RESUMO
Nutrition exerts considerable effects on health, and dietary interventions are commonly used to treat diseases of metabolic aetiology. Although cancer has a substantial metabolic component1, the principles that define whether nutrition may be used to influence outcomes of cancer are unclear2. Nevertheless, it is established that targeting metabolic pathways with pharmacological agents or radiation can sometimes lead to controlled therapeutic outcomes. By contrast, whether specific dietary interventions can influence the metabolic pathways that are targeted in standard cancer therapies is not known. Here we show that dietary restriction of the essential amino acid methionine-the reduction of which has anti-ageing and anti-obesogenic properties-influences cancer outcome, through controlled and reproducible changes to one-carbon metabolism. This pathway metabolizes methionine and is the target of a variety of cancer interventions that involve chemotherapy and radiation. Methionine restriction produced therapeutic responses in two patient-derived xenograft models of chemotherapy-resistant RAS-driven colorectal cancer, and in a mouse model of autochthonous soft-tissue sarcoma driven by a G12D mutation in KRAS and knockout of p53 (KrasG12D/+;Trp53-/-) that is resistant to radiation. Metabolomics revealed that the therapeutic mechanisms operate via tumour-cell-autonomous effects on flux through one-carbon metabolism that affects redox and nucleotide metabolism-and thus interact with the antimetabolite or radiation intervention. In a controlled and tolerated feeding study in humans, methionine restriction resulted in effects on systemic metabolism that were similar to those obtained in mice. These findings provide evidence that a targeted dietary manipulation can specifically affect tumour-cell metabolism to mediate broad aspects of cancer outcome.
Assuntos
Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , Modelos Animais de Doenças , Metabolômica , Metionina/administração & dosagem , Metionina/farmacologia , Sarcoma/tratamento farmacológico , Neoplasias de Tecidos Moles/tratamento farmacológico , Animais , Linhagem Celular Tumoral , Neoplasias Colorretais/genética , Dieta , Feminino , Fluoruracila/farmacologia , Fluoruracila/uso terapêutico , Genes p53 , Genes ras , Voluntários Saudáveis , Humanos , Masculino , Metionina/metabolismo , Camundongos , Pessoa de Meia-Idade , Mutação , Estudo de Prova de Conceito , Sarcoma/genética , Sarcoma/metabolismo , Neoplasias de Tecidos Moles/genética , Neoplasias de Tecidos Moles/metabolismo , Enxofre/metabolismo , Resultado do TratamentoRESUMO
Methionine restriction (MR) extends the lifespan across several species, such as rodents, fruit flies, roundworms, and yeast. MR studies have been conducted on various rodent organs, such as liver, adipose tissue, heart, bones, and skeletal muscle, to elucidate its benefits to the healthspan; however, studies of the direct effect of MR on kidneys are lacking. To investigate the renal effects of MR, we used young and aged unilateral nephrectomized and 5/6 nephrectomized (5/6Nx) mice. Our studies indicated that MR mice experienced polydipsia and polyuria compared with control-fed counterparts. Urine albumin, creatinine, albumin-to-creatinine ratio, sulfur amino acids, and electrolytes were reduced in MR mice. Kidneys of MR mice up-regulated genes that are involved in ion transport, such as Aqp2, Scnn1a, and Slc6a19, which indicated a response to maintain osmotic balance. In addition, we identified renoprotective biomarkers that are affected by MR, such as clusterin and cystatin C. Of importance, MR attenuated kidney injury in 5/6Nx mice by down-regulating inflammation and fibrosis mechanisms. Thus, our studies in mice show the important role of kidneys during MR in maintaining osmotic homeostasis. Moreover, our studies also show that the MR diet delays the progression of kidney disease.-Cooke, D., Ouattara, A., Ables, G. P. Dietary methionine restriction modulates renal response and attenuates kidney injury in mice.
Assuntos
Injúria Renal Aguda/metabolismo , Rim/metabolismo , Metionina/deficiência , Polidipsia/metabolismo , Poliúria/metabolismo , Injúria Renal Aguda/dietoterapia , Injúria Renal Aguda/patologia , Animais , Rim/patologia , Masculino , Camundongos , Osmose , Polidipsia/dietoterapia , Polidipsia/patologia , Poliúria/dietoterapia , Poliúria/patologiaRESUMO
Dietary methionine restriction (MR) has been suggested to be comparable to endurance exercise with respect to its beneficial effects on health. To further investigate the effects of MR and endurance exercise on growing bone, 7-wk-old male Sprague-Dawley rats were fed different l-methionine (Met)-containing diets with or without endurance exercise intervention (Ex; 0.86% Met, 0.52% Met, 0.17% Met, 0.86% Met-Ex, 0.52% Met-Ex, and 0.17% Met-Ex groups). After an 8-wk intervention period, exercise-trained rats had a 9.2% lower body weight (BW) than did sedentary rats (P < 0.05). Additionally, 0.17% Met-fed rats had 32% lower BW when compared with rats fed the other 2 diets (P < 0.05). Serum osteocalcin was lower in the 0.17% Met-Ex group compared with the other 2 exercise groups and the 0.17% Met group (P < 0.05). Serum concentrations of C-terminal telopeptide of type 1 collagen were lower in exercise-trained and 0.17% Met-fed rats than in sedentary rats and rats fed the other 2 diets (P < 0.05 for both). Rats fed the 0.17% Met diet had lower trabecular bone volume, bone mineralization activities, and bone mineral content (BMC; e.g., total, cortical, and spongy BMC) and bone mineral density (BMD; e.g., total and spongy BMD) indices compared with rats fed the other 2 diets (P < 0.05). Exercise-trained rats also had lower bone mineralization activity, trabecular osteoclast density, total BMC, cortical BMC, and total BMD compared with sedentary rats (P < 0.05). In total BMD, only the 0.17% Met-Ex group had values lower than the other 2 exercise groups and the 0.17% Met group (P < 0.05). Compared with rats fed the other 2 diets and sedentary rats, the femora of 0.17% Met-fed and exercise-trained rats, respectively, had smaller size and/or lower extrinsic strength but enhanced intrinsic biomechanical properties (P < 0.05). The results indicate that MR and endurance exercise caused lower whole bone mass, size, and/or strength but might enhance intrinsic bone strength.
Assuntos
Ração Animal , Desenvolvimento Ósseo/efeitos dos fármacos , Fêmur/efeitos dos fármacos , Metionina/farmacologia , Tíbia/efeitos dos fármacos , Animais , Biomarcadores/sangue , Fenômenos Biomecânicos/efeitos dos fármacos , Fenômenos Biomecânicos/fisiologia , Peso Corporal/efeitos dos fármacos , Peso Corporal/fisiologia , Densidade Óssea/efeitos dos fármacos , Densidade Óssea/fisiologia , Desenvolvimento Ósseo/fisiologia , Fêmur/fisiologia , Lâmina de Crescimento/efeitos dos fármacos , Lâmina de Crescimento/fisiologia , Masculino , Modelos Biológicos , Condicionamento Físico Animal/fisiologia , Resistência Física/efeitos dos fármacos , Resistência Física/fisiologia , Ratos , Ratos Sprague-Dawley , Tíbia/fisiologiaRESUMO
OBJECTIVE: Differences in white adipose tissue (WAT) expression of mesoderm-specific transcript (Mest) in C57BL6/J mice fed a high-fat diet (HFD) are concomitant with and predictive for the development of obesity. However, the basis for differences in WAT Mest among mice is unknown. This study investigated whether HFD-inducible WAT Mest, as well as susceptibility to obesity, is transmissible from parents to offspring. METHODS: WAT biopsies of mice fed an HFD for 2 weeks identified parents with low and high WAT Mest for breeding. Obesity phenotypes, WAT Mest, hepatic gene expression, and serum metabolites were determined in offspring fed an HFD for 2 weeks. RESULTS: Offspring showed no heritability of obesity or WAT Mest phenotypes from parents but did show hepatic and serum metabolite changes consistent with their WAT Mest. Importantly, retired male breeders showed WAT Mest expression congruent with initial WAT biopsies even though HFD exposure occurred early in life. CONCLUSIONS: Disparity of HFD-induced Mest in mice is not heritable but, rather, is reestablished during each generation and remains fixed from an early age to adulthood. Short-term HFD feeding reveals variation of WAT Mest expression within isogenic mice that is positively associated with the development of obesity.
Assuntos
Tecido Adiposo Branco , Dieta Hiperlipídica , Fígado , Camundongos Endogâmicos C57BL , Obesidade , Animais , Tecido Adiposo Branco/metabolismo , Camundongos , Masculino , Obesidade/genética , Obesidade/metabolismo , Feminino , Fígado/metabolismo , Fenótipo , Gorduras na Dieta/efeitos adversosRESUMO
Sulfur amino acid restriction (SAAR)-the reduction of methionine and cysteine concentrations either in the diet or by genetic manipulation-promotes health span and extends lifespan, but its effects on physical activity remain unclear. We investigated whether age of diet initiation and biological sex could influence physical activity in mice fed either a control diet (CF, 0.86% methionine w/w) or SAAR (0.12% methionine w/w). Quadriceps femoris muscle mass is smaller in SAAR than in CF mice. Young mice fed a chronic SAAR diet at 8 weeks of age exhibited improved wire hang and running wheel activities compared to young CF mice, while aged mice showed comparable results. The effects of chronic SAAR on physical activity was mildly influenced by sex as observed in middle-aged male SAAR mice who showed minor improvements than CF males while middle-aged females displayed no discernible effects. Muscle mass is minimally affected by changes in markers of protein synthesis, autophagy and atrophy. Improvements to physical activity in young SAAR mice could be partially attributed to increased skeletal muscle mitochondrial activity. Furthermore, SAAR in C2C12 myotubes increased citrate synthase protein expression and enhanced succinyl dehydrogenase enzyme activity compared to CF myotubes. Overall, our data reveal that SAAR can improve mouse physical activity without compromising muscle proteostasis. This is partially due to enhanced mitochondrial activity, but the effects are influenced by age of diet initiation and sex.
Assuntos
Aminoácidos Sulfúricos , Feminino , Camundongos , Masculino , Animais , Dieta/métodos , Metionina/metabolismo , Cisteína/metabolismoRESUMO
OBJECTIVE: Perivascular adipose tissue (PVAT) regulates vascular health. Dietary methionine restriction (MetR) impacts age-related adiposity, and this study addresses its effects in PVAT. METHODS: Male C57BL/6 mice at 8, 52, and 102 weeks of age were fed a standard (0.86%) or low-methionine (0.12%) diet for 52 weeks in 8-week-old and 52-week-old mice and for 15 weeks in 102-week-old mice. RESULTS: Mice with dietary MetR were resistant to weight gain and maintained a healthy blood profile. Aging increased lipid accumulation, and MetR reversed this phenotype. Notch signaling in inguinal white adipose tissue (iWAT) was decreased by MetR but increased in gonadal white adipose tissue. However, the Notch phenotype of brown adipose tissue (BAT) was not affected by MetR. Uncoupling protein 1 (UCP1) was increased in PVAT, iWAT, and BAT by MetR when initiated in young mice, but this effect was lost in middle-aged mice. CONCLUSIONS: Lipid in mouse PVAT peaked at 1 year of age, consistent with peak body mass. MetR reduced body weight, normalized metabolic parameters, and decreased lipid in PVAT in all age cohorts. Mice fed a MetR diet from early maturity to 1 year of age displayed an increased thermogenic adipocyte phenotype in iWAT, PVAT, and BAT, all tissues with thermogenic capacity.
Assuntos
Tecido Adiposo Marrom , Metionina , Camundongos , Masculino , Animais , Metionina/metabolismo , Camundongos Endogâmicos C57BL , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , Racemetionina/metabolismo , Racemetionina/farmacologia , LipídeosRESUMO
Dietary methionine restriction (MR) increases longevity by improving health. In experimental models, MR is accompanied by decreased cystathionine ß-synthase activity and increased cystathionine γ-lyase activity. These enzymes are parts of the transsulfuration pathway which produces cysteine and 2-oxobutanoate. Thus, the decrease in cystathionine ß-synthase activity is likely to account for the loss of tissue cysteine observed in MR animals. Despite this decrease in cysteine levels, these tissues exhibit increased H2S production which is thought to be generated by ß-elimination of the thiol moiety of cysteine, as catalyzed by cystathionine ß-synthase or cystathionine γ-lyase. Another possibility for this H2S production is the cystathionine γ-lyase-catalyzed ß-elimination of cysteine persulfide from cystine, which upon reduction yields H2S and cysteine. Here, we demonstrate that MR increases cystathionine γ-lyase production and activities in the liver and kidneys, and that cystine is a superior substrate for cystathionine γ-lyase catalyzed ß-elimination as compared to cysteine. Moreover, cystine and cystathionine exhibit comparable Kcat/Km values (6000 M-1 s-1) as substrates for cystathionine γ-lyase-catalyzed ß-elimination. By contrast, cysteine inhibits cystathionine γ-lyase in a non-competitive manner (Ki ~ 0.5 mM), which limits its ability to function as a substrate for ß-elimination by this enzyme. Cysteine inhibits the enzyme by reacting with its pyridoxal 5'-phosphate cofactor to form a thiazolidine and in so doing prevents further catalysis. These enzymological observations are consistent with the notion that during MR cystathionine γ-lyase is repurposed to catabolize cystine and thereby form cysteine persulfide, which upon reduction produces cysteine.
RESUMO
Acyl CoA:diacylglycerol acyltransferase (DGAT) 1 catalyzes the final step of triglyceride (TG) synthesis. We show that acute administration of a DGAT1 inhibitor (DGAT1i) by oral gavage or genetic deletion of intestinal Dgat1 (intestine-Dgat1(-/-)) markedly reduced postprandial plasma TG and retinyl ester excursions by inhibiting chylomicron secretion in mice. Loss of DGAT1 activity did not affect the efficiency of retinol esterification, but it did reduce TG and retinoid accumulation in the small intestine. In contrast, inhibition of microsomal triglyceride transfer protein (MTP) reduced chylomicron secretion after oral fat/retinol loads, but with accumulation of dietary TG and retinoids in the small intestine. Lack of intestinal accumulation of TG and retinoids in DGAT1i-treated or intestine-Dgat1(-/-) mice resulted, in part, from delayed gastric emptying associated with increased plasma levels of glucagon-like peptide (GLP)-1. However, neither bypassing the stomach through duodenal oil injection nor inhibiting the receptor for GLP-1 normalized postprandial TG or retinyl esters excursions in the absence of DGAT1 activity. In summary, intestinal DGAT1 inhibition or deficiency acutely delayed gastric emptying and inhibited chylomicron secretion; however, the latter occurred when gastric emptying was normal or when lipid was administered directly into the small intestine. Long-term hepatic retinoid metabolism was not impacted by DGAT1 inhibition.
Assuntos
Quilomícrons/metabolismo , Diacilglicerol O-Aciltransferase/deficiência , Diacilglicerol O-Aciltransferase/metabolismo , Esvaziamento Gástrico/genética , Período Pós-Prandial/fisiologia , Triglicerídeos/metabolismo , Animais , Carbamatos/farmacologia , Proteínas de Transporte/antagonistas & inibidores , Proteínas de Transporte/metabolismo , Diacilglicerol O-Aciltransferase/antagonistas & inibidores , Diacilglicerol O-Aciltransferase/genética , Esvaziamento Gástrico/efeitos dos fármacos , Peptídeo 1 Semelhante ao Glucagon/sangue , Receptor do Peptídeo Semelhante ao Glucagon 1 , Indóis/farmacologia , Masculino , Camundongos , Camundongos Mutantes , Fragmentos de Peptídeos/farmacologia , Período Pós-Prandial/genética , Receptores de Glucagon/antagonistas & inibidores , Retinoides/metabolismo , Triglicerídeos/sangueRESUMO
Decreasing the dietary intake of methionine exerts robust anti-adiposity effects in rodents but modest effects in humans. Since cysteine can be synthesized from methionine, animal diets are formulated by decreasing methionine and eliminating cysteine. Such diets exert both methionine restriction (MR) and cysteine restriction (CR), that is, sulfur amino acid restriction (SAAR). Contrarily, SAAR diets formulated for human consumption included cysteine, and thus might have exerted only MR. Epidemiological studies positively correlate body adiposity with plasma cysteine but not methionine, suggesting that CR, but not MR, is responsible for the anti-adiposity effects of SAAR. Whether this is true, and, if so, the underlying mechanisms are unknown. Using methionine- and cysteine-titrated diets, we demonstrate that the anti-adiposity effects of SAAR are due to CR. Data indicate that CR increases serinogenesis (serine biosynthesis from non-glucose substrates) by diverting substrates from glyceroneogenesis, which is essential for fatty acid reesterification and triglyceride synthesis. Molecular data suggest that CR depletes hepatic glutathione and induces Nrf2 and its downstream targets Phgdh (the serine biosynthetic enzyme) and Pepck-M. In mice, the magnitude of SAAR-induced changes in molecular markers depended on dietary fat concentration (60% fat >10% fat), sex (males > females), and age-at-onset (young > adult). Our findings are translationally relevant as we found negative and positive correlations of plasma serine and cysteine, respectively, with triglycerides and metabolic syndrome criteria in a cross-sectional epidemiological study. Controlled feeding of low-SAA, high-polyunsaturated fatty acid diets increased plasma serine in humans. Serinogenesis might be a target for treating hypertriglyceridemia.
Assuntos
Aminoácidos Sulfúricos , Cisteína , Masculino , Feminino , Camundongos , Humanos , Animais , Cisteína/metabolismo , Metabolismo dos Lipídeos , Estudos Transversais , Aminoácidos Sulfúricos/metabolismo , Metionina/metabolismo , Obesidade/metabolismo , Serina/metabolismoRESUMO
Diacylglycerol (DAG) acyl transferase 1 (Dgat1) knockout ((-/-)) mice are resistant to high-fat-induced obesity and insulin resistance, but the reasons are unclear. Dgat1(-/-) mice had reduced mRNA levels of all three Ppar genes and genes involved in fatty acid oxidation in the myocardium of Dgat1(-/-) mice. Although DGAT1 converts DAG to triglyceride (TG), tissue levels of DAG were not increased in Dgat1(-/-) mice. Hearts of chow-diet Dgat1(-/-) mice were larger than those of wild-type (WT) mice, but cardiac function was normal. Skeletal muscles from Dgat1(-/-) mice were also larger. Muscle hypertrophy factors phospho-AKT and phospho-mTOR were increased in Dgat1(-/-) cardiac and skeletal muscle. In contrast to muscle, liver from Dgat1(-/-) mice had no reduction in mRNA levels of genes mediating fatty acid oxidation. Glucose uptake was increased in cardiac and skeletal muscle in Dgat1(-/-) mice. Treatment with an inhibitor specific for DGAT1 led to similarly striking reductions in mRNA levels of genes mediating fatty acid oxidation in cardiac and skeletal muscle. These changes were reproduced in cultured myocytes with the DGAT1 inhibitor, which also blocked the increase in mRNA levels of Ppar genes and their targets induced by palmitic acid. Thus, loss of DGAT1 activity in muscles decreases mRNA levels of genes involved in lipid uptake and oxidation.
Assuntos
Diacilglicerol O-Aciltransferase/metabolismo , Músculo Esquelético/metabolismo , Miocárdio/metabolismo , Receptores Ativados por Proliferador de Peroxissomo/genética , Absorciometria de Fóton , Animais , Western Blotting , Linhagem Celular , Ceramidas/metabolismo , Diacilglicerol O-Aciltransferase/deficiência , Diacilglicerol O-Aciltransferase/genética , Diglicerídeos/metabolismo , Ecocardiografia , Inibidores Enzimáticos/farmacologia , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/genética , Glucose/metabolismo , Lipoproteínas VLDL/metabolismo , Masculino , Camundongos , Camundongos Knockout , Mioblastos/efeitos dos fármacos , Mioblastos/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Tamanho do Órgão/genética , Ácido Palmítico/farmacologia , Reação em Cadeia da PolimeraseRESUMO
OBJECTIVE: Identifying novel approaches to combat obesity is important to improve health span. It was hypothesized that methionine restriction (MR) will induce weight loss in obese mice by reducing adipose tissue mass caused by increased energy expenditure and reprogramming of adipose tissue homeostasis. The roles of adiponectin (ADIPOQ) and fibroblast growth factor 21 (FGF21) during weight loss in MR mice were also tested. METHODS: Diet-induced obese (DIO) male C57BL/6J (wild type), Adipoq-deficient (Adipoq knockout [KO]), Fgf21-KO, and Adipoq-Fgf21 double-KO mice were used. Following a switch to high-fat control (DIO-CF, 60% fat/0.86% methionine) or MR (DIO-MR, 60% fat/0.12% methionine) diet, physiological parameters were measured, and inguinal and perigonadal adipose tissues were examined. RESULTS: Obese mice subjected to MR showed loss of body weight and adiposity, increased energy expenditure, and improved glucose tolerance that were independent of the actions of ADIPOQ and FGF21. MR induced reduction of circulating lipids, glucose, insulin, leptin, and insulin like growth factor 1 and increased ß-hydroxybutyrate, ADIPOQ, and FGF21 concentrations. In fat, MR upregulated protein levels of adipose triglyceride lipase, apoptosis-inducing factor, lysosomal-associated membrane proteins 1 and 2, autophagy-related protein 5, beclin-1, and light chain 3B I and II. CONCLUSIONS: MR reduction of adipose tissue mass in obese mice is associated with elevated lipolysis, apoptosis, and autophagy and occurs independently of the actions of ADIPOQ and FGF21.
Assuntos
Adiponectina/metabolismo , Adiposidade/fisiologia , Fatores de Crescimento de Fibroblastos/metabolismo , Metionina/metabolismo , Camundongos Obesos/genética , Redução de Peso/fisiologia , Animais , Masculino , CamundongosRESUMO
Several pharmacological, dietary, and genetic interventions that increase mammalian lifespan are known, but general principles of lifespan extension remain unclear. Here, we performed RNA sequencing (RNA-seq) analyses of mice subjected to 8 longevity interventions. We discovered a feminizing effect associated with growth hormone regulation and diminution of sex-related differences. Expanding this analysis to 17 interventions with public data, we observed that many interventions induced similar gene expression changes. We identified hepatic gene signatures associated with lifespan extension across interventions, including upregulation of oxidative phosphorylation and drug metabolism, and showed that perturbed pathways may be shared across tissues. We further applied the discovered longevity signatures to identify new lifespan-extending candidates, such as chronic hypoxia, KU-0063794, and ascorbyl-palmitate. Finally, we developed GENtervention, an app that visualizes associations between gene expression changes and longevity. Overall, this study describes general and specific transcriptomic programs of lifespan extension in mice and provides tools to discover new interventions.
Assuntos
Envelhecimento/genética , Longevidade/genética , Transcriptoma , Envelhecimento/efeitos dos fármacos , Animais , Ácido Ascórbico/análogos & derivados , Ácido Ascórbico/farmacologia , Restrição Calórica , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Técnicas de Inativação de Genes , Hipóxia/genética , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Expectativa de Vida , Fígado/metabolismo , Longevidade/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Morfolinas/farmacologia , Pirimidinas/farmacologia , Sirolimo/farmacologiaRESUMO
The presence of adipocytes in mammalian bone marrow (BM) has been recognized histologically for decades, yet, until recently, these cells have received little attention from the research community. Advancements in mouse transgenics and imaging methods, particularly in the last 10 years, have permitted more detailed examinations of marrow adipocytes than ever before and yielded data that show these cells are critical regulators of the BM microenvironment and whole-body metabolism. Indeed, marrow adipocytes are anatomically and functionally separate from brown, beige, and classic white adipocytes. Thus, areas of BM space populated by adipocytes can be considered distinct fat depots and are collectively referred to as marrow adipose tissue (MAT) in this review. In the proceeding text, we focus on the developmental origin and physiologic functions of MAT. We also discuss the signals that cause the accumulation and loss of marrow adipocytes and the ability of these cells to regulate other cell lineages in the BM. Last, we consider roles for MAT in human physiology and disease.
Assuntos
Adiposidade , Medula Óssea/metabolismo , Adipócitos , Animais , Medula Óssea/crescimento & desenvolvimento , Medula Óssea/fisiologia , Humanos , Transdução de SinaisRESUMO
Methionine restriction (MR) extends lifespan across different species. The main responses of rodent models to MR are well-documented in adipose tissue (AT) and liver, which have reduced mass and improved insulin sensitivity, respectively. Recently, molecular mechanisms that improve healthspan have been identified in both organs during MR. In fat, MR induced a futile lipid cycle concomitant with beige AT accumulation, producing elevated energy expenditure. In liver, MR upregulated fibroblast growth factor 21 and improved glucose metabolism in aged mice and in response to a high-fat diet. Furthermore, MR also reduces mitochondrial oxidative stress in various organs such as liver, heart, kidneys, and brain. Other effects of MR have also been reported in such areas as cardiac function in response to hyperhomocysteinemia (HHcy), identification of molecular mechanisms in bone development, and enhanced epithelial tight junction. In addition, rodent models of cancer responded positively to MR, as has been reported in colon, prostate, and breast cancer studies. The beneficial effects of MR have also been documented in a number of invertebrate model organisms, including yeast, nematodes, and fruit flies. MR not only promotes extended longevity in these organisms, but in the case of yeast has also been shown to improve stress tolerance. In addition, expression analyses of yeast and Drosophila undergoing MR have identified multiple candidate mediators of the beneficial effects of MR in these models. In this review, we emphasize other in vivo effects of MR such as in cardiovascular function, bone development, epithelial tight junction, and cancer. We also discuss the effects of MR in invertebrates.
Assuntos
Envelhecimento/metabolismo , Longevidade , Metionina/deficiência , Envelhecimento/genética , Envelhecimento/patologia , Animais , Desenvolvimento Ósseo , Caenorhabditis elegans/crescimento & desenvolvimento , Caenorhabditis elegans/metabolismo , Sistema Cardiovascular/metabolismo , Drosophila melanogaster/crescimento & desenvolvimento , Drosophila melanogaster/metabolismo , Células Epiteliais/metabolismo , Regulação da Expressão Gênica , Humanos , Neoplasias/metabolismo , Neoplasias/patologia , Estresse Fisiológico , Junções Íntimas/metabolismo , Leveduras/crescimento & desenvolvimento , Leveduras/metabolismoRESUMO
Despite well-documented evidence for lifespan extension by methionine restriction (MR), underlying mechanisms remain unknown. As methionine can alter S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH), the substrate and product of DNA methyltransferase-1 (DNMT1), we hypothesized that MR diet alters DNA methylation. Young (8-week-old) and adult (1-year-old) male C57BL/6J mice were fed diets with different levels of methionine (0.12%-MR, 0.84%-CD) for 12weeks. Functional indicators of DNA methylation, including global methylation (GM), gene-specific methylation (GSM) and LINE-1 methylation; and biochemical factors affecting DNA methylation, SAH, SAM, and DNMT1 were assessed in different tissues. MR altered DNA methylation depending on the age of intervention. While MR had no effect on hepatic GM in young animals, it increased GM by 27% over CD in adults (p<0.01). In comparison with young animals, hepatic GM levels were 17% lower in CD adults (p<0.05), but not different in MR adults. The MR-induced increase in hepatic GM was associated with a 38% decrease in SAH levels in adults (p<0.001), with SAH and GM levels being negatively correlated (r2=0.33, p<0.001). No changes were observed in DNMT protein levels in liver. In adipose tissue, MR caused a 6% decline in GM in adults (p<0.05), a corresponding 2-fold increase in SAH (p<0.05), and a 2-fold decrease in DNMT1 (p<0.01). MR caused both increases and decreases in GSM of liver and adipose. No changes were observed in LINE-1. Together, these findings provide evidence for protective effects of MR diet on hepatic DNA hypomethylation in adults, apparently mediated by SAH. These findings also indicate that altered DNA methylation might be playing a role in benefits conferred by MR diet.
Assuntos
Envelhecimento , Restrição Calórica , Metilação de DNA/efeitos dos fármacos , Fígado/metabolismo , Metionina/farmacologia , Animais , Dieta , Fígado/efeitos dos fármacos , Masculino , Metionina/administração & dosagem , Camundongos , Camundongos Endogâmicos C57BL , Fatores de TempoRESUMO
Adipocytes were identified in human bone marrow more than a century ago, yet until recently little has been known about their origin, development, function or interactions with other cells in the bone marrow. Little functional significance has been attributed to these cells, a paradigm that still persists today. However, we now know that marrow adipose tissue increases with age and in response to a variety of physiologic induction signals. Bone marrow adipocytes have recently been shown to influence other cell populations within the marrow and can affect whole body metabolism by the secretion of a defined set of adipokines. Recent research shows that marrow adipocytes are distinct from white, brown and beige adipocytes, indicating that the bone marrow is a distinct adipose depot. This review will highlight recent data regarding these areas and the interactions of marrow adipose tissue (MAT) with cells within and outside of the bone marrow.
Assuntos
Adipócitos/fisiologia , Tecido Adiposo/fisiologia , Células da Medula Óssea/citologia , Adipócitos/metabolismo , Adipócitos Marrons/metabolismo , Adipócitos Brancos/metabolismo , Adipogenia/fisiologia , Adipocinas/fisiologia , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , Animais , Medula Óssea/metabolismo , Medula Óssea/fisiologia , Células da Medula Óssea/fisiologia , Diferenciação Celular/fisiologia , Humanos , Camundongos , TermogêneseRESUMO
Caloric restriction (CR), protein restriction (PR), and specific amino acid restriction (e.g., methionine restriction (MR)) are different dietary interventions that have been confirmed with regard to their comprehensive benefits to metabolism and health. Based on bone densitometric measurements, weight loss induced by dietary restriction is known to be accompanied by reduced areal bone mineral density, bone mass, and/or bone size, and it is considered harmful to bone health. However, because of technological advancements in bone densitometric instruments (e.g., high-resolution X-ray tomography), dietary restrictions have been found to cause a reduction in bone mass/size rather than volumetric bone mineral density. Furthermore, when considering bone quality, bone health consists of diverse indices that cannot be fully represented by densitometric measurements alone. Indeed, there is evidence that moderate dietary restrictions do not impair intrinsic bone material properties, despite the reduction in whole-bone strength because of a smaller bone size. In the present review, we integrate research evidence from traditional densitometric measurements, metabolic status assays (e.g., energy metabolism, oxidative stresses, and inflammatory responses), and biomaterial analyses to provide revised conclusions regarding the effects of CR, PR, and MR on the skeleton.
Assuntos
Densidade Óssea , Osso e Ossos/fisiologia , Restrição Calórica , Dieta , Envelhecimento , Animais , Fenômenos Biomecânicos , Densitometria , Metabolismo Energético , HumanosRESUMO
Dietary methionine restriction (MR) extends life span across species via various intracellular regulatory mechanisms. In rodents, MR induces resistance against adiposity, improves hepatic glucose metabolism, preserves cardiac function, and reduces body size, all of which can affect the onset of age-related diseases. Recent studies have shown that MR-affected biomarkers, such as fibroblast growth factor 21, adiponectin, leptin, cystathionine ß synthase, and insulin-like growth factor 1, can potentially alter physiology. The beneficial effects of MR could be explained in part by its ability to reduce mitochondrial oxidative stress. Studies have revealed that MR can reduce reactive oxygen species that damage cells and promote cancer progression. It has been demonstrated that either MR or the targeting of specific genes in the methionine cycle could induce cell apoptosis while decreasing proliferation in several cancer models. The complete mechanism underlying the actions of MR on the cell cycle during cancer has not been fully elucidated. Epigenetic mechanisms, such as methylation and noncoding RNAs, are also possible downstream effectors of MR; future studies should help to elucidate some of these mechanisms. Despite evidence that changes in dietary methionine can affect epigenetics, it remains unknown whether epigenetics is a mechanism in MR. This review summarizes research on MR and its involvement in metabolism, cancer, and epigenetics.
Assuntos
Restrição Calórica , Dieta , Expectativa de Vida , Metionina/metabolismo , Adiposidade , Animais , Osso e Ossos/anatomia & histologia , Osso e Ossos/metabolismo , Progressão da Doença , Epigênese Genética , Glucose/metabolismo , Humanos , Metabolismo dos Lipídeos , Fígado/metabolismo , Fígado/patologia , Miocárdio/metabolismo , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo , Transdução de SinaisRESUMO
Methionine restriction (MR) extends the lifespan of a wide variety of species, including rodents, drosophila, nematodes, and yeasts. MR has also been demonstrated to affect the overall growth of mice and rats. The objective of this study was to evaluate the effect of MR on bone structure in young and aged male and female C57BL/6J mice. This study indicated that MR affected the growth rates of males and young females, but not aged females. MR reduced volumetric bone mass density (vBMD) and bone mineral content (BMC), while bone microarchitecture parameters were decreased in males and young females, but not in aged females compared to control-fed (CF) mice. However, when adjusted for bodyweight, the effect of MR in reducing vBMD, BMC and microarchitecture measurements was either attenuated or reversed suggesting that the smaller bones in MR mice is appropriate for its body size. In addition, CF and MR mice had similar intrinsic strength properties as measured by nanoindentation. Plasma biomarkers suggested that the low bone mass in MR mice could be due to increased collagen degradation, which may be influenced by leptin, IGF-1, adiponectin and FGF21 hormone levels. Mouse preosteoblast cell line cultured under low sulfur amino acid growth media attenuated gene expression levels of Col1al, Runx2, Bglap, Alpl and Spp1 suggesting delayed collagen formation and bone differentiation. Collectively, our studies revealed that MR altered bone morphology which could be mediated by delays in osteoblast differentiation.
RESUMO
Dietary methionine restriction (MR) in rodents increased lifespan despite higher heart-to-body weight ratio (w/w) and hyperhomocysteinemia, which are symptoms associated with increased risk for cardiovascular disease. We investigated this paradoxical effect of MR on cardiac function using young, old, and apolipoprotein E-deficient (ApoE-KO) mice. Indeed, MR animals exhibited higher heart-to-body weight ratio (w/w) and hyperhomocysteinemia with a molecular pattern consistent with cardiac stress while maintaining the integrity of cardiac structure. Baseline cardiac function, which was measured by non-invasive electrocardiography (ECG), showed that young MR mice had prolonged QRS intervals compared with control-fed (CF) mice, whereas old and ApoE-KO mice showed similar results for both groups. Following ß-adrenergic challenge, responses of MR mice were either similar or attenuated compared with CF mice. Cardiac contractility, which was measured by isolated heart retrograde perfusion, was similar in both groups of old mice. Finally, the MR diet induced secretion of cardioprotective hormones, adiponectin and fibroblast growth factor 21 (FGF21), in MR mice with concomitant alterations in cardiac metabolic molecular signatures. Our findings demonstrate that MR diet does not alter cardiac function in mice despite the presence of hyperhomocysteinemia because of the adaptive responses of increased adiponectin and FGF21 levels.