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Methionine restriction alleviates age-associated cognitive decline via fibroblast growth factor 21.

ABSTRACT: Methionine restriction (MR) extends lifespan and delays the onset of aging-associated pathologies. However, the effect of MR on age-related cognitive decline remains unclear. Here, we find that a 3-month MR ameliorates working memory, short-term memory, and spatial memory in 15-month-old and 18-month-old mice by preserving synaptic ultrastructure, increasing mitochondrial biogenesis, and reducing the brain MDA level in aged mice hippocampi. Transcriptome data suggest that the receptor of fibroblast growth factor 21 (FGF21)-related gene expressions were altered in the hippocampi of MR-treated aged mice. MR increased FGF21 expression in serum, liver, and brain. Integrative modelling reveals strong correlations among behavioral performance, MR altered nervous structure-related genes, and circulating FGF21 levels. Recombinant FGF21 treatment balanced the cellular redox status, prevented mitochondrial structure damages, and upregulated antioxidant enzymes HO-1 and NQO1 expression by transcriptional activation of Nrf2 in SH-SY5Y cells. Moreover, knockdown of Fgf21 by i.v. injection of adeno-associated virus abolished the neuroprotective effects of MR in aged mice. In conclusion, the MR exhibited the protective effects against age-related behavioral disorders, which could be partly explained by activating circulating FGF21 and promoting mitochondrial biogenesis, and consequently suppressing the neuroinflammation and oxidative damages. These results demonstrate that FGF21 can be used as a potential nutritional factor in dietary restriction-based strategies for improving cognition associated with neurodegeneration disorders.

SUBMITTER: Ren B

PROVIDER: S-EPMC8022247 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Methionine restriction alleviates age-associated cognitive decline via fibroblast growth factor 21

Project description:We reported a 3-month MR intervention alleviated age-related cognitive impairment. Here we present transcriptomics data of mice hippocampus to further investigate how MR regulates vital biological processes and pathways. After mapping clean RNA-seq reads of all mice against the Mus musculus genome, we detected 13,218 genes (including 3,187 new predicted genes with no annotation) with fragments per kilobase of transcripts per million mapped reads (FPKM) value. Gene set enrichment analysis (GSEA) was used for pathway or functional analysis of RNA-seq data.

2021-12-31 | GSE164097 | GEO

Methionine restriction alleviates age-associated cognitive decline via fibroblast growth factor 21

Project description:Methionine restriction alleviates age-associated cognitive decline via fibroblast growth factor 21

| PRJNA688895 | ENA

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

Project description: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, with a concomitant decrease in IRE1? phosphorylation. 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.

| S-EPMC4331744 | biostudies-literature

Dietary Methionine Restriction Signals to the Brain Through Fibroblast Growth Factor 21 to Regulate Energy Balance and Remodeling of Adipose Tissue.

Project description:ObjectiveRestricting dietary methionine to 0.17% in mice increases energy expenditure (EE), reduces fat deposition, and improves metabolic health by increasing hepatic fibroblast growth factor 21 (FGF21). The goal of this study was to compare each of these responses in mice with the coreceptor for FGF21 deleted in either adipose tissue or the brain.MethodsMethionine-restriction (MR) diets were fed to age-matched cohorts of mice with the coreceptor for FGF21 deleted in either adipose tissue or the brain. The physiological and transcriptional responses to MR were compared in the respective cohorts.ResultsTissue-specific deletion of the FGF21 coreceptor in adipose tissue did not abrogate the ability of dietary MR to increase EE and reduce fat deposition. Tissue-specific deletion of the FGF21 coreceptor from the brain produced mice that were unable to respond to the effects of MR on EE or the remodeling of adipose tissue.ConclusionsThe increase in FGF21 produced by dietary MR acts primarily in the brain to produce its physiological effects on energy balance. In contrast, the effects of MR on hepatic gene expression were intact in both models, supporting a mechanism that directly links detection of reduced methionine in the liver to transcriptional mechanisms that alter gene expression in the liver.

| S-EPMC7513464 | biostudies-literature

Fibroblast growth factor 21 alleviates acute pancreatitis via activation of the Sirt1-autophagy signalling pathway.

Project description:Fibroblast growth factor 21 (FGF21), a metabolic hormone with pleiotropic effects on glucose and lipid metabolism and insulin sensitivity, alleviates the process of acute pancreatitis (AP). However, its mechanism remains elusive. The pathological and physiological characteristics of FGF21 are observed in both patients with AP and cerulein-induced AP models, and the mechanisms of FGF21 in response to AP are investigated by evaluating the impact of autophagy in FGF21-treated mice and cultured pancreatic cells. Circulating levels of FGF21 significantly increase in both AP patients and cerulein-induced AP mice, which is accompanied by the change of pathology in pancreatic injury. Replenishment of FGF21 distinctly reverses cerulein-induced pancreatic injury and improves cerulein-induced autophagy damage in vivo and in vitro. Mechanically, FGF21 acts on pancreatic acinar cells to up-regulate Sirtuin-1 (Sirt1) expression, which in turn repairs impaired autophagy and removes damaged organs. In addition, blockage of Sirt1 accelerates cerulein-induced pancreatic injury and weakens the regulative effect in FGF21-activated autophagy in mice. These results showed that FGF21 protects against cerulein-induced AP by activation of Sirtuin-1-autophagy axis.

| S-EPMC7205819 | biostudies-literature

Fibroblast growth factor-21 alleviates proteasome injury via activation of autophagy flux in Parkinson's disease.

Project description:Parkinson's disease (PD) is one of the most common and complex Neurodegeneration, with an inherited metabolic disorder. Fibroblast growth factor 21 (FGF21), an endocrine hormone that belongs to the fibroblast growth factor superfamily, plays an extensive role in metabolic regulation. However, our understandings of the specific function and mechanisms of FGF21 on PD are still quite limited. Here, we aimed to elucidate the actions and the underlying mechanisms of FGF21 on dopaminergic neurodegeneration using cellular models of parkinsonism. To investigate the effects of FGF21 on dopaminergic neurodegeneration in vitro, proteasome impairment models of PD were utilized. Human dopaminergic neuroblastoma SH-SY5Y cells were treated with the proteasome inhibitor lactacystin (5 μmol/L) for 12 h, then with 50 ng/ml FGF-21 with or without 5 mmol/L of 3-methyladenine.The cells were dissected to assess alterations in autophagy using immunofluorescence, immunoblotting and electron microscopy assays. Our data indicate that FGF21 prevents dopaminergic neuron loss and shows beneficial effects against proteasome impairment induced PD syndrome, indicating it might be a potent candidate for developing novel drugs to deal with PD.

| S-EPMC10786996 | biostudies-literature

<i>Bifidobacterium adolescentis</i> Alleviates Liver Steatosis and Steatohepatitis by Increasing Fibroblast Growth Factor 21 Sensitivity.

Project description:The gut microbiota is a newly identified contributor to the development of non-alcoholic fatty liver disease (NAFLD). Previous studies of Bifidobacterium adolescentis (B. adolescentis), a species of Bifidobacterium that is common in the human intestinal tract, have demonstrated that it can alleviate liver steatosis and steatohepatitis. Fibroblast growth factor 21 (FGF21) has long been considered as a biomarker of NAFLD, and recent studies have shown the protective effect of FGF21 analogs on NAFLD. We wondered whether B. adolescentis treatment would alleviate NAFLD via the interaction with FGF21. To this end, male C57BL/6J mice on a choline-deficient high-fat diet (CDHFD) were treated with drinking water supplemented with B. adolescentis for 8 weeks, followed by the acute administration of recombinant mouse FGF21 protein (rmFGF21) to conduct the FGF21 response test. Consistent with previous studies, B. adolescentis supplementation reversed the CDHFD-induced liver steatosis and steatohepatitis. This was evaluated on the NAFLD activity score (NAS), reduced liver enzymes, and lipid accumulation. Further studies demonstrated that B. adolescentis supplementation preserved the gut barrier, reduced the gut microbiota-derived lipopolysaccharide (LPS), and inhibited the hepatic TLR4/NF-κB pathway. This was accompanied by the elevated expressions of the receptors of FGF21, fibroblast growth factor receptor 1 (FGFR1) and β-klotho (KLB), in the liver and the decreased expression of FGF21. The results of FGF21 response test showed that B. adolescentis supplementation alleviated the CDHFD-induced FGF21 resistance. In vivo experiments suggested that LPS could suppress the expression of FGF21 and KLB in a dose-dependent manner. Collectively, this study showed that B. adolescentis supplementation could alleviate NAFLD by increasing FGF21 sensitivity.

| S-EPMC8756294 | biostudies-literature

An association between fibroblast growth factor 21 and cognitive impairment in iron-overload thalassemia.

Project description:Although an increased fibroblast growth factor 21 (FGF21) level was related to mild cognitive impairment (MCI) in metabolic syndrome patients, any association regarding FGF21 and MCI in thalassemia patients as well as mechanistic insight are questionable. Therefore, the objectives of this study were: (1) to investigate the prevalence and associative risk factors of MCI in thalassemia patients, (2) to evaluate the association between levels of FGF21 and MCI in thalassemia patients, and (3) to investigate brain FGF21 signaling in iron-overload thalassemia. Thalassemia patients were enrolled onto the study (n = 131). Montreal cognitive assessment (MoCA) was used to determine cognitive performance. Plasma FGF21 level was determined in all patients. Iron-overload β-thalassemic (HT) mice were used to investigate brain FGF21 level and signaling, the expression of synaptic proteins, and Alzheimer's like pathology. We found that 70% of thalassemia patients developed MCI. FGF21 level was positively correlated with the MCI. Interestingly, brain FGF21 resistance, as indicated by increased brain FGF21 levels with impaired FGF21 signaling, was found in iron-overload HT mice. The reduced synaptic protein expression and increased Alzheimer's like pathology were also observed. These suggest that FGF21 may play a role in MCI in thalassemia patients.

| S-EPMC8044130 | biostudies-literature

Fibroblast Activation Protein Cleaves and Inactivates Fibroblast Growth Factor 21.

Project description:FGF21 is a stress-induced hormone with potent anti-obesity, insulin-sensitizing, and hepatoprotective properties. Although proteolytic cleavage of recombinant human FGF21 in preclinical species has been observed previously, the regulation of endogenously produced FGF21 is not well understood. Here we identify fibroblast activation protein (FAP) as the enzyme that cleaves and inactivates human FGF21. A selective chemical inhibitor, immunodepletion, or genetic deletion of Fap stabilized recombinant human FGF21 in serum. In addition, administration of a selective FAP inhibitor acutely increased circulating intact FGF21 levels in cynomolgus monkeys. On the basis of our findings, we propose selective FAP inhibition as a potential therapeutic approach to increase endogenous FGF21 activity for the treatment of obesity, type 2 diabetes, non-alcoholic steatohepatitis, and related metabolic disorders.

| S-EPMC4786731 | biostudies-literature

Modulating fibroblast growth factor 21 in hyperphagic OLETF rats with daily exercise and caloric restriction.

Project description:Chronic treatment with fibroblast growth factor 21 (FGF-21) favorably improves obesity and nonalcoholic fatty liver disease (NAFLD) outcomes; however, FGF-21 expression is paradoxically elevated in obese conditions. Here, we sought to determine the effects of obesity prevention by daily exercise (EX) vs. caloric restriction (CR) on hepatic FGF-21 in the hyperphagic, Otsuka Long-Evans Tokushima Fatty (OLETF) rat. Four-week-old male OLETF rats were randomized into groups (n = 7-8 per group) of ad libitum fed, sedentary (OLETF-SED), voluntary wheel running exercise (OLETF-EX), or CR (OLETF-CR; 70% of SED) until 40 weeks of age. Nonhyperphagic, Long-Evans Tokushima Otsuka (LETO-SED) rats served as controls. Both daily EX and CR prevented obesity and NAFLD development observed in the OLETF-SED animals. This was associated with significantly (p < 0.01) lower serum FGF-21 (~80% lower) and hepatic FGF-21 mRNA expression (~65% lower) in the OLETF-EX and OLETF-CR rats compared with the OLETF-SED rats. However, hepatic FGF-21 protein content was reduced to the greatest extent in the OLETF-EX animals (50% of OLETF-SED) and did not differ between the OLETF-SED and OLETF-CR rats. Hepatic FGF-21 signaling mediators - hepatic FGF-21 receptor 2 (FGFR2, mRNA expression), hepatic FGF-21 receptor substrate 2 (FRS2, protein content), and co-receptor β-Klotho (protein content) - were all elevated (60%-100%, ~40%, and +30%-50%, respectively) in the OLETF-EX and OLETF-CR animals compared with the OLETF-SED animals. Daily exercise and caloric restriction modulate hepatic FGF-21 and its primary signaling mediators in the hyperphagic OLETF rat. Enhanced metabolic action of FGF-21 may partially explain the benefits of exercise and caloric restriction on NAFLD outcomes.

| S-EPMC5572191 | biostudies-other

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