title: Methionine restriction restores a younger metabolic phenotype in adult mice with alterations in fibroblast growth factor 21.
abstract: Methionine restriction (MR) decreases body weight and adiposity and improves glucose homeostasis in rodents. Similar to caloric restriction, MR extends lifespan, but is accompanied by increased food intake and energy expenditure. Most studies have examined MR in young animals; therefore, the aim of this study was to investigate the ability of MR to reverse age-induced obesity and insulin resistance in adult animals. Male C57BL/6J mice aged 2 and 12 months old were fed MR (0.172% methionine) or control diet (0.86% methionine) for 8 weeks or 48 h. Food intake and whole-body physiology were assessed and serum/tissues analyzed biochemically. Methionine restriction in 12-month-old mice completely reversed age-induced alterations in body weight, adiposity, physical activity, and glucose tolerance to the levels measured in healthy 2-month-old control-fed mice. This was despite a significant increase in food intake in 12-month-old MR-fed mice. Methionine restriction decreased hepatic lipogenic gene expression and caused a remodeling of lipid metabolism in white adipose tissue, alongside increased insulin-induced phosphorylation of the insulin receptor (IR) and Akt in peripheral tissues. Mice restricted of methionine exhibited increased circulating and hepatic gene expression levels of FGF21, phosphorylation of eIF2a, and expression of ATF4, with a concomitant decrease in IRE1α phosphorylation. Short-term 48-h MR treatment increased hepatic FGF21 expression/secretion and insulin signaling and improved whole-body glucose homeostasis without affecting body weight. Our findings suggest that MR feeding can reverse the negative effects of aging on body mass, adiposity, and insulin resistance through an FGF21 mechanism. These findings implicate MR dietary intervention as a viable therapy for age-induced metabolic syndrome in adult humans.
authors.affiliation: Institute of Medical Sciences, College of Life Sciences and Medicine, University of Aberdeen, Aberdeen, AB25 2ZD, UK.
authors.forename: Emma K
authors.initials: EK
authors.lastname: Lees
authors.forename: Elżbieta
authors.initials: E
authors.lastname: Król
authors.forename: Louise
authors.initials: L
authors.lastname: Grant
authors.forename: Kirsty
authors.initials: K
authors.lastname: Shearer
authors.forename: Cathy
authors.initials: C
authors.lastname: Wyse
authors.forename: Eleanor
authors.initials: E
authors.lastname: Moncur
authors.forename: Aleksandra S
authors.initials: AS
authors.lastname: Bykowska
authors.forename: Nimesh
authors.initials: N
authors.lastname: Mody
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Gettys
authors.forename: Mirela
authors.initials: M
authors.lastname: Delibegovic
mesh_terms: D000818:Animals; D004734:Energy Metabolism / Q000187:drug effects; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D005947:Glucose / Q000378:metabolism; D007333:Insulin Resistance; D050356:Lipid Metabolism; D008297:Male; D008715:Methionine / Q000008:administration & dosage* / Q000172:deficiency* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000178:diet therapy* / Q000378:metabolism; D010641:Phenotype
chemical_list: C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors; D008715:Methionine; D005947:Glucose
keywords: activating transcription factor 4; aging; fibroblast growth factor 21; lipid; metabolism; unfolded protein response