RESUMO
Over the past two decades, bile acids (BAs) have become established as important signaling molecules that enable fine-tuned inter-tissue communication from the liver, their site of production, over the intestine, where they are modified by the gut microbiota, to virtually any organ, where they exert their pleiotropic physiological effects. The chemical variety of BAs, to a large extent determined by the gut microbiome, also allows for a complex fine-tuning of adaptive responses in our body. This review provides an overview of the mechanisms by which BA receptors coordinate several aspects of physiology and highlights new therapeutic strategies for diseases underlying pathological BA signaling.
Assuntos
Envelhecimento/patologia , Envelhecimento/fisiologia , Ácidos e Sais Biliares/fisiologia , Animais , Ácidos e Sais Biliares/biossíntese , Doenças dos Ductos Biliares/metabolismo , Doenças dos Ductos Biliares/fisiopatologia , Microbioma Gastrointestinal , Trato Gastrointestinal/metabolismo , Trato Gastrointestinal/microbiologia , Humanos , Fígado/metabolismoRESUMO
Immune mediators affect multiple biological functions of intestinal epithelial cells (IECs) and, like Paneth and Paneth-like cells, play an important role in intestinal epithelial homeostasis. IFN-γ a prototypical proinflammatory cytokine disrupts intestinal epithelial homeostasis. However, the mechanism underlying the process remains unknown. In this study, using in vivo and in vitro models we demonstrate that IFN-γ is spontaneously secreted in the small intestine. Furthermore, we observed that this cytokine stimulates mitochondrial activity, ROS production, and Paneth and Paneth-like cell secretion. Paneth and Paneth-like secretion downstream of IFN-γ, as identified here, is mTORC1 and necroptosis-dependent. Thus, our findings revealed that the pleiotropic function of IFN-γ also includes the regulation of Paneth cell function in the homeostatic gut.
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Genistein is an isoflavone present in soybeans and is considered a bioactive compound due to its widely reported biological activity. We have previously shown that intraperitoneal genistein administration and diet supplementation activates the thermogenic program in rats and mice subcutaneous white adipose tissue (scWAT) under multiple environmental cues, including cold exposure and high-fat diet feeding. However, the mechanistic insights of this process were not previously unveiled. Uncoupling protein 1 (UCP1), a mitochondrial membrane polypeptide responsible for dissipating energy into heat, is considered the most relevant thermogenic marker; thus, we aimed to evaluate whether genistein regulates UCP1 transcription. Here we show that genistein administration to thermoneutral-housed mice leads to the appearance of beige adipocyte markers, including a sharp upregulation of UCP1 expression and protein abundance in scWAT. Reporter assays showed an increase in UCP1 promoter activity after genistein stimulation, and in silico analysis revealed the presence of estrogen (ERE) and cAMP (CRE) response elements as putative candidates of genistein activation. Mutation of the CRE but not the ERE reduced genistein-induced promoter activity by 51%. Additionally, in vitro and in vivo ChIP assays demonstrated the binding of CREB to the UCP1 promoter after acute genistein administration. Taken together, these data elucidate the mechanism of genistein-mediated UCP1 induction and confirm its potential applications in managing metabolic disorders.
Assuntos
Adipócitos Bege , Camundongos , Ratos , Animais , Ativação Transcricional , Adipócitos Bege/metabolismo , Genisteína/farmacologia , Proteína Desacopladora 1/genética , Proteína Desacopladora 1/metabolismo , Tecido Adiposo Branco/metabolismo , Termogênese/genética , Elementos de Resposta , Tecido Adiposo Marrom/metabolismoRESUMO
The post-nutritional intervention modulation of miRNA expression has been previously investigated; however, post-acute dietary-ingestion-related miRNA expression dynamics in individuals with obesity and insulin resistance (IR) are unknown. We aimed to determine the acute effects of protein ingestion from different dietary sources on the postprandial metabolic response, amino acid levels, and circulating miRNA expression in adults with obesity and IR. This clinical trial included adults with obesity and IR who consumed (1) animal-source protein (AP; calcium caseinate) or (2) vegetable-source protein (VP; soy protein isolate). Glycaemic, insulinaemic, and glucagon responses, amino acid levels, and exosomal microRNAs isolated from plasma were analysed. Post-AP ingestion, the area under the curve (AUC) of insulin (p = 0.04) and the plasma concentrations of branched-chain (p = 0.007) and gluconeogenic (p = 0.01) amino acids increased. The effects of different types of proteins on the concentration of miRNAs were evaluated by measuring their plasma circulating levels. Compared with the baseline, the AP group presented increased circulating levels of miR-27a-3p, miR-29b-3p, and miR-122-5p (p < 0.05). Subsequent analysis over time at 0, 30, and 60 min revealed the same pattern and differences between treatments. We demonstrated that a single dose of dietary protein has acute effects on hormonal and metabolic regulation and increases exosomal miRNA expression in individuals with obesity and IR.
Assuntos
Aminoácidos , MicroRNA Circulante , Proteínas Alimentares , Resistência à Insulina , Obesidade , Período Pós-Prandial , Humanos , Proteínas Alimentares/administração & dosagem , Masculino , Obesidade/sangue , Obesidade/dietoterapia , Obesidade/genética , Obesidade/metabolismo , Feminino , Adulto , MicroRNA Circulante/sangue , MicroRNA Circulante/genética , Aminoácidos/sangue , Pessoa de Meia-Idade , Insulina/sangue , Glicemia/metabolismo , MicroRNAs/sangue , MicroRNAs/genéticaRESUMO
Hypothalamic circuits compute systemic information to control metabolism. Astrocytes residing within the hypothalamus directly sense nutrients and hormones, integrating metabolic information, and modulating neuronal responses. Nevertheless, the role of the astrocytic circadian clock on the control of energy balance remains unclear. We used mice with a targeted ablation of the core-clock gene Bmal1 within Gfap-expressing astrocytes to gain insight on the role played by this transcription factor in astrocytes. While this mutation does not substantially affect the phenotype in mice fed normo-caloric diet, under high-fat diet we unmasked a thermogenic phenotype consisting of increased energy expenditure, and catabolism in brown adipose and overall metabolic improvement consisting of better glycemia control, and body composition. Transcriptomic analysis in the ventromedial hypothalamus revealed an enhanced response to moderate cellular stress, including ER-stress response, unfolded protein response and autophagy. We identified Xbp1 and Atf1 as two key transcription factors enhancing cellular stress responses. Therefore, we unveiled a previously unknown role of the astrocytic circadian clock modulating energy balance through the regulation of cellular stress responses within the VMH.
Assuntos
Relógios Circadianos , Camundongos , Animais , Relógios Circadianos/genética , Astrócitos/metabolismo , Hipotálamo/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Metabolismo Energético/genéticaRESUMO
SIRT7 is a NAD+ -dependent deacetylase that controls important aspects of metabolism, cancer, and bone formation. However, the molecular targets and functions of SIRT7 in the kidney are currently unknown. In silico analysis of kidney transcripts of the BXD murine genetic reference population revealed a positive correlation between Sirt7 and Slc12a7 mRNA expression, suggesting a link between the corresponding proteins that these transcripts encode, SIRT7, and the K-Cl cotransporter KCC4, respectively. Here, we find that protein levels and activity of heterologously expressed KCC4 are significantly modulated depending on its acetylation status in Xenopus laevis oocytes. Moreover, SIRT7 interacts with KCC4 in a NAD+ -dependent manner and increases its stability and activity in HEK293 cells. Interestingly, metabolic acidosis increases SIRT7 expression in kidney, as occurs with KCC4. In contrast, total SIRT7-deficient mice present lower KCC4 expression and an exacerbated metabolic acidosis than wild-type mice during an ammonium chloride challenge. Altogether, our data suggest that SIRT7 interacts with, stabilizes and modulates KCC4 activity through deacetylation, and reveals a novel role for SIRT7 in renal physiology.
Assuntos
Sirtuínas , Simportadores , Acetilação , Animais , Células HEK293 , Humanos , Rim , Camundongos , Sirtuínas/genética , Sirtuínas/metabolismo , Simportadores/genética , Simportadores/metabolismo , Cotransportadores de K e Cl-RESUMO
Carbohydrate responsive element-binding protein (ChREBP) has been identified as a primary transcription factor that maintains energy homeostasis through transcriptional regulation of glycolytic, lipogenic, and gluconeogenic enzymes in response to a high-carbohydrate diet. Amino acids are important substrates for gluconeogenesis, but nevertheless, knowledge is lacking about whether this transcription factor regulates genes involved in the transport or use of these metabolites. Here, we demonstrate that ChREBP represses the expression of the amino acid transporter sodium-coupled neutral amino acid transporter 2 (SNAT2) in response to a high-sucrose diet in rats by binding to a carbohydrate response element (ChoRE) site located -160 bp upstream of the transcriptional start site in the SNAT2 promoter region. Additionally, immunoprecipitation assays revealed that ChREBP and silencing mediator of retinoic acid and thyroid hormone receptor (SMRT) interact with each other, as part of the complex that repress SNAT2 expression. The interaction between these proteins was confirmed by an in vivo chromatin immunoprecipitation assay. These findings suggest that glucogenic amino acid uptake by the liver is controlled by ChREBP through the repression of SNAT2 expression in rats consuming a high-carbohydrate diet.NEW & NOTEWORTHY This study highlights the key role of carbohydrate responsive element-binding protein (ChREBP) in the fine-tuned regulation between glucose and amino acid metabolism in the liver via regulation of the amino acid transporter sodium-coupled neutral amino acid transporter 2 (SNAT2) expression after the consumption of a high-carbohydrate diet. ChREBP binds to a carbohydrate response element (ChoRE) site in the SNAT2 promoter region and recruits silencing mediator of retinoic acid and thyroid hormone receptor (SMRT) corepressor to reduce SNAT2 transcription. This study revealed that ChREBP prevents the uptake of glucogenic amino acids upon the consumption of a high-carbohydrate diet.
Assuntos
Sistema A de Transporte de Aminoácidos/metabolismo , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Carboidratos da Dieta/farmacologia , Correpressor 2 de Receptor Nuclear/metabolismo , Sistema A de Transporte de Aminoácidos/genética , Animais , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Glicemia/análise , Glicemia/metabolismo , Imunoprecipitação da Cromatina , Dieta , Regulação para Baixo , Hepatócitos/metabolismo , Masculino , Correpressor 2 de Receptor Nuclear/genética , Cultura Primária de Células , Ratos , Ratos Wistar , Sacarose/farmacologia , Transcrição Gênica/efeitos dos fármacosRESUMO
The sodium-coupled neutral amino acid transporter 2 (SNAT2) translocates small neutral amino acids into the mammary gland to promote cell proliferation during gestation. It is known that SNAT2 expression increases during pregnancy, and in vitro studies indicate that this transporter is induced by 17ß-estradiol. In this study, we elucidated the mechanism by which 17ß-estradiol regulates the transcription of SNAT2. In silico analysis revealed the presence of a potential estrogen response element (ERE) in the SNAT2 promoter. Reporter assays showed an increase in SNAT2 promoter activity when cotransfected with estrogen receptor alpha (ER-α) after 17ß-estradiol stimulation. Deletion of the ERE reduced estradiol-induced promoter activity by 63%. Additionally, EMSAs and supershift assays showed that ER-α binds to the SNAT2 ERE and that this binding competes with the interaction of ER-α with its consensus ERE. An in vivo ChIP assay demonstrated that the binding of ER-α to the SNAT2 promoter gradually increased in the mammary gland during gestation and that maximal binding occurred at the highest 17ß-estradiol serum concentration. Liquid chromatography-elevated energy mass spectrometry and Western blot analysis revealed that the SNAT2 ER-α-ERE complex contained poly(ADP-ribose) polymerase 1, Lupus Ku autoantigen protein p70, and glyceraldehyde 3-phosphate dehydrogenase (GAPDH) proteins and that the silencing of each of these proteins nearly abolished 17ß-estradiol-stimulated SNAT2 promoter activity. Nuclear levels of GAPDH increased progressively during gestation in the mammary gland, and GAPDH binding was nucleotide-specific for the SNAT2 ERE. Thus, this study provides new insights into how the mammary epithelium adapts to control amino acid uptake through the transcriptional regulation of the SNAT2 transporter via 17ß-estradiol.
Assuntos
Sistemas de Transporte de Aminoácidos/genética , Estradiol/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Transcrição Gênica/efeitos dos fármacos , Sistema A de Transporte de Aminoácidos , Sistemas de Transporte de Aminoácidos/metabolismo , Animais , Antígenos Nucleares/metabolismo , Sequência de Bases , Núcleo Celular/metabolismo , Proteínas de Ligação a DNA/metabolismo , Epitélio/metabolismo , Receptor alfa de Estrogênio/metabolismo , Feminino , Gliceraldeído-3-Fosfato Desidrogenases/metabolismo , Células HeLa , Humanos , Autoantígeno Ku , Glândulas Mamárias Animais/metabolismo , Dados de Sequência Molecular , Fragmentos de Peptídeos/metabolismo , Poli(ADP-Ribose) Polimerases/metabolismo , Gravidez , Ligação Proteica/efeitos dos fármacos , Ligação Proteica/genética , Ratos , Elementos de Resposta/genéticaRESUMO
SMCTs move several important fuel molecules that are involved in lipid, carbohydrate, and amino acid metabolism, but their regulation has been poorly studied. Insulin controls the translocation of several solutes that are involved in energetic cellular metabolism, including glucose. We studied the effect of insulin on the function of human SMCT1 expressed in Xenopus oocytes. The addition of insulin reduced α-keto-isocaproate (KIC)-dependent 22Na+ uptake by 29%. Consistent with this result, the coinjection of SMCT1 with SGK1 cRNA decreased the KIC-dependent 22Na+ uptake by 34%. The reduction of SMCT1 activity by SGK1 depends on its kinase activity, and it was observed that the coinjection of SMCT1 with S442D-SGK1 (a constitutively active mutant) decreased the KIC-dependent 22Na+ uptake by 50%. In contrast, an SMCT1 coinjection with K127M-SGK1 (an inactive mutant) had no effect on the KIC-dependent Na+ uptake. The decreasing SMCT1 function by insulin or SGK1 was corroborated by measuring [1-14C]acetate uptake and the electric currents of SMCT1-injected oocytes. Previously, we found that SMCT2/Slc5a12-mRNA, but not SMCT1/Slc5a8-mRNA, is present in zebrafish pancreas (by in situ hybridization); however, SLC5a8 gene silencing was associated with the development of human pancreatic cancer. We confirmed that the mRNA and protein of both transporters were present in rat pancreas using RT-PCR with specific primers, Western blot analysis, and immunohistochemistry. Additionally, significant propionate-dependent 22Na+ uptake occurred in pancreatic islets and was reduced by insulin treatment. Our data indicate that human SMCT1 is regulated by insulin and SGK1 and that both SMCTs are present in the mammalian pancreas.
Assuntos
Proteínas Imediatamente Precoces/metabolismo , Insulina/metabolismo , Transportadores de Ácidos Monocarboxílicos/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Sódio/metabolismo , Animais , DNA Complementar/metabolismo , Humanos , Masculino , Oócitos/metabolismo , Pâncreas/metabolismo , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Xenopus laevis/metabolismo , Peixe-Zebra/metabolismoRESUMO
The sodium coupled neutral amino acid transporter 2 (SNAT2/SAT2/ATA2) is expressed in the mammary gland (MG) and plays an important role in the uptake of alanine and glutamine which are the most abundant amino acids transported into this tissue during lactation. Thus, the aim of this study was to assess the amount and localization of SNAT2 before delivery and during lactation in rat MG, and to evaluate whether prolactin and the dietary protein/carbohydrate ratio might influence SNAT2 expression in the MG, liver and adipose tissue during lactation. Our results showed that SNAT2 protein abundance in the MG increased during lactation and this increase was maintained along this period, while 24 h after weaning it tended to decrease. To study the effect of prolactin on SNAT2 expression, we incubated MG explants or T47D cells transfected with the SNAT2 promoter with prolactin, and we observed in both studies an increase in the SNAT2 expression or promoter activity. Consumption of a high-protein/low carbohydrate diet increased prolactin concentration, with a concomitant increase in SNAT2 expression not only in the MG during lactation, but also in the liver and adipose tissue. There was a correlation between SNAT2 expression and serum prolactin levels depending on the amount of dietary protein/carbohydrate ratio consumed. These findings suggest that prolactin actively supports lactation providing amino acids to the gland through SNAT2 for the synthesis of milk proteins.
Assuntos
Sistema A de Transporte de Aminoácidos/metabolismo , Carboidratos da Dieta/metabolismo , Proteínas Alimentares/metabolismo , Lactação/metabolismo , Glândulas Mamárias Animais/metabolismo , Prolactina/metabolismo , Tecido Adiposo/metabolismo , Sistema A de Transporte de Aminoácidos/genética , Fenômenos Fisiológicos da Nutrição Animal , Animais , Carboidratos da Dieta/administração & dosagem , Proteínas Alimentares/administração & dosagem , Feminino , Regulação da Expressão Gênica , Lactação/sangue , Lactação/genética , Fígado/metabolismo , Fenômenos Fisiológicos da Nutrição Materna , Proteínas do Leite/biossíntese , Estado Nutricional , Gravidez , Prolactina/sangue , Regiões Promotoras Genéticas , RNA Mensageiro/metabolismo , Ratos Wistar , Técnicas de Cultura de Tecidos , Transfecção , DesmameRESUMO
BACKGROUND: Glutamine is catabolized in the liver by glutaminase 2 (GLS2). Evidence suggests that peroxisome proliferator-activated receptor α (PPARα) represses the expression of several amino acid-catabolizing enzymes, but for Gls2 this is unknown. OBJECTIVE: The aim of the study was to assess whether PPARα regulates Gls2 expression. METHODS: For 8 d, 7-9-wk-old male C57BL/6 wild-type (WT) and Ppara-null mice weighing 23.4 ± 0.5 g were fed diets with different dietary protein:carbohydrate (DP:DCH) ratios (6%:77%, 20%:63%, or 50%:33%). Liver samples were obtained after 16 h of feed deprivation or 3 h of refeeding, and microarrays were performed. Hepatic glutaminase expression was measured by quantitative polymerase chain reaction and Western blotting. Cotransfection analyses in hepatocellular carcinoma cell line (HepG2) cells with PPARα and hepatocyte nuclear factor 4α (HNF4α) expression vectors were performed. RESULTS: The microarray results showed that Gls2 was the only upregulated gene in WT mice, but not in the Ppara-null mice. In the feed-deprived WT mice, the Gls2 mRNA and protein abundances in the 50%:33% group were 2.5- and 1.1-fold greater (P < 0.05), respectively, than those in the 20%:63% group, which were 2.3- and 0.4-fold greater than those in the 6%:77% group (P < 0.01). Gls2 mRNA expression in the 6%:77% group of feed-deprived Ppara-null mice was 33-fold greater than that in the same group of WT mice (P < 0.0001). GLS2 protein abundance in HepG2 cells was 78% greater than that in the controls (P < 0.0001) after HNF4α overexpression, and it was 99% greater after transfection with a short hairpin targeting PPARα. CONCLUSIONS: In Ppara-null mice, Gls2 mRNA expression was greater than in WT mice, regardless of the DP:DCH ratio. In HepG2 cells overexpressing HNF4α, Gls2 expression increased, an effect repressed by overexpression of PPARα. This suggests that Gls2 depends on the PPARα/HNF4α counterregulatory transcriptional control.
Assuntos
Regulação para Baixo , Glutaminase/metabolismo , Fígado/enzimologia , PPAR alfa/metabolismo , Animais , Sequência de Bases , Dieta , Carboidratos da Dieta/administração & dosagem , Proteínas Alimentares/administração & dosagem , Regulação Enzimológica da Expressão Gênica , Glutaminase/genética , Células Hep G2 , Fator 4 Nuclear de Hepatócito/genética , Fator 4 Nuclear de Hepatócito/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , PPAR alfa/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Regulação para CimaRESUMO
Jatropha curcas is an oil seed plant that belongs to the Euphorbiaceae family. Nontoxic genotypes have been reported in Mexico. The purpose of the present work was to evaluate the effect of a Mexican variety of J. curcas protein concentrate (JCP) on weight gain, biochemical parameters, and the expression of genes and proteins involved in insulin signaling, lipogenesis, cholesterol and protein synthesis in rats. The results demonstrated that short-term consumption of JCP increased serum glucose, insulin, triglycerides and cholesterol levels as well as the expression of transcription factors involved in lipogenesis and cholesterol synthesis (SREBP-1 and LXRα). Moreover, there was an increase in insulin signaling mediated by Akt phosphorylation and mTOR. JCP also increased PKCα protein abundance and the activation of downstream signaling pathway targets such as the AP1 and NF-κB transcription factors typically activated by phorbol esters. These results suggested that phorbol esters are present in JCP, and that they could be involved in the activation of PKC which may be responsible for the high insulin secretion and consequently the activation of insulin-dependent pathways. Our data suggest that this Mexican Jatropha variety contains toxic compounds that produce negative metabolic effects which require caution when using in the applications of Jatropha-based products in medicine and nutrition.
Assuntos
Insulina/metabolismo , Jatropha/química , Lipogênese/efeitos dos fármacos , Ésteres de Forbol/efeitos adversos , Proteínas de Plantas/farmacologia , Biossíntese de Proteínas/efeitos dos fármacos , Proteína Quinase C-alfa/metabolismo , Animais , Glicemia/metabolismo , Proteínas Alimentares/farmacologia , Jatropha/classificação , Fígado/efeitos dos fármacos , Fígado/metabolismo , México , Ésteres de Forbol/farmacologia , Extratos Vegetais/farmacologia , Ratos Sprague-Dawley , Sementes/química , Transdução de Sinais , Especificidade da Espécie , Fatores de Transcrição/metabolismoRESUMO
Sodium-glucose cotransporter 2 (SGLT2) inhibitor, dapagliflozin (Dapa), exhibited nephroprotective effects in patients with chronic kidney disease (CKD). We assessed the efficacy of short-term Dapa administration following acute kidney injury (AKI) in preventing CKD. Male Wistar rats were randomly assigned to Sham surgery, bilateral ischemia for 30 minutes (abbreviated as IR), and IR + Dapa groups. Daily treatment with Dapa was initiated just 24 hours after IR and maintained for only 10 days. Initially, rats were euthanized at this point to study early renal repair. After severe AKI, Dapa promptly restored creatinine clearance (CrCl) and significantly reduced renal vascular resistance compared with the IR group. Furthermore, Dapa effectively reversed the mitochondrial abnormalities, including increased fission, altered mitophagy, metabolic dysfunction, and proapoptotic signaling. To study this earlier, another set of rats was studied just 5 days after AKI. Despite persistent renal dysfunction, our data reveal a degree of mitochondrial protection. Remarkably, a 10-day treatment with Dapa demonstrated effectiveness in preventing CKD transition in an independent cohort monitored for 5 months after AKI. This was evidenced by improvements in proteinuria, CrCl, glomerulosclerosis, and fibrosis. Our findings underscore the potential of Dapa in preventing maladaptive repair following AKI, emphasizing the crucial role of early intervention in mitigating AKI long-term consequences.
Assuntos
Injúria Renal Aguda , Insuficiência Renal Crônica , Traumatismo por Reperfusão , Animais , Humanos , Masculino , Ratos , Injúria Renal Aguda/tratamento farmacológico , Injúria Renal Aguda/prevenção & controle , Injúria Renal Aguda/metabolismo , Glucose , Ratos Wistar , Insuficiência Renal Crônica/tratamento farmacológico , Traumatismo por Reperfusão/complicações , Traumatismo por Reperfusão/metabolismo , Sódio/metabolismo , Transportador 2 de Glucose-Sódio/efeitos dos fármacos , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Compostos Benzidrílicos/farmacologia , Compostos Benzidrílicos/uso terapêuticoRESUMO
BACKGROUND: Mitochondrial dysfunction occurs in monocytes during obesity and contributes to a low-grade inflammatory state; therefore, maintaining good mitochondrial conditions is a key aspect of maintaining health. Dietary interventions are primary strategies for treating obesity, but little is known about their impact on monocyte bioenergetics. Thus, the aim of this study was to evaluate the effects of calorie restriction (CR), intermittent fasting (IF), a ketogenic diet (KD), and an ad libitum habitual diet (AL) on mitochondrial function in monocytes and its modulation by the gut microbiota. METHODS AND FINDINGS: A randomized controlled clinical trial was conducted in which individuals with obesity were assigned to one of the 4 groups for 1 month. Subsequently, the subjects received rifaximin and continued with the assigned diet for another month. The oxygen consumption rate (OCR) was evaluated in isolated monocytes, as was the gut microbiota composition in feces and anthropometric and biochemical parameters. Forty-four subjects completed the study, and those who underwent CR, IF and KD interventions had an increase in the maximal respiration OCR (p = 0.025, n2p = 0.159 [0.05, 0.27] 95% confidence interval) in monocytes compared to that in the AL group. The improvement in mitochondrial function was associated with a decrease in monocyte dependence on glycolysis after the IF and KD interventions. Together, diet and rifaximin increased the gut microbiota diversity in the IF and KD groups (p = 0.0001), enriched the abundance of Phascolarctobacterium faecium (p = 0.019) in the CR group and Ruminococcus bromii (p = 0.020) in the CR and KD groups, and reduced the abundance of lipopolysaccharide (LPS)-producing bacteria after CR, IF and KD interventions compared to the AL group at the end of the study according to ANCOVA with covariate adjustment. Spearman's correlation between the variables measured highlighted LPS as a potential modulator of the observed effects. In line with this findings, serum LPS and intracellular signaling in monocytes decreased with the three interventions (CR, p = 0.002; IF, p = 0.001; and KD, p = 0.001) compared to those in the AL group at the end of the study. CONCLUSIONS: We conclude that these dietary interventions positively regulate mitochondrial bioenergetic health and improve the metabolic profile of monocytes in individuals with obesity via modulation of the gut microbiota. Moreover, the evaluation of mitochondrial function in monocytes could be used as an indicator of metabolic and inflammatory status, with potential applications in future clinical trials. TRIAL REGISTRATION: This trial was registered with ClinicalTrials.gov (NCT05200468).
Assuntos
Restrição Calórica , Dieta Cetogênica , Microbioma Gastrointestinal , Mitocôndrias , Monócitos , Obesidade , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Restrição Calórica/métodos , Dieta Cetogênica/métodos , Jejum Intermitente , Lipopolissacarídeos , Mitocôndrias/metabolismo , Monócitos/metabolismo , Obesidade/dietoterapia , Obesidade/metabolismo , Consumo de Oxigênio , Transdução de SinaisRESUMO
Amino acids have been extensively studied in nutrition, mainly as key elements for maintaining optimal protein synthesis in the body as well as precursors of various nitrogen-containing compounds. However, it is now known that amino acid catabolism is an important element for the metabolic control of different biological processes, although it is still a developing field to have a deeper understanding of its biological implications. The mechanisms involved in the regulation of amino acid catabolism now include the contribution of the gut microbiota to amino acid oxidation and metabolite generation in the intestine, the molecular mechanisms of transcriptional control, and the participation of specific miRNAs involved in the regulation of amino acid degrading enzymes. In addition, molecules derived from amino acid catabolism play a role in metabolism as they are used in the epigenetic regulation of many genes. Thus, this review aims to examine the mechanisms of amino acid catabolism and to support the idea that this process is associated with the immune response, abnormalities during obesity, in particular insulin resistance, and the regulation of thermogenesis.
Assuntos
Resistência à Insulina , MicroRNAs , Humanos , Epigênese Genética , Aminoácidos/metabolismo , ObesidadeRESUMO
The circadian clock is an endogenous time-tracking system that anticipates daily environmental changes. Misalignment of the clock can cause obesity, which is accompanied by reduced levels of the clock-controlled, rhythmic metabolite NAD+. Increasing NAD+ is becoming a therapy for metabolic dysfunction; however, the impact of daily NAD+ fluctuations remains unknown. Here, we demonstrate that time-of-day determines the efficacy of NAD+ treatment for diet-induced metabolic disease in mice. Increasing NAD+ prior to the active phase in obese male mice ameliorated metabolic markers including body weight, glucose and insulin tolerance, hepatic inflammation and nutrient sensing pathways. However, raising NAD+ immediately before the rest phase selectively compromised these responses. Remarkably, timed NAD+ adjusted circadian oscillations of the liver clock until completely inverting its oscillatory phase when increased just before the rest period, resulting in misaligned molecular and behavioral rhythms in male and female mice. Our findings unveil the time-of-day dependence of NAD+-based therapies and support a chronobiology-based approach.
Assuntos
Relógios Circadianos , Doenças Metabólicas , Camundongos , Masculino , Feminino , Animais , Ritmo Circadiano/fisiologia , NAD/metabolismo , Dieta , Doenças Metabólicas/metabolismo , Fígado/metabolismoRESUMO
Excessive consumption of fat and carbohydrates, together with a decrease in traditional food intake, has been related to obesity and the development of metabolic alterations. Ramon seed is a traditional Mayan food used to obtain Ramon flour (RF) with high biological value in terms of protein, fiber, micronutrients, and bioactive compounds such as polyphenols. However, few studies have evaluated the beneficial effects of RF. Thus, we aimed to determine the metabolic effects of RF consumption on a high-fat-diet-induced obesity mouse model. We divided male BALB/c mice into four groups (n = 5 each group) and fed them for 90 days with the following diets: Control (C): control diet (AIN-93), C + RF: control diet adjusted with 25% RF, HFD: high-fat diet + 5% sugar in water, and HFD + RF: high-fat diet adjusted with 25% RF + 5% sugar in water. The RF prevented the increase in serum total cholesterol (TC) and alanine transaminase (ALT) that occurred in the C and HFD groups. Notably, RF together with HFD increased serum polyphenols and antioxidant activity, and it promoted a decrease in the adipocyte size in white adipose tissue, along with lower hepatic lipid accumulation than in the HFD group. In the liver, the HFD + RF group showed an increase in the expression of ß-oxidation-related genes, and downregulation of the fatty acid synthase (Fas) gene compared with the HFD group. Moreover, the HFD + RF group had increased hepatic phosphorylation of AMP-activated protein kinase (AMPK), along with increased nuclear factor erythroid 2-related factor 2 (NRF2) and superoxide dismutase 2 (SOD2) protein expression compared with the HFD group. Thus, RF may be used as a nutritional strategy to decrease metabolic alterations during obesity.
RESUMO
SCOPE: Genistein increases whole body energy expenditure by stimulating white adipose tissue (WAT) browning and thermogenesis. G-Coupled receptor GPR30 can mediate some actions of genistein, however, it is not known whether it is involved in the activation of WAT-thermogenesis. Thus, the aim of the study is to determine whether genistein activates thermogenesis coupled to an increase in WAT browning and mitochondrial activity, in GPR30+/+ and GPR30-/- mice. METHODS AND RESULTS: GPR30+/+ and GPR30-/- mice are fed control or high fat sucrose diets containing or not genistein for 8 weeks. Body weight and composition, energy expenditure, glucose tolerance, and browning markers in WAT, and oxygen consumption rate, 3', 5'-cyclic adenosine monophosphate (cAMP) concentration and browning markers in adipocytes are evaluated. Genistein consumption reduces body weight and fat mass gain in a different extent in both genotypes, however, energy expenditure is lower in GPR30-/- compared to GPR30+/+ mice, accompanied by a reduction in browning markers, maximal mitochondrial respiration, cAMP concentration, and browning markers in cultured adipocytes from GPR30-/- mice. Genistein improves glucose tolerance in GPR30+/+ , but this is partially observed in GPR30-/- mice. CONCLUSION: The results show that GPR30 partially mediates genistein stimulation of WAT thermogenesis and the improvement of glucose tolerance.
Assuntos
Tecido Adiposo Marrom , Genisteína , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , Animais , Peso Corporal , Metabolismo Energético , Genisteína/metabolismo , Genisteína/farmacologia , Glucose/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Termogênese/genéticaRESUMO
Bile acids (BAs) are complex and incompletely understood enterohepatic-derived hormones that control whole-body metabolism. Here, we profiled postprandial BAs in the liver, feces, and plasma of 360 chow- or high-fat-diet-fed BXD male mice and demonstrated that both genetics and diet strongly influence BA abundance, composition, and correlation with metabolic traits. Through an integrated systems approach, we mapped hundreds of quantitative trait loci that modulate BAs and identified both known and unknown regulators of BA homeostasis. In particular, we discovered carboxylesterase 1c (Ces1c) as a genetic determinant of plasma tauroursodeoxycholic acid (TUDCA), a BA species with established disease-preventing actions. The association between Ces1c and plasma TUDCA was validated using data from independent mouse cohorts and a Ces1c knockout mouse model. Collectively, our data are a unique resource to dissect the physiological importance of BAs as determinants of metabolic traits, as underscored by the identification of CES1C as a master regulator of plasma TUDCA levels.
Assuntos
Ácidos e Sais Biliares , Dieta Hiperlipídica , Animais , Ácidos e Sais Biliares/metabolismo , Hidrolases de Éster Carboxílico/metabolismo , Homeostase , Hormônios/metabolismo , Fígado/metabolismo , Masculino , Camundongos , Análise de Sistemas , Ácido TauroquenodesoxicólicoRESUMO
The increase in incidence and prevalence of metabolic diseases, such as diabetes, obesity, and metabolic syndrome, is a health problem worldwide. Nutritional strategies that can impact on mitochondrial activity represent a novel and effective option to modulate energy expenditure and energetic metabolism in cells and tissues and could be used as adjuvant treatments for metabolic-associated disorders. Dietary bioactive compounds also known as "food bioactives" have proven to exert multiple health benefits and counteract metabolic alterations. In the last years, it has been consistently reported that the modulation of mitochondrial function represents one of the mechanisms behind the bioactive compounds-dependent health improvements. In this review, we focus on gathering, summarizing, and discussing the evidence that supports the effect of dietary bioactive compounds on mitochondrial activity and the relation of these effects in the pathological context. Despite the evidence presented here on in vivo and in vitro effects, more studies are needed to determine their effectiveness in humans.