title: Methionine restriction improves renal insulin signalling in aged kidneys.
abstract: Dietary methionine restriction (MR) leads to loss of adiposity, improved insulin sensitivity and lifespan extension. The possibility that dietary MR can protect the kidney from age-associated deterioration has not been addressed. Aged (10-month old) male and female mice were placed on a MR (0.172% methionine) or control diet (0.86% methionine) for 8-weeks and blood glucose, renal insulin signalling, and gene expression were assessed. Methionine restriction lead to decreased blood glucose levels compared to control-fed mice, and enhanced insulin-stimulated phosphorylation of PKB/Akt and S6 in kidneys, indicative of improved glucose homeostasis. Increased expression of lipogenic genes and downregulation of PEPCK were observed, suggesting that kidneys from MR-fed animals are more insulin sensitive. Interestingly, renal gene expression of the mitochondrial uncoupling protein UCP1 was upregulated in MR-fed animals, as were the anti-ageing and renoprotective genes Sirt1, FGF21, klotho, and β-klotho. This was associated with alterations in renal histology trending towards reduced frequency of proximal tubule intersections containing vacuoles in mice that had been on dietary MR for 190days compared to control-fed mice, which exhibited a pre-diabetic status. Our results indicate that dietary MR may offer therapeutic potential in ameliorating the renal functional decline related to ageing and other disorders associated with metabolic dysfunction by enhancing renal insulin sensitivity and renoprotective gene expression.
authors.affiliation: Institute of Medical Sciences, University of Aberdeen, College of Life Sciences and Medicine, Foresterhill Health Campus, Aberdeen, UK.
authors.forename: Louise
authors.initials: L
authors.lastname: Grant
authors.affiliation: Institute of Medical Sciences, University of Aberdeen, College of Life Sciences and Medicine, Foresterhill Health Campus, Aberdeen, UK; Liverpool Hope University, Liverpool, UK.
authors.forename: Emma K
authors.initials: EK
authors.lastname: Lees
authors.affiliation: Nutrient Sensing and Adipocyte Signaling Department, Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA.
authors.forename: Laura A
authors.initials: LA
authors.lastname: Forney
authors.affiliation: Institute of Medical Sciences, University of Aberdeen, College of Life Sciences and Medicine, Foresterhill Health Campus, Aberdeen, 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.
authors.forename: Thomas
authors.initials: T
authors.lastname: Gettys
authors.affiliation: Pathology Department, Aberdeen Royal Infirmary, Aberdeen, UK.
authors.forename: Paul A J
authors.initials: PA
authors.lastname: Brown
authors.affiliation: Institute of Medical Sciences, University of Aberdeen, College of Life Sciences and Medicine, Foresterhill Health Campus, Aberdeen, UK. Electronic address: h.m.wilson@abdn.ac.uk.
authors.forename: Heather M
authors.initials: HM
authors.lastname: Wilson
authors.affiliation: Institute of Medical Sciences, University of Aberdeen, College of Life Sciences and Medicine, Foresterhill Health Campus, Aberdeen, UK. Electronic address: m.delibegovic@abdn.ac.uk.
authors.forename: Mirela
authors.initials: M
authors.lastname: Delibegovic
mesh_terms: D000375:Aging / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D005260:Female; D005786:Gene Expression Regulation; D007328:Insulin / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008715:Methionine / Q000172:deficiency*; D051379:Mice; D015398:Signal Transduction
chemical_list: D007328:Insulin; D008715:Methionine
keywords: Ageing; Diet; Insulin; Kidney; Methionine; Renoprotection