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Publication
Liver-specific deletion of protein-tyrosine phosphatase 1B (PTP1B) improves
metabolic syndrome and attenuates diet-induced endoplasmic reticulum stress.
Authors Delibegovic M, Zimmer D, Kauffman C, Rak K, Hong EG, Cho YR, Kim JK, Kahn BB,
Neel BG, Bence KK
Submitted By David Wasserman on 7/16/2010
Status Published
Journal Diabetes
Year 2009
Date Published 3/1/2009
Volume : Pages 58 : 590 - 599
PubMed Reference 19074988
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 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.






Genes
SymbolDescription
Fasnfatty acid synthase
G6pcglucose-6-phosphatase, catalytic
Mapk14mitogen activated protein kinase 14
Pck1phosphoenolpyruvate carboxykinase 1, cytosolic
Ptpn1protein tyrosine phosphatase, non-receptor type 1
FasFas (TNF receptor superfamily member)
Eif2s1eukaryotic translation initiation factor 2, subunit 1 alpha
Mapk8mitogen-activated protein kinase 8

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