Inducible Liver-Specific Knockdown of Protein Tyrosine Phosphatase 1B Improves Glucose and Lipid Homeostasis in Adult Mice

C. Owen, E. K. Lees, L. Grant, D. J. Zimmer, N. Mody, K. K. Bence, M. Delibegovic

Research output: Contribution to journalArticlepeer-review

46 Citations (Scopus)

Abstract

Abstract
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 NH2-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.
Original languageEnglish
Pages (from-to)2286-2296
Number of pages10
JournalDiabetologia
Volume56
Issue number10
Early online date6 Jul 2013
DOIs
Publication statusPublished - Oct 2013

Keywords

  • disease
  • ER stress
  • glucose
  • insulin
  • leptin
  • lipid
  • liver
  • NAFLD
  • phosphatase
  • PTP1B

Fingerprint Dive into the research topics of 'Inducible Liver-Specific Knockdown of Protein Tyrosine Phosphatase 1B Improves Glucose and Lipid Homeostasis in Adult Mice'. Together they form a unique fingerprint.

Cite this