期刊
AGING CELL
卷 13, 期 5, 页码 817-827出版社
WILEY-BLACKWELL
DOI: 10.1111/acel.12238
关键词
activating transcription factor 4; aging; fibroblast growth factor 21; lipid; metabolism; unfolded protein response
资金
- Tenovus Scotland project grant
- British Heart Foundation [PG/09/048/27675, PG/11/8/28703]
- Diabetes UK [BDA/RD08/0003597]
- EFSD/Lilly
- Royal Society
- BBSRC
- British Heart Foundation intermediate basic research fellowship
- [ADA 1-12-BS-58]
- [NIH DK-096311]
- [ADA 7-13-MI-05]
- [NIH P20-GM103528]
- Biotechnology and Biological Sciences Research Council [1091530] Funding Source: researchfish
- British Heart Foundation [PG/11/8/28703] Funding Source: researchfish
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 48h. 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 IRE1 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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