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 eIF2alpha 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.
