Dietary Methionine Restriction Improves The Learning And Memory Function Of Obese Mice And Aging Mice

As obesity and aging become increasingly global severe problems,the impairment of learning and memory function caused by obesity and aging is one of the importment researching fields in nutriology.Chronic inflammation and oxidative stress induced by the two issues are two critical factors responsible for the impairment.Dietary methionine restriction?MR?has attracted increasing attention for its pleiotropic functions such as extending lifespan,improving insulin sensitivity,and enhancing metabolic flexibility.In particular,recent studies suggest that dietary MR can increase endogenous hydrogen sulfide?H₂S?production in multiple tissues.Endogenous H₂S is a vital anti-inflammatory,anti-oxidative,and anti-apoptotic molecule in the central nervous system,which also regulates learning and memory functions as a gaseous signal molecule.The purpose of this study was to investigate the effects of dietary MR on learning and memory function in obese mice and aging mice and to explore possible mechanisms focused on the metabolic pathways of endogenous H₂S in the hippocampus,and to further explore the learning and memory function of normal mice fed with different methionine content dites.The study was conducted in three parts.The first part:60 and 20 four-week-old male C57BL/6J mice were fed a high-fat diet or a normal diet to induce the obese mice model,then20 normal-diet mice and 40 selected obese mice were divided into normal diet group?CON group,4.2%fat,0.86%methionine?,high-fat diet group?HF group,24%fat,0.86%methionine?,and high-fat+methionine-restricted diet group?MR group,24%fat,0.17%methionine?,and fed for another 16 weeks.The second part:45 eight-week-old male ICR mice were randomly divided into normal diet group?CON group,0.86%methionine,injected with saline?,D-galactose?D-Gal?group?D+CON group,0.86%methionine,injected with D-Gal solution?,and D-galactose+methionine-restricted diet group?D+MR group,0.17%methionine,injected with D-Gal solution?,and fed for 8 weeks.The third part:45 eight-week-old male ICR mice were randomly divided into methionine-restricted diet group?MR group,0.17%methionine?,normal diet group?CON group,0.86%methionine?and high methionine group?HM group,2.58%methionine?,and fed for 8 weeks.After that,the animals were subjected to a series of behavioral experiments before sacrificed,then the samples were collected.And the indexes related to redox status and inflammation in the blood and hippocampus,related to H₂S production and Hcy metabolism in the hippocampus were detected.In addition,the expression of multiple genes modulated by H₂S and related to learning and memory function in the hippocampus was detected.What is more,the fecal flora structure was also analyzed in the second part of the study.In obese mice,D-Gal-induced aging mice,and normal mice fed with high methionine content dite,non-spatial recognition memory,working memory,and hippocampal-dependent spatial memory were impaired,and anxiety-related behavior also occurred in these mice.Besides,oxidative stress and inflammatory response in the blood and hippocampus were increased.In addition,endogenous H₂S levels in the blood and hippocampus and hippocampal cystathionine?-synthase?CBS?expression levels were significantly decreased,and hippocampal homocysteine?Hcy?levels were significantly increased,and the expression of hippocampal methylenetetrahydrofolate reductase?MTHFR?gene was significantly decreased,and the expression of hippocampal methionine synthase?MTR?gene was significantly increased.What is more,the expression of multiple genes modulated by H₂S and related to learning and memory function in the hippocampus was disordered.However,dietary MR ameliorated the impairment of non-spatial recognition memory,working memory,hippocampal-dependent spatial memory,and anxiety induced by obesity and aging.Besides,dietary MR also ameliorated oxidative stress and inflammatory response,increased the H₂S levels in the blood and hippocampus,and promoted the expression of CBS and MTHFR in the hippocampus in obese mice and D-Gal aging mice.What's more,dietary MR up-regulated the expression of multiple genes modulated by H₂S and related to learning and memory function in the hippocampus in obese mice and D-Gal induced aging mice.Meanwhile,dietary MR also adjusted the structure of fecal flora associated with inflammation,oxidative stress and butyric acid in D-Gal-induced aging mice,increased the abundance of Desulfovibrionaceae,and reduced the levels of lipopolysaccharides in the plasma.In normal mice,dietary MR enhanced non-spatial recognition memory and hippocampal-dependent spatial memory,reduced the ROS levels in the blood and cerebral cortex,increased H₂S levels and the expression of CBS,MTHFR,and MTR in the hippocampals,and up-regulated the expression of multiple genes modulated by H₂S and related to learning and memory function in the hippocampus.Our results suggested that dietary MR ameliorated the impairment of learning and memory function,ameliorated oxidative stress and inflammatory response in the hippocampus,and up-regulated the expression of multiple genes related to learning and memory function in the hippocampus in obese mice,D-Gal-induced aging mice,and normal mice,likely by promoting endogenous H₂S production and regulating the metabolism of Hcy.Meanwhile,the adjustment of the fecal flora structure in D-Gal-induced aging mice by dietary MR may also benefit for the reduction of systemic inflammation and the increasing of systemic H₂S levels.However,the high methionine content diet impaired the learning and memory function and increased oxidative stress and inflammatory response in the hippocampus of normal mice,likely by inhibiting the production of endogenous H₂S and the metabolism of Hcy.