Methionine restriction restores a younger metabolic phenotype in adult mice with alterations in fibroblast growth factor 21

Emma K. Lees, Elzbieta Krol, Louise Grant, Kirsty Shearer, Cathy Wyse, Eleanor Moncur, Aleksandra S. Bykowska, Nimesh Mody, Thomas Gettys, Mirela Delibegovic

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Abstract

Methionine restriction (MR) decreases body weight and adiposity and improves glucose homeostasis in rodents. Similarly 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-hours. Food intake and whole-body physiology were assessed and serum/tissues analyzed biochemically. MR-feeding 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 MR-fed mice. MR 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. MR-fed mice 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-hour MR-treatment increased hepatic FGF21 xpression/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 MRdietary intervention as a viable therapy for age-induced metabolic syndrome in adult humans.
Original languageEnglish
Pages (from-to)817-827
Number of pages11
JournalAging Cell
Volume13
Issue number5
Early online date17 Jun 2014
DOIs
Publication statusPublished - Oct 2014

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Methionine
Phenotype
Adiposity
Eating
Body Weight
Phosphorylation
Glucose
fibroblast growth factor 21
Insulin Resistance
Liver
Homeostasis
Insulin
Gene Expression
Caloric Restriction
White Adipose Tissue
Insulin Receptor
Inbred C57BL Mouse
Lipid Metabolism
Energy Metabolism
Rodentia

Keywords

  • activating transcription factor 4
  • aging
  • fibroblast growth factor 21
  • lipid
  • metabolism
  • unfolded protein response

Cite this

Methionine restriction restores a younger metabolic phenotype in adult mice with alterations in fibroblast growth factor 21. / Lees, Emma K.; Krol, Elzbieta; Grant, Louise; Shearer, Kirsty; Wyse, Cathy; Moncur, Eleanor; Bykowska, Aleksandra S. ; Mody, Nimesh; Gettys, Thomas; Delibegovic, Mirela.

In: Aging Cell, Vol. 13, No. 5, 10.2014, p. 817-827.

Research output: Contribution to journalArticle

Lees, Emma K. ; Krol, Elzbieta ; Grant, Louise ; Shearer, Kirsty ; Wyse, Cathy ; Moncur, Eleanor ; Bykowska, Aleksandra S. ; Mody, Nimesh ; Gettys, Thomas ; Delibegovic, Mirela. / Methionine restriction restores a younger metabolic phenotype in adult mice with alterations in fibroblast growth factor 21. In: Aging Cell. 2014 ; Vol. 13, No. 5. pp. 817-827.
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abstract = "Methionine restriction (MR) decreases body weight and adiposity and improves glucose homeostasis in rodents. Similarly 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-hours. Food intake and whole-body physiology were assessed and serum/tissues analyzed biochemically. MR-feeding 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 MR-fed mice. MR 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. MR-fed mice 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-hour MR-treatment increased hepatic FGF21 xpression/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 MRdietary intervention as a viable therapy for age-induced metabolic syndrome in adult humans.",
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AU - Wyse, Cathy

AU - Moncur, Eleanor

AU - Bykowska, Aleksandra S.

AU - Mody, Nimesh

AU - Gettys, Thomas

AU - Delibegovic, Mirela

N1 - Funded by Tenovus Scotland British Heart Foundation. Grant Numbers: PG/09/048/27675, PG/11/8/28703 Diabetes UK. Grant Number: BDA/RD08/0003597 EFSD/Lilly and the Royal Society BBSRC postgraduate studentship British Heart Foundation intermediate basic research fellowship. Grant Numbers: ADA 1-12-BS-58, NIH DK-096311, ADA 7-13-MI-05, NIH P20-GM103528

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N2 - Methionine restriction (MR) decreases body weight and adiposity and improves glucose homeostasis in rodents. Similarly 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-hours. Food intake and whole-body physiology were assessed and serum/tissues analyzed biochemically. MR-feeding 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 MR-fed mice. MR 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. MR-fed mice 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-hour MR-treatment increased hepatic FGF21 xpression/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 MRdietary intervention as a viable therapy for age-induced metabolic syndrome in adult humans.

AB - Methionine restriction (MR) decreases body weight and adiposity and improves glucose homeostasis in rodents. Similarly 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-hours. Food intake and whole-body physiology were assessed and serum/tissues analyzed biochemically. MR-feeding 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 MR-fed mice. MR 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. MR-fed mice 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-hour MR-treatment increased hepatic FGF21 xpression/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 MRdietary intervention as a viable therapy for age-induced metabolic syndrome in adult humans.

KW - activating transcription factor 4

KW - aging

KW - fibroblast growth factor 21

KW - lipid

KW - metabolism

KW - unfolded protein response

U2 - 10.1111/acel.12238

DO - 10.1111/acel.12238

M3 - Article

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JO - Aging Cell

JF - Aging Cell

SN - 1474-9718

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ER -