Dietary methionine restriction ameliorates the impairment of learning and memory function induced by obesity in mice

Dietary methionine restriction (MR) has been reported to extend lifespan, improve insulin sensitivity, reduce adiposity and inflammation response, and in particular, increase endogenous hydrogen sulfide (H2S) production. H2S is a critical anti-inflammatory molecule in the central nervous system and a gaseous signal molecule that mediates learning and memory function. Hence, the present study aimed to investigate whether MR can ameliorate the impairment of learning and memory function induced by obesity, and to clarify its possible mechanisms. C57BL/6J mice were fed a control diet or a high-fat (HF) diet to induce obesity, and were then fed a control diet (CON group, 4.2% fat, 0.86% methionine), a HF diet (HF group, 24% fat, 0.86% methionine), or an MR diet (MR group, 24% fat, 0.17% methionine) for 16 consecutive weeks. Our results showed that HF-induced obesity impaired learning and memory function, reduced H2S production in the hippocampus, cortex, and plasma, and increased plasma and hippocampal inflammation response in the mice. MR improved the impairment of learning and memory function accompanied by selective modulation of the expression of multiple related genes, reduced plasma and hippocampal inflammatory response, normalized H2S levels in the hippocampus, cortex, and plasma, up-regulated the mRNA and protein expression levels of cystathionine β-synthase in the hippocampus, and reduced hippocampal homocysteine level. These findings suggest that MR can ameliorate the impairment of learning and memory function, likely by increasing H2S production in the hippocampus.