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

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.