Effects of hepatic protein tyrosine phosphatase 1B and methionine restriction on hepatic and whole-body glucose and lipid metabolism in mice

Emma Katherine Lees, Elzbieta Krol, Kirsty Shearer, Nimesh Mody, Thomas W Gettys, Mirela Delibegovic

Research output: Contribution to journalArticle

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Abstract

Aims: Methionine restriction (MR) and hepatic protein tyrosine phosphatase 1B (PTP1B) knockdown both improve hepatic insulin sensitivity by targeting different proteins within the insulin signaling pathway, as well as diminishing hepatic triglyceride content through decreasing hepatic lipogenesis. We hypothesised that a combined approach of hepatic PTP1B inhibition and methionine restriction could lead to a synergistic effect on improvements in glucose homeostasis and lipid metabolism.
Methods: Male and female hepatic-PTP1B knockout (Alb-Ptp1b-/-) and control wild-type (Ptp1bfl/fl) mice were maintained on control diet (0.86% methionine) or MR diet (0.172% methionine) for 8 weeks. Body weight and food intake were recorded and physiological tests for whole-body glucose homeostasis were performed. Serum and tissues were analysed biochemically.
Results: MR decreased body weight and increased food intake in Ptp1bfl/fl mice as expected, without changing PTP1B protein expression levels or activity. In females, MR treatment alone improved glucose tolerance in Ptp1bfl/fl mice, which was further amplified with hepatic-PTP1B deficiency. However, other markers of glucose homeostasis were similar between MR-fed groups. In males, MR improved glucose homeostasis in both, Alb-Ptp1b-/- and wild-type Ptp1bfl/fl mice to a similar extent. Hepatic-PTP1B inhibition in combination with MR could not further enhance insulin-stimulated hepatic protein kinase B/Akt phosphorylation compared to MR treatment alone and therefore led to no further increase in hepatic insulin signaling. The combined treatment did not further improve lipid metabolism relative to MR diet alone.
Conclusions: Methionine restriction improves glucose and lipid homeostasis; however, adding hepatic PTP1B inhibition to MR is unlikely to yield any additional protective effects.
Original languageEnglish
Pages (from-to)305-314
Number of pages10
JournalMetabolism
Volume64
Issue number2
Early online date5 Nov 2014
DOIs
Publication statusPublished - Feb 2015

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Non-Receptor Type 1 Protein Tyrosine Phosphatase
Lipid Metabolism
Methionine
Glucose
Liver
Homeostasis
Insulin
Diet
Eating
Body Weight
Proto-Oncogene Proteins c-akt
Lipogenesis
Protein Transport

Keywords

  • glucose
  • insulin
  • liver
  • diabetes

Cite this

Effects of hepatic protein tyrosine phosphatase 1B and methionine restriction on hepatic and whole-body glucose and lipid metabolism in mice. / Lees, Emma Katherine; Krol, Elzbieta; Shearer, Kirsty; Mody, Nimesh; Gettys, Thomas W; Delibegovic, Mirela.

In: Metabolism, Vol. 64, No. 2, 02.2015, p. 305-314.

Research output: Contribution to journalArticle

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title = "Effects of hepatic protein tyrosine phosphatase 1B and methionine restriction on hepatic and whole-body glucose and lipid metabolism in mice",
abstract = "Aims: Methionine restriction (MR) and hepatic protein tyrosine phosphatase 1B (PTP1B) knockdown both improve hepatic insulin sensitivity by targeting different proteins within the insulin signaling pathway, as well as diminishing hepatic triglyceride content through decreasing hepatic lipogenesis. We hypothesised that a combined approach of hepatic PTP1B inhibition and methionine restriction could lead to a synergistic effect on improvements in glucose homeostasis and lipid metabolism.Methods: Male and female hepatic-PTP1B knockout (Alb-Ptp1b-/-) and control wild-type (Ptp1bfl/fl) mice were maintained on control diet (0.86{\%} methionine) or MR diet (0.172{\%} methionine) for 8 weeks. Body weight and food intake were recorded and physiological tests for whole-body glucose homeostasis were performed. Serum and tissues were analysed biochemically.Results: MR decreased body weight and increased food intake in Ptp1bfl/fl mice as expected, without changing PTP1B protein expression levels or activity. In females, MR treatment alone improved glucose tolerance in Ptp1bfl/fl mice, which was further amplified with hepatic-PTP1B deficiency. However, other markers of glucose homeostasis were similar between MR-fed groups. In males, MR improved glucose homeostasis in both, Alb-Ptp1b-/- and wild-type Ptp1bfl/fl mice to a similar extent. Hepatic-PTP1B inhibition in combination with MR could not further enhance insulin-stimulated hepatic protein kinase B/Akt phosphorylation compared to MR treatment alone and therefore led to no further increase in hepatic insulin signaling. The combined treatment did not further improve lipid metabolism relative to MR diet alone.Conclusions: Methionine restriction improves glucose and lipid homeostasis; however, adding hepatic PTP1B inhibition to MR is unlikely to yield any additional protective effects.",
keywords = "glucose, insulin, liver, diabetes",
author = "Lees, {Emma Katherine} and Elzbieta Krol and Kirsty Shearer and Nimesh Mody and Gettys, {Thomas W} and Mirela Delibegovic",
note = "Copyright {\circledC} 2014 Elsevier Inc. All rights reserved. This work was funded by Tenovus Scotland project grant to MD and NM. MD is also supported by the British Heart Foundation [PG/14/43/30889, PG/09/048/27675, PG/11/8/28703]; Diabetes UK [BDA/RD08/0003597]; European Foundation for the Study of Diabetes (EFSD)/Lilly; and the Royal Society. EKL is the recipient of a Biotechnology and Biological Sciences Research Council (BBSRC) postgraduate studentship. NM is the recipient of a British Heart Foundation intermediate basic research fellowship. TWG is supported in part by American Diabetes Association [1-12-BS-58, 7-13-MI-05]; and National Institutes of Health [DK-096311, P20-GM103528].",
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TY - JOUR

T1 - Effects of hepatic protein tyrosine phosphatase 1B and methionine restriction on hepatic and whole-body glucose and lipid metabolism in mice

AU - Lees, Emma Katherine

AU - Krol, Elzbieta

AU - Shearer, Kirsty

AU - Mody, Nimesh

AU - Gettys, Thomas W

AU - Delibegovic, Mirela

N1 - Copyright © 2014 Elsevier Inc. All rights reserved. This work was funded by Tenovus Scotland project grant to MD and NM. MD is also supported by the British Heart Foundation [PG/14/43/30889, PG/09/048/27675, PG/11/8/28703]; Diabetes UK [BDA/RD08/0003597]; European Foundation for the Study of Diabetes (EFSD)/Lilly; and the Royal Society. EKL is the recipient of a Biotechnology and Biological Sciences Research Council (BBSRC) postgraduate studentship. NM is the recipient of a British Heart Foundation intermediate basic research fellowship. TWG is supported in part by American Diabetes Association [1-12-BS-58, 7-13-MI-05]; and National Institutes of Health [DK-096311, P20-GM103528].

PY - 2015/2

Y1 - 2015/2

N2 - Aims: Methionine restriction (MR) and hepatic protein tyrosine phosphatase 1B (PTP1B) knockdown both improve hepatic insulin sensitivity by targeting different proteins within the insulin signaling pathway, as well as diminishing hepatic triglyceride content through decreasing hepatic lipogenesis. We hypothesised that a combined approach of hepatic PTP1B inhibition and methionine restriction could lead to a synergistic effect on improvements in glucose homeostasis and lipid metabolism.Methods: Male and female hepatic-PTP1B knockout (Alb-Ptp1b-/-) and control wild-type (Ptp1bfl/fl) mice were maintained on control diet (0.86% methionine) or MR diet (0.172% methionine) for 8 weeks. Body weight and food intake were recorded and physiological tests for whole-body glucose homeostasis were performed. Serum and tissues were analysed biochemically.Results: MR decreased body weight and increased food intake in Ptp1bfl/fl mice as expected, without changing PTP1B protein expression levels or activity. In females, MR treatment alone improved glucose tolerance in Ptp1bfl/fl mice, which was further amplified with hepatic-PTP1B deficiency. However, other markers of glucose homeostasis were similar between MR-fed groups. In males, MR improved glucose homeostasis in both, Alb-Ptp1b-/- and wild-type Ptp1bfl/fl mice to a similar extent. Hepatic-PTP1B inhibition in combination with MR could not further enhance insulin-stimulated hepatic protein kinase B/Akt phosphorylation compared to MR treatment alone and therefore led to no further increase in hepatic insulin signaling. The combined treatment did not further improve lipid metabolism relative to MR diet alone.Conclusions: Methionine restriction improves glucose and lipid homeostasis; however, adding hepatic PTP1B inhibition to MR is unlikely to yield any additional protective effects.

AB - Aims: Methionine restriction (MR) and hepatic protein tyrosine phosphatase 1B (PTP1B) knockdown both improve hepatic insulin sensitivity by targeting different proteins within the insulin signaling pathway, as well as diminishing hepatic triglyceride content through decreasing hepatic lipogenesis. We hypothesised that a combined approach of hepatic PTP1B inhibition and methionine restriction could lead to a synergistic effect on improvements in glucose homeostasis and lipid metabolism.Methods: Male and female hepatic-PTP1B knockout (Alb-Ptp1b-/-) and control wild-type (Ptp1bfl/fl) mice were maintained on control diet (0.86% methionine) or MR diet (0.172% methionine) for 8 weeks. Body weight and food intake were recorded and physiological tests for whole-body glucose homeostasis were performed. Serum and tissues were analysed biochemically.Results: MR decreased body weight and increased food intake in Ptp1bfl/fl mice as expected, without changing PTP1B protein expression levels or activity. In females, MR treatment alone improved glucose tolerance in Ptp1bfl/fl mice, which was further amplified with hepatic-PTP1B deficiency. However, other markers of glucose homeostasis were similar between MR-fed groups. In males, MR improved glucose homeostasis in both, Alb-Ptp1b-/- and wild-type Ptp1bfl/fl mice to a similar extent. Hepatic-PTP1B inhibition in combination with MR could not further enhance insulin-stimulated hepatic protein kinase B/Akt phosphorylation compared to MR treatment alone and therefore led to no further increase in hepatic insulin signaling. The combined treatment did not further improve lipid metabolism relative to MR diet alone.Conclusions: Methionine restriction improves glucose and lipid homeostasis; however, adding hepatic PTP1B inhibition to MR is unlikely to yield any additional protective effects.

KW - glucose

KW - insulin

KW - liver

KW - diabetes

U2 - 10.1016/j.metabol.2014.10.038

DO - 10.1016/j.metabol.2014.10.038

M3 - Article

VL - 64

SP - 305

EP - 314

JO - Metabolism

JF - Metabolism

SN - 0026-0495

IS - 2

ER -