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

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 (HFD)-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 chow or HFD. Results: Compared to 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. Liverspecific-PTP1B deletion also protects against HFD-induced ER 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.