Methionine Restriction and FGF21 in Mice

All near alternatives to calorie restriction with optimal nutrition are attracting more scientific attention these days, among them intermittent fasting and methionine restriction. All three of these have been demonstrated to extend life in mice and rats to varying degrees, and the collection of mechanisms involved appears to be somewhat different in each case: overlapping sets of metabolic reactions to low levels of food or reduced amounts of one of a few dietary constitutents such as methionine.

It is interesting to see FGF21 levels mentioned in the methionine restriction study below, as using genetic engineering to increase the levels of FGF21 in mice has been shown to extend life by influencing one of the better known longevity mechanisms in mammals. Everything touches on everything else in metabolism, and the diversity of methods by which aging can be slowed in laboratory species really reflects a smaller number of core mechanisms that can be altered in many different ways:

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. 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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