title: Effects of hepatic protein tyrosine phosphatase 1B and methionine restriction on hepatic and whole-body glucose and lipid metabolism in mice.
abstract: OBJECTIVE
  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 hypothesized 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 (Ptp1b(fl/fl)) mice were maintained on control diet (0.86% methionine) or MR diet (0.172% methionine) for 8weeks. Body weight and food intake were recorded and physiological tests for whole-body glucose homeostasis were performed. Serum and tissues were analyzed biochemically.
  
  
  RESULTS
  MR decreased body weight and increased food intake in Ptp1b(fl/fl) mice as expected, without changing PTP1B protein expression levels or activity. In females, MR treatment alone improved glucose tolerance in Ptp1b(fl/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 Ptp1b(fl/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.
authors.affiliation: Institute of Medical Sciences, School of Medical Sciences, University of Aberdeen, Aberdeen, UK. Electronic address: r01ekl11@abdn.ac.uk.
authors.forename: Emma Katherine
authors.initials: EK
authors.lastname: Lees
authors.affiliation: School of Biological Sciences, University of Aberdeen, Aberdeen, UK. Electronic address: e.krol@abdn.ac.uk.
authors.forename: Elzbieta
authors.initials: E
authors.lastname: Krol
authors.affiliation: Institute of Medical Sciences, School of Medical Sciences, University of Aberdeen, Aberdeen, UK. Electronic address: k.d.shearer@abdn.ac.uk.
authors.forename: Kirsty
authors.initials: K
authors.lastname: Shearer
authors.affiliation: Institute of Medical Sciences, School of Medical Sciences, University of Aberdeen, Aberdeen, UK. Electronic address: n.mody@abdn.ac.uk.
authors.forename: Nimesh
authors.initials: N
authors.lastname: Mody
authors.affiliation: Nutrient Sensing and Adipocyte Signaling Department, Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA. Electronic address: Thomas.Gettys@pbrc.edu.
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Gettys
authors.affiliation: Institute of Medical Sciences, School of Medical Sciences, University of Aberdeen, Aberdeen, UK. Electronic address: m.delibegovic@abdn.ac.uk.
authors.forename: Mirela
authors.initials: M
authors.lastname: Delibegovic
mesh_terms: D052636:Allostasis; D000818:Animals; D003433:Crosses, Genetic; D002149:Energy Intake; D005260:Female; D018149:Glucose Intolerance / Q000097:blood / Q000378:metabolism / Q000517:prevention & control*; D007328:Insulin / Q000097:blood / Q000378:metabolism; D007333:Insulin Resistance; D050356:Lipid Metabolism; D008099:Liver / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D008715:Methionine / Q000172:deficiency* / Q000378:metabolism; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D011897:Random Allocation; D011972:Receptor, Insulin / Q000819:agonists / Q000378:metabolism; D015398:Signal Transduction; D015431:Weight Loss
chemical_list: D007328:Insulin; D008715:Methionine; D011972:Receptor, Insulin; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; C516609:Ptpn1 protein, mouse
keywords: Diabetes; Glucose; Insulin; Liver