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Inducible liver-specific knockdown of protein tyrosine phosphatase 1B improves glucose and lipid homeostasis in adult mice
Ist Teil von
Diabetologia, 2013-10, Vol.56 (10), p.2286-2296
Ort / Verlag
Berlin/Heidelberg: Springer Berlin Heidelberg
Erscheinungsjahr
2013
Quelle
MEDLINE
Beschreibungen/Notizen
Aims/hypothesis
Protein tyrosine phosphatase 1B (PTP1B) is a key negative regulator of insulin signalling. Hepatic PTP1B deficiency, using the
Alb-Cre
promoter to drive
Ptp1b
deletion from birth in mice, improves glucose homeostasis, insulin sensitivity and lipid metabolism. The aim of this study was to investigate the therapeutic potential of decreasing liver PTP1B levels in obese and insulin-resistant adult mice.
Methods
Inducible
Ptp1b
liver-specific knockout mice were generated using
SA-Cre-ER
T2
mice crossed with
Ptp1b
floxed (
Ptp1b
fl/fl
) mice. Mice were fed a high-fat diet (HFD) for 12 weeks to induce obesity and insulin resistance. Tamoxifen was administered in the HFD to induce liver-specific deletion of
Ptp1b
(
SA-Ptp1b
−/−
mice). Body weight, glucose homeostasis, lipid homeostasis, serum adipokines, insulin signalling and endoplasmic reticulum (ER) stress were examined.
Results
Despite no significant change in body weight relative to HFD-fed
Ptp1b
fl/fl
control mice, HFD-fed
SA-Ptp1b
−/−
mice exhibited a reversal of glucose intolerance as determined by improved glucose and pyruvate tolerance tests, decreased fed and fasting blood glucose and insulin levels, lower HOMA of insulin resistance, circulating leptin, serum and liver triacylglycerols, serum NEFA and decreased HFD-induced ER stress. This was associated with decreased glycogen synthase, eukaryotic translation initiation factor-2α kinase 3, eukaryotic initiation factor 2α and c-Jun NH
2
-terminal kinase 2 phosphorylation, and decreased expression of
Pepck
.
Conclusions/interpretation
Inducible liver-specific PTP1B knockdown reverses glucose intolerance and improves lipid homeostasis in HFD-fed obese and insulin-resistant adult mice. This suggests that knockdown of liver PTP1B in individuals who are already obese/insulin resistant may have relatively rapid, beneficial therapeutic effects.