Journal
DIABETES
Volume 58, Issue 3, Pages 590-599Publisher
AMER DIABETES ASSOC
DOI: 10.2337/db08-0913
Keywords
-
Categories
Funding
- National Institutes of Health (NIH) [DK 60838, DK 60839, R37 CA49152, U24-DK59635]
- Physiology Core Grant [DK57521]
- American Diabetes Association [1-04-RA-47]
- Research Councils UK
- Diabetes UK project
- Royal Society
- Penn Center for Molecular Studies in Digestive and Liver Disease [DK50306]
- University of Pennsylvania Research Foundation
- USDA
- Pennsylvania State Department of Health
Ask authors/readers for more resources
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 mid 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 eIF2 alpha 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. Diabetes 58:590-599, 2009
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available