Methionine restriction prevents onset of type 2 diabetes in NZO mice

Abstract

Dietary methionine restriction (MR) is well known to reduce body weight by increasing energy expenditure (EE) and insulin sensitivity. An elevated concentration of circulating fibroblast growth factor 21 (FGF21) has been implicated as a potential underlying mechanism. The aims of our study were to test whether dietary MR in the context of a high-fat regimen protects against type 2 diabetes in mice and to investigate whether vegan and vegetarian diets, which have naturally low methionine levels, modulate circulating FGF21 in humans. New Zealand obese (NZO) mice, a model for polygenic obesity and type 2 diabetes, were placed on isocaloric high-fat diets (protein, 16 kcal%; carbohydrate, 52 kcal%; fat, 32 kcal%) that provided methionine at control (Con; 0.86% methionine) or low levels (0.17%) for 9 wk. Markers of glucose homeostasis and insulin sensitivity were analyzed. Among humans, low methionine intake and circulating FGF21 levels were investigated by comparing a vegan and a vegetarian diet to an omnivore diet and evaluating the effect of a short-term vegetarian diet on FGF21 induction. In comparison with the Con group, MR led to elevated plasma FGF21 levels and prevented the onset of hyperglycemia in NZO mice. MR-fed mice exhibited increased insulin sensitivity, higher plasma adiponectin levels, increased EE, and up-regulated expression of thermogenic genes in subcutaneous white adipose tissue. Food intake and fat mass did not change. Plasma FGF21 levels were markedly higher in vegan humans compared with omnivores, and circulating FGF21 levels increased significantly in omnivores after 4 d on a vegetarian diet. These data suggest that MR induces FGF21 and protects NZO mice from high-fat diet–induced glucose intolerance and type 2 diabetes. The normoglycemic phenotype in vegans and vegetarians may be caused by induced FGF21. MR akin to vegan and vegetarian diets in humans may offer metabolic benefits via increased circulating levels of FGF21 and merits further investigation.—Castaño-Martinez, T., Schumacher, F., Schumacher, S., Kochlik, B., Weber, D., Grune, T., Biemann, R., McCann, A., Abraham, K., Weikert, C., Kleuser, B., Schürmann, A., Laeger, T. Methionine restriction prevents onset of type 2 diabetes in NZO mice.

Effects of dietary methionine and cysteine restriction on plasma biomarkers, serum fibroblast growth factor 21, and adipose tissue gene expression in women with overweight or obesity: a double-blind randomized controlled pilot study

“…The increases in serum FGF21 in the Met/Cys -low group is in line with preclinical studies showing upregulated hepatic gene expression and elevated circulating FGF21 in response to methionine restriction [14,18,39]. The range of serum FGF21 concentrations was wide and may have introduced some bias in our analyses, however, our findings also agree with a human study (n = 72) that showed increased plasma FGF21 concentrations in vegans and vegetarians compared with omnivores, and that plasma FGF21 concentrations increased significantly in omnivore subjects (n = 16) given a vegetarian diet for 4 d [40]. Many plant foods in vegetarian diets are naturally low in sulfur amino acid, whereas certain fruits, vegetables and grains have higher content of methionine and cysteine.…”

Weight Loss and Concomitant Adipose Autophagy in Methionine‐Restricted Obese Mice is Not Dependent on Adiponectin or FGF21

“…In rodents, methionine restriction (MR) prevents adipose tissue accumulation because of a futile lipid cycle (3). Additionally, MR increases energy expenditure (EE) and induces beige adipose tissue formation in rodents compared with controls (4,5). However, the ability of MR to reverse obesity has not yet been thoroughly examined.…”

“…The roles of ADIPOQ and FGF21 during MR under obese conditions have not been fully examined. Circulating ADIPOQ and FGF21 are consistently elevated during MR (4,6), suggesting that these two hormones are required for the beneficial effects of MR. Though initial studies have demonstrated that ADIPOQ is mainly secreted from fat (7) and FGF21 from the liver (8), recent findings have indicated that both hormones have pleiotropic targets and that they are secreted from multiple organs (9,10).…”

Effects of Short-Term Methionine and Cysteine Restriction and Enrichment With Polyunsaturated Fatty Acids on Oral Glucose Tolerance, Plasma Amino Acids, Fatty Acids, Lactate and Pyruvate: Results From a Pilot Study

“…As this was a pilot study with no formal comparisons, this particular relationship may be worthy of further investigation. Although some work has been done in animals with respect to sulfur amino acids insulin sensitivity 3,24,25 , data is currently lacking from human observational and experimental studies. One study showed that plasma concentrations of total cysteine were associated with insulin resistance in Hispanic adolescents 26 , but more work is warranted and required preferably in long-term, adequately powered studies in individuals at risk of developing insulin resistance.…”