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 journalArticle

39 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

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Non-Receptor Type 1 Protein Tyrosine Phosphatase
Homeostasis
High Fat Diet
Lipids
Glucose
Liver
Insulin
Eukaryotic Initiation Factor-2
Insulin Resistance
Endoplasmic Reticulum Stress
Glucose Intolerance
Serum
Eukaryotic Initiation Factors
Glycogen Synthase
Body Weight Changes
Adipokines
JNK Mitogen-Activated Protein Kinases
Therapeutic Uses
Tamoxifen
Glucose Tolerance Test

Keywords

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

Cite this

Inducible Liver-Specific Knockdown of Protein Tyrosine Phosphatase 1B Improves Glucose and Lipid Homeostasis in Adult Mice. / Owen, C.; Lees, E. K.; Grant, L.; Zimmer, D. J.; Mody, N.; Bence, K. K. ; Delibegovic, M.

In: Diabetologia, Vol. 56, No. 10, 10.2013, p. 2286-2296.

Research output: Contribution to journalArticle

Owen, C. ; Lees, E. K. ; Grant, L. ; Zimmer, D. J. ; Mody, N. ; Bence, K. K. ; Delibegovic, M. / Inducible Liver-Specific Knockdown of Protein Tyrosine Phosphatase 1B Improves Glucose and Lipid Homeostasis in Adult Mice. In: Diabetologia. 2013 ; Vol. 56, No. 10. pp. 2286-2296.
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T1 - Inducible Liver-Specific Knockdown of Protein Tyrosine Phosphatase 1B Improves Glucose and Lipid Homeostasis in Adult Mice

AU - Owen, C.

AU - Lees, E. K.

AU - Grant, L.

AU - Zimmer, D. J.

AU - Mody, N.

AU - Bence, K. K.

AU - Delibegovic, M.

PY - 2013/10

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N2 - 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.

AB - 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.

KW - disease

KW - ER stress

KW - glucose

KW - insulin

KW - leptin

KW - lipid

KW - liver

KW - NAFLD

KW - phosphatase

KW - PTP1B

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DO - 10.1007/s00125-013-2992-z

M3 - Article

VL - 56

SP - 2286

EP - 2296

JO - Diabetologia

JF - Diabetologia

SN - 0012-186X

IS - 10

ER -