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

Authors

  • Emma K. Lees,

    1. Institute of Medical Sciences, College of Life Sciences and Medicine, University of Aberdeen, Aberdeen, AB25 2ZD, UK
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  • Elżbieta Król,

    1. Institute of Biological and Environmental Sciences, University of Aberdeen, Aberdeen, AB24 2TZ, UK
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  • Louise Grant,

    1. Institute of Medical Sciences, College of Life Sciences and Medicine, University of Aberdeen, Aberdeen, AB25 2ZD, UK
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  • Kirsty Shearer,

    1. Institute of Medical Sciences, College of Life Sciences and Medicine, University of Aberdeen, Aberdeen, AB25 2ZD, UK
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  • Cathy Wyse,

    1. Institute of Biological and Environmental Sciences, University of Aberdeen, Aberdeen, AB24 2TZ, UK
    Current affiliation:
    1. Institute of Biodiversity, Animal Health and Comparative Medicine, University of Glasgow, Glasgow, UK
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  • Eleanor Moncur,

    1. Institute of Medical Sciences, College of Life Sciences and Medicine, University of Aberdeen, Aberdeen, AB25 2ZD, UK
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  • Aleksandra S. Bykowska,

    1. Institute of Medical Sciences, College of Life Sciences and Medicine, University of Aberdeen, Aberdeen, AB25 2ZD, UK
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  • Nimesh Mody,

    1. Institute of Medical Sciences, College of Life Sciences and Medicine, University of Aberdeen, Aberdeen, AB25 2ZD, UK
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  • Thomas W. Gettys,

    1. Nutrient Sensing and Adipocyte Signaling Department, Pennington Biomedical Research Center, Baton Rouge, LA, USA
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  • Mirela Delibegovic

    Corresponding author
    1. Institute of Medical Sciences, College of Life Sciences and Medicine, University of Aberdeen, Aberdeen, AB25 2ZD, UK
    • Correspondence

      Dr. Mirela Delibegović, Institute of Medical Sciences, School of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, UK. Tel.: +44 1224 437587; fax: +44 1224 437465; e-mail: m.delibegovic@abdn.ac.uk

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Summary

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.

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