disseminated to the academic community through poster presentations at local and national conferences, including the University of Pennsylvania School of Veterinary Medicine annual retreat in 2008, the Penn GI and Liver Center annual retreat, and the Keystone Scientific Symposium. The most significant output over the life of this project was a poster presentation at the International Keystone Symposium on Insulin Resistance and Diabetes in Banff, Canada. PARTICIPANTS: This project provided partial salary support for Derek Zimmer, a research technician in the lab. He had the opportunity to learn many new techniques as part of this project and has since go on ot train others in the lab. TARGET AUDIENCES: Not relevant to this project. PROJECT MODIFICATIONS: Not relevant to this project.
Impacts
Project Background: Fatty liver disease, or hepatic lipidosis, is a major metabolic disorder of dairy cows in lactation, and can result in serious health consequences and a loss of reproductive performance. The biochemical mechanisms that lead to the disease are not well understood. Insulin resistance is the classical pathophysiological hallmark of this disease, and alterations in insulin action may in fact precede the development of liver disease. Protein-tyrosine phosphatase-1B (PTP1B) is an abundant non-receptor tyrosine phosphatase and is classically known as an insulin receptor phosphatase. PTP1B-/- mice are insulin hyper-sensitive, consistent with a role for PTP1B as a negative regulator of insulin signaling. Due to the ubiquitous expression of this phosphatase, however, the tissue(s) mediating the insulin hyper-sensitivity have remained unclear. The specific aims of this project were to determine whether deficiency of PTP1B in the liver could protect against (or reverse) the development of insulin resistance and non-alcoholic fatty liver disease (NAFLD) in mice, and to study the role of PTP1B in signaling pathways involved in the pathogenesis of NAFLD. Outcomes/Impacts: 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. 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 eIF2alpha, and lower expression of the transcription factors C/EBP homologous protein and spliced X box-binding protein 1. Preliminary studies in HepG2 hepatocyte cell lines also indicate that PTP1B-deficiency protects against endoplasmic reticulum stress in liver cells. Overall we conclude that liver PTP1B plays an important role in glucose and lipid metabolism, independent of alterations in adiposity. Inhibition of PTP1B in peripheral tissues may be clinically useful for the treatment of metabolic syndrome and fatty liver disease. The resources provided in this USDA grant allowed for the breeding of the necessary mice to perform the outlined experiments, paid a portion of a research technician's salary, and paid for essential research supplies including special rodent diets and reagents.
Publications
- Keystone Abstract: Liver-specific Deletion of Protein-Tyrosine Phosphatase 1B (PTP1B) Improves Glucose Homeostasis and Lipid Metabolism and Attenuates Diet-Induced ER Stress. M. Delibegovic, D. Zimmer, C. Kauffmann, K. Rak, E.-G. Hong, Y.-R. Cho, J. Kim, B. Kahn, B.G. Neel, and K.K. Bence. Keystone Symposium on Type 2 Diabetes and Insulin Resistance program book (poster 148), January 2009, Banff, Alberta, Canada.
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