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1.
Crit Care ; 24(1): 536, 2020 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-32867803

RESUMO

BACKGROUND: In critically ill children, omitting early use of parenteral nutrition (late-PN versus early-PN) reduced infections, accelerated weaning from mechanical ventilation, and shortened PICU stay. We hypothesized that fasting-induced ketogenesis mediates these benefits. METHODS: In a secondary analysis of the PEPaNIC RCT (N = 1440), the impact of late-PN versus early-PN on plasma 3-hydroxybutyrate (3HB), and on blood glucose, plasma insulin, and glucagon as key ketogenesis regulators, was determined for 96 matched patients staying ≥ 5 days in PICU, and the day of maximal 3HB-effect, if any, was identified. Subsequently, in the total study population, plasma 3HB and late-PN-affected ketogenesis regulators were measured on that average day of maximal 3HB effect. Multivariable Cox proportional hazard and logistic regression analyses were performed adjusting for randomization and baseline risk factors. Whether any potential mediator role for 3HB was direct or indirect was assessed by further adjusting for ketogenesis regulators. RESULTS: In the matched cohort (n = 96), late-PN versus early-PN increased plasma 3HB throughout PICU days 1-5 (P < 0.0001), maximally on PICU day 2. Also, blood glucose (P < 0.001) and plasma insulin (P < 0.0001), but not glucagon, were affected. In the total cohort (n = 1142 with available plasma), late-PN increased plasma 3HB on PICU day 2 (day 1 for shorter stayers) from (median [IQR]) 0.04 [0.04-0.04] mmol/L to 0.75 [0.04-2.03] mmol/L (P < 0.0001). The 3HB effect of late-PN statistically explained its impact on weaning from mechanical ventilation (P = 0.0002) and on time to live PICU discharge (P = 0.004). Further adjustment for regulators of ketogenesis did not alter these findings. CONCLUSION: Withholding early-PN in critically ill children significantly increased plasma 3HB, a direct effect that statistically mediated an important part of its outcome benefit.


Assuntos
Corpos Cetônicos/biossíntese , Nutrição Parenteral , Suspensão de Tratamento , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Unidades de Terapia Intensiva Pediátrica , Masculino , Resultado do Tratamento
3.
Life Sci ; 253: 117748, 2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-32387415

RESUMO

AIMS: Hindlimb ischemia-reperfusion (IR) was previously demonstrated by our group to decrease blood sugar levels by suppressing hepatic gluconeogenesis and enhancing glucose uptake using activation of the parasympathetic nervous system. While IR attenuated hyperglycemia in diabetic mice, it was unclear whether IR regulated energy metabolism in the liver. We investigated the mechanisms by which IR regulates energy metabolism in the liver from type1 diabetic mice. MAIN METHODS: Streptozotocin-induced diabetic male C57BL/6J mice were used to determine the effect of IR on the factors involved in energy metabolism in the liver (i.e., activation levels of AMP-activated protein kinase, aconitase and pyruvate dehydrogenase; adenosine triphosphate and fumarate concentrations; sirtuin (Sirt) 1 expression). These various signaling pathways and key enzyme activities were examined using western blot analysis and a biochemical technique including a colorimetric assay. KEY FINDINGS: Under feeding conditions (free access to normal murine chow and water), blood glucose levels and serum ketone body levels were significantly suppressed by IR, whereas phospho-AMP-activated protein kinase and its activity, pyruvate dehydrogenase, aconitase activity, and Sirt 1expression were upregulated. In contrast, peroxisome proliferator-activated receptor γ coactivator-1, which accelerated fatty acid use, was suppressed by IR. SIGNIFICANCE: These results indicated that in the IR-treated diabetic liver, energy production was promoted through acceleration of the tricarboxylic acid cycle linked with increased glucose preference rather than fatty acid under feeding conditions. Therefore, IR may be beneficial against diabetic hyperglycemia, but also ketoacidosis.


Assuntos
Diabetes Mellitus Experimental/complicações , Cetoacidose Diabética/prevenção & controle , Precondicionamento Isquêmico , Fígado/metabolismo , Animais , Glicemia/metabolismo , Ciclo do Ácido Cítrico/fisiologia , Metabolismo Energético/fisiologia , Ácidos Graxos/metabolismo , Glicólise/fisiologia , Corpos Cetônicos/sangue , Fígado/irrigação sanguínea , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estreptozocina
4.
Gene ; 745: 144647, 2020 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-32247738

RESUMO

AIMS: Post-translational modifications (PTMs) of histones are regulated by the availability of their respective acyl-CoAs. Among these histone PTMs, the metabolic origin of histone butyrylation (Kbu) is still poorly understood. MATERIAL AND METHODS: The impact of starvation on the levels of Kbu was determined by western blotting on histones extracted from the liver of fed and fasted C57BL/6 mice and immunohistochemistry on liver paraffin sections. KEY FINDINGS: Using animal model we provide evidence that the stimulation of ketogenesis following starvation, in addition to histone beta-hydroxybutyrylation (Kbhb), also leads to an increase in histone butyrylation (Kbu). Using an immunohistochemistry (IHC) approach we report first that hepatocytes contained butyrylated histones with important cell-to-cell heterogeneity. More importantly, our investigations based on western blotting and IHC also proposed that the basal levels of Kbu differ between male and female mice, with female mouse hepatocytes containing higher levels of butyrylated histones. Starvation enhanced solely histone Kbu levels in the liver of males but not females. SIGNIFICANCE: This is the first demonstration of a sex-dependent large-scale stimulation of histone acylation. Our data also point to different basal metabolic conditions of the male and female liver cells with a sex-dependent impact on the hepatocytes' epigenome.


Assuntos
Histonas/metabolismo , Fígado/patologia , Lisina/metabolismo , Processamento de Proteína Pós-Traducional , Inanição/patologia , Ácido 3-Hidroxibutírico/metabolismo , Acil Coenzima A/metabolismo , Acilação , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Hepatócitos/patologia , Código das Histonas , Humanos , Corpos Cetônicos/metabolismo , Fígado/citologia , Masculino , Camundongos , Fatores Sexuais
5.
PLoS One ; 15(3): e0229868, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32163448

RESUMO

The purpose of this study was to examine the influence of medium-chain fatty acid-containing triglycerides (MCT), long-chain polyunsaturated fatty acid-containing triglycerides, and their combination on the plasma metabolome of cats (Felis catus), including circulating microbiome-derived postbiotics. After a 14-day lead-in on the control food, cats were randomized to one of four foods (control, with 6.9% MCT, with fish oil [FO; 0.14% eicosapentaenoate, 1.0% docosahexaenoate], or with FO+MCT; n = 16 per group) for 28 days. Analysis of plasma metabolites showed that the addition of FO and MCT led to synergistic effects not seen with either alone across a number of lipid classes, including fatty acids, acylcarnitines, and acylated amines including endocannabinoids. Notably, the FO+MCT group had an increase in ketone body production relative to baseline and beyond that seen with MCT alone. N-acyl taurines, the accumulation of which has been implicated in the onset of type 2 diabetes, were significantly decreased in the FO+MCT group. Significant decreases in the gut microbiome-derived postbiotic classes of indoles/indolic sulfates and phenols/phenolic sulfates were observed only the FO+MCT group. Overall, the combination of MCT and FO led to number of changes in plasma metabolites that were not observed with either oil alone, particularly in postbiotics.


Assuntos
Ração Animal , Ácidos Docosa-Hexaenoicos/administração & dosagem , Microbioma Gastrointestinal/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Triglicerídeos/administração & dosagem , Animais , Gatos , Feminino , Indóis/sangue , Indóis/metabolismo , Corpos Cetônicos/sangue , Corpos Cetônicos/metabolismo , Lipidômica , Lipídeos/sangue , Masculino , Fenóis/sangue , Fenóis/metabolismo
6.
J Dairy Sci ; 103(5): 4691-4701, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32173015

RESUMO

The Orai calcium release-activated calcium modulator 1 (ORAI1) is a key component of the store-operated Ca2+ entry mechanism regulating cellular Ca2+ balance in nonruminants. Alterations in ORAI1 abundance have been associated with endoplasmic reticulum (ER) stress and changes in lipid metabolism in hepatocytes, an important lipogenic organ in nonruminants. Objectives were to (1) determine abundance of ORAI1 and components of the ER stress response in mammary tissue of ketotic cows, and (2) the potential role of ORAI1 on mammary cell responses to high levels of ß-hydroxybutyrate (BHB). Healthy (n = 6, plasma BHB < 0.60 mmol/L) and clinically ketotic (n = 6, plasma BHB > 2.0 mmol/L) Holstein cows (days in milk = 10.13 ± 1.90) were used for mammary gland tissue and blood sample collection. Although milk production (22.5 ± 1.26, 33 ± 1.59, kg of milk/cow per day) and dry matter intake (19.5 ± 1.05, 21.9 ± 0.95, kg/d) were lower in ketotic cows, abundance of ORAI1 protein was greater and was associated with greater mRNA abundance of ER stress proteins (PERK, IRE1, ATF6, and GRP78) and lipogenic genes (FASN, SREBP1, and ACACA). Cellular mechanisms to establish links between BHB and mammary cell responses were evaluated using the immortalized cell line bovine mammary epithelial cells (MAC-T). First, a dose response study was performed with 0, 0.6, 1.2, 1.8, 2.4, or 4.8 mM BHB for 24 h. The mRNA abundance of FASN, SREBP1, and ACACA and lipid droplet formation peaked at 1.2 mM BHB. A subsequent study involved transfecting MAC-T with small interfering Orai 1 (siORAI1) or the ORAI1 inhibitor BTP2 for 24 h followed by a challenge with 1.2 mM BHB for 24 h. Transcription and protein abundance of FASN, SREBP1, ACACA, and ER stress proteins returned to basal levels when ORAI1 was silenced or inhibited. Furthermore, the Ca2+ ionophore ionomycin (raises the intracellular level of Ca2+) also increased abundance of ORAI1, FASN, SREBP1, ACACA, and ER stress proteins. Data suggest that the mammary gland experiences ER stress during ketosis, partly due to the greater supply of BHB originating from ketogenesis in the liver. Intracellular Ca2+ signaling and ORAI1 seem to mediate in part the BHB-induced ER stress in mammary cells.


Assuntos
Ácido 3-Hidroxibutírico/administração & dosagem , Sinalização do Cálcio , Bovinos/fisiologia , Corpos Cetônicos/efeitos adversos , Cetose/veterinária , Leite/metabolismo , Proteína ORAI1/metabolismo , Ácido 3-Hidroxibutírico/sangue , Animais , Cálcio/metabolismo , Estresse do Retículo Endoplasmático , Células Epiteliais/metabolismo , Feminino , Lactação , Metabolismo dos Lipídeos , Lipogênese , Fígado/metabolismo , Glândulas Mamárias Animais/metabolismo , Proteína ORAI1/genética
7.
Am Heart J ; 221: 39-47, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31901799

RESUMO

BACKGROUND: Sodium glucose cotransporter 2 (SGLT2) inhibitors are established antidiabetic drugs with proven cardiovascular benefit. Although growing evidence suggests beneficial effects on myocardial remodeling, fluid balance and cardiac function, the impact of empagliflozin initiated early after acute myocardial infarction (AMI) has not been investigated yet. Therefore, the impact of EMpagliflozin on cardiac function and biomarkers of heart failure in patients with acute MYocardial infarction (EMMY) trial was designed to investigate the efficacy and safety of empagliflozin in diabetic and non-diabetic patients after severe AMI. METHODS: Within a multicenter, randomized, double-blind, placebo-controlled, phase 3b trial we will enroll patients with AMI and characteristics suggestive of severe myocardial necrosis are randomized in a 1:1 ratio to empagliflozin (10 mg once daily) or matching placebo. The primary endpoint is the impact of empagliflozin on changes in NT-proBNP within 6 months after AMI. Secondary endpoints include changes in echocardiographic parameters, levels of ketone body concentrations, HbA1c levels and body weight, respectively. Hospitalization rate due to heart failure or other causes, the duration of hospital stay and all-cause mortality will be assessed as exploratory secondary endpoints. DISCUSSION: The EMMY trial will test empagliflozin in patients with AMI regardless of their diabetic status. The EMMY trial may therefore underpin the concept of SGLT2 inhibition to improve cardiac remodeling, pre-and afterload reduction and cardiac metabolism regardless of its antidiabetic effects. Results will provide the rationale for the conduct of a cardiovascular outcome trial to test the effect of empagliflozin in patients with AMI.


Assuntos
Compostos Benzidrílicos/uso terapêutico , Glucosídeos/uso terapêutico , Insuficiência Cardíaca/diagnóstico por imagem , Infarto do Miocárdio/tratamento farmacológico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/metabolismo , Método Duplo-Cego , Ecocardiografia , Hemoglobina A Glicada/metabolismo , Insuficiência Cardíaca/metabolismo , Hospitalização , Humanos , Corpos Cetônicos/metabolismo , Tempo de Internação , Mortalidade , Infarto do Miocárdio/complicações , Infarto do Miocárdio/diagnóstico por imagem , Infarto do Miocárdio/metabolismo , Peptídeo Natriurético Encefálico/metabolismo , Fragmentos de Peptídeos/metabolismo
8.
Int J Mol Sci ; 20(24)2019 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-31817290

RESUMO

There are three human enzymes with HMG-CoA lyase activity that are able to synthesize ketone bodies in different subcellular compartments. The mitochondrial HMG-CoA lyase was the first to be described, and catalyzes the cleavage of 3-hydroxy-3-methylglutaryl CoA to acetoacetate and acetyl-CoA, the common final step in ketogenesis and leucine catabolism. This protein is mainly expressed in the liver and its function is metabolic, since it produces ketone bodies as energetic fuels when glucose levels are low. Another isoform is encoded by the same gene for the mitochondrial HMG-CoA lyase (HMGCL), but it is located in peroxisomes. The last HMG-CoA lyase to be described is encoded by a different gene, HMGCLL1, and is located in the cytosolic side of the endoplasmic reticulum membrane. Some activity assays and tissue distribution of this enzyme have shown the brain and lung as key tissues for studying its function. Although the roles of the peroxisomal and cytosolic HMG-CoA lyases remain unknown, recent studies highlight the role of ketone bodies in metabolic remodeling, homeostasis, and signaling, providing new insights into the molecular and cellular function of these enzymes.


Assuntos
Citosol/enzimologia , Mitocôndrias/enzimologia , Oxo-Ácido-Liases/metabolismo , Peroxissomos/enzimologia , Metabolismo Energético , Evolução Molecular , Humanos , Isoenzimas/classificação , Isoenzimas/genética , Isoenzimas/metabolismo , Corpos Cetônicos/metabolismo , Fígado/enzimologia , Oxo-Ácido-Liases/classificação , Oxo-Ácido-Liases/genética
9.
Mol Cell Neurosci ; 101: 103415, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31676432

RESUMO

Energy supply to the brain is essential to ensure correct neuronal function, and glucose is the main fuel utilized by neurons. In metabolically challenging situations when glucose availability is restricted, brain cells may switch to alternative carbon substrates. This ensures energy supply to preserve the functions of the central nervous system. In this regard, ketone bodies, a by-product of fat metabolism, play a key role. They can replace glucose as the main source of ATP in the brain when glucose availability is very low, such as during fasting, extenuating exercise, or pathological situations such as diabetes. However, the mechanisms through which brain cells reprogram their metabolism are not fully understood. Fibroblast growth factor-21 (FGF21) is an endocrine hormone that contributes to modulate systemic adaptation to fasting, and it is known to regulate ketone body metabolism in peripheral tissues. However, its role in the brain, except for neuroendocrine regions, has not been studied in depth. In this work, we have used a combination of cell biology, biochemistry and extracellular flux analysis to examine the role of FGF21 in neuronal metabolism. We show that FGF21 increases the ability of neurons to utilize ketone bodies in cortical neurons as illustrated by a larger mitochondrial respiratory capacity in the presence of ketone bodies. Finally, we observe that the effect of FGF21 is mediated through a mechanism partly dependent on AMP-dependent kinase (AMPK). We propose that this mechanism could contribute to prepare the brain for fasting, thus preventing metabolic decline.


Assuntos
Fatores de Crescimento de Fibroblastos/farmacologia , Corpos Cetônicos/metabolismo , Neurônios/metabolismo , Proteínas Quinases/metabolismo , Animais , Córtex Cerebral/citologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Neurônios/efeitos dos fármacos
10.
Proc Natl Acad Sci U S A ; 116(47): 23813-23821, 2019 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-31685604

RESUMO

Ketone bodies, including ß-hydroxybutyrate and acetoacetate, are important alternative energy sources during energy shortage. ß-Hydroxybutyrate also acts as a signaling molecule via specific G protein-coupled receptors (GPCRs); however, the specific associated GPCRs and physiological functions of acetoacetate remain unknown. Here we identified acetoacetate as an endogenous agonist for short-chain fatty acid (SCFA) receptor GPR43 by ligand screening in a heterologous expression system. Under ketogenic conditions, such as starvation and low-carbohydrate diets, plasma acetoacetate levels increased markedly, whereas plasma and cecal SCFA levels decreased dramatically, along with an altered gut microbiota composition. In addition, Gpr43-deficient mice showed reduced weight loss and suppressed plasma lipoprotein lipase activity during fasting and eucaloric ketogenic diet feeding. Moreover, Gpr43-deficient mice exhibited minimal weight decrease after intermittent fasting. These observations provide insight into the role of ketone bodies in energy metabolism under shifts in nutrition and may contribute to the development of preventive medicine via diet and foods.


Assuntos
Dieta Cetogênica , Corpos Cetônicos/metabolismo , Metabolismo dos Lipídeos/fisiologia , Receptores Acoplados a Proteínas-G/fisiologia , Animais , Jejum , Células HEK293 , Humanos , Ligantes , Lipase Lipoproteica/sangue , Camundongos , Camundongos Endogâmicos C57BL , Receptores Acoplados a Proteínas-G/genética , Transdução de Sinais
12.
Nutrients ; 11(10)2019 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-31627352

RESUMO

Diets low in carbohydrates and proteins and enriched in fat stimulate the hepatic synthesis of ketone bodies (KB). These molecules are used as alternative fuel for energy production in target tissues. The synthesis and utilization of KB are tightly regulated both at transcriptional and hormonal levels. The nuclear receptor peroxisome proliferator activated receptor α (PPARα), currently recognized as one of the master regulators of ketogenesis, integrates nutritional signals to the activation of transcriptional networks regulating fatty acid ß-oxidation and ketogenesis. New factors, such as circadian rhythms and paracrine signals, are emerging as important aspects of this metabolic regulation. However, KB are currently considered not only as energy substrates but also as signaling molecules. ß-hydroxybutyrate has been identified as class I histone deacetylase inhibitor, thus establishing a connection between products of hepatic lipid metabolism and epigenetics. Ketogenic diets (KD) are currently used to treat different forms of infantile epilepsy, also caused by genetic defects such as Glut1 and Pyruvate Dehydrogenase Deficiency Syndromes. However, several researchers are now focusing on the possibility to use KD in other diseases, such as cancer, neurological and metabolic disorders. Nonetheless, clear-cut evidence of the efficacy of KD in other disorders remains to be provided in order to suggest the adoption of such diets to metabolic-related pathologies.


Assuntos
Dieta Cetogênica , Gorduras na Dieta/farmacologia , Metabolismo dos Lipídeos/fisiologia , Fígado/metabolismo , Gorduras na Dieta/metabolismo , Humanos , Corpos Cetônicos/metabolismo , Fígado/efeitos dos fármacos
13.
Nutrients ; 11(10)2019 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-31561520

RESUMO

The ketogenic diet (KD) has gained a resurgence in popularity due to its purported reputation for fighting obesity. The KD has also acquired attention as an alternative and/or supplemental method for producing energy in the form of ketone bodies. Recent scientific evidence highlights the KD as a promising strategy to treat obesity, diabetes, and cardiac dysfunction. In addition, studies support ketone body supplements as a potential method to induce ketosis and supply sustainable fuel sources to promote exercise performance. Despite the acceptance in the mainstream media, the KD remains controversial in the medical and scientific communities. Research suggests that the KD or ketone body supplementation may result in unexpected side effects, including altered blood lipid profiles, abnormal glucose homeostasis, increased adiposity, fatigue, and gastrointestinal distress. The purpose of this review article is to provide an overview of ketone body metabolism and a background on the KD and ketone body supplements in the context of obesity and exercise performance. The effectiveness of these dietary or supplementation strategies as a therapy for weight loss or as an ergogenic aid will be discussed. In addition, the recent evidence that indicates ketone body metabolism is a potential target for cardiac dysfunction will be reviewed.


Assuntos
Dieta Cetogênica/métodos , Suplementos Nutricionais , Corpos Cetônicos/farmacologia , Obesidade/dietoterapia , Substâncias para Melhoria do Desempenho/farmacologia , Exercício Físico/fisiologia , Humanos , Obesidade/metabolismo , Desempenho Físico Funcional
14.
Cell ; 178(5): 1115-1131.e15, 2019 08 22.
Artigo em Inglês | MEDLINE | ID: mdl-31442404

RESUMO

Little is known about how metabolites couple tissue-specific stem cell function with physiology. Here we show that, in the mammalian small intestine, the expression of Hmgcs2 (3-hydroxy-3-methylglutaryl-CoA synthetase 2), the gene encoding the rate-limiting enzyme in the production of ketone bodies, including beta-hydroxybutyrate (ßOHB), distinguishes self-renewing Lgr5+ stem cells (ISCs) from differentiated cell types. Hmgcs2 loss depletes ßOHB levels in Lgr5+ ISCs and skews their differentiation toward secretory cell fates, which can be rescued by exogenous ßOHB and class I histone deacetylase (HDAC) inhibitor treatment. Mechanistically, ßOHB acts by inhibiting HDACs to reinforce Notch signaling, instructing ISC self-renewal and lineage decisions. Notably, although a high-fat ketogenic diet elevates ISC function and post-injury regeneration through ßOHB-mediated Notch signaling, a glucose-supplemented diet has the opposite effects. These findings reveal how control of ßOHB-activated signaling in ISCs by diet helps to fine-tune stem cell adaptation in homeostasis and injury.


Assuntos
Dieta Hiperlipídica , Corpos Cetônicos/metabolismo , Células-Tronco/metabolismo , Ácido 3-Hidroxibutírico/sangue , Ácido 3-Hidroxibutírico/farmacologia , Idoso de 80 Anos ou mais , Animais , Diferenciação Celular/efeitos dos fármacos , Autorrenovação Celular , Feminino , Inibidores de Histona Desacetilases/farmacologia , Humanos , Hidroximetilglutaril-CoA Sintase/deficiência , Hidroximetilglutaril-CoA Sintase/genética , Hidroximetilglutaril-CoA Sintase/metabolismo , Intestinos/citologia , Intestinos/patologia , Masculino , Camundongos , Camundongos Knockout , Receptores Acoplados a Proteínas-G/metabolismo , Receptores Notch/metabolismo , Transdução de Sinais/efeitos dos fármacos , Células-Tronco/citologia , Adulto Jovem
17.
Neuroscience ; 413: 239-251, 2019 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-31220541

RESUMO

Ketogenic diet is reported to protect against cognitive decline, drug-resistant epilepsy, Alzheimer's Disease, damaging effect of ischemic stroke and many neurological diseases. Despite mounting evidence that this dietary treatment works, the exact mechanism of its protective activity is largely unknown. Ketogenic diet acts systemically, not only changing GABA signaling in neurons, but also influencing the reliance on mitochondrial respiration, known to be disrupted in many neurological diseases. Normally, human body is driven by glucose while ketogenic diet mimics starvation and energy required for proper functioning comes from fatty acids oxidation. In the brain astrocytes are believed to be the sole neural cells capable of fatty oxidation. Here we try to explain that not exclusively neurons, but also morphological changes of astroglia and/or microglia due to different metabolic state are important for the mechanism underlying the protective role of ketogenic diet. By quantifying different parameters describing cellular morphology like ramification index or fractal dimension and using Principal Component Analysis to discover the regularities between them, we demonstrate that in normal adult rat brain, ketogenic diet itself is able to change glial morphology, indicating an important role of these underappreciated cells in the brain metabolism.


Assuntos
Encéfalo/citologia , Dieta Cetogênica , Neuroglia/citologia , Tecido Adiposo , Animais , Peso Corporal , Encéfalo/metabolismo , Ingestão de Energia , Processamento de Imagem Assistida por Computador , Corpos Cetônicos/metabolismo , Masculino , Neuroglia/metabolismo , Neurônios/citologia , Neurônios/metabolismo , Análise de Componente Principal , Ratos Wistar
18.
Commun Biol ; 2: 200, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31149644

RESUMO

Glioblastoma (GBM) is an aggressive primary human brain tumour that has resisted effective therapy for decades. Although glucose and glutamine are the major fuels that drive GBM growth and invasion, few studies have targeted these fuels for therapeutic management. The glutamine antagonist, 6-diazo-5-oxo-L-norleucine (DON), was administered together with a calorically restricted ketogenic diet (KD-R) to treat late-stage orthotopic growth in two syngeneic GBM mouse models: VM-M3 and CT-2A. DON targets glutaminolysis, while the KD-R reduces glucose and, simultaneously, elevates neuroprotective and non-fermentable ketone bodies. The diet/drug therapeutic strategy killed tumour cells while reversing disease symptoms, and improving overall mouse survival. The therapeutic strategy also reduces edema, hemorrhage, and inflammation. Moreover, the KD-R diet facilitated DON delivery to the brain and allowed a lower dosage to achieve therapeutic effect. The findings support the importance of glucose and glutamine in driving GBM growth and provide a therapeutic strategy for non-toxic metabolic management.


Assuntos
Neoplasias Encefálicas/terapia , Restrição Calórica , Dieta Cetogênica , Glioblastoma/terapia , Glutamina/metabolismo , Animais , Peso Corporal , Encéfalo/metabolismo , Neoplasias Encefálicas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Diazo-Oxo-Norleucina/uso terapêutico , Modelos Animais de Doenças , Feminino , Fermentação , Glioblastoma/metabolismo , Glucose/metabolismo , Humanos , Imuno-Histoquímica , Corpos Cetônicos/metabolismo , Cetonas , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Transplante de Neoplasias
19.
EBioMedicine ; 44: 607-617, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31202815

RESUMO

BACKGROUND: Traumatic brain injury (TBI) is recognized as a metabolic disease, characterized by acute cerebral glucose hypo-metabolism. Adaptive metabolic responses to TBI involve the utilization of alternative energy substrates, such as ketone bodies. Cerebral microdialysis (CMD) has evolved as an accurate technique allowing continuous sampling of brain extracellular fluid and assessment of regional cerebral metabolism. We present the successful application of a combined hypothesis- and data-driven metabolomics approach using repeated CMD sampling obtained routinely at patient bedside. Investigating two patient cohorts (n = 26 and n = 12), we identified clinically relevant metabolic patterns at the acute post-TBI critical care phase. METHODS: Clinical and CMD metabolomics data were integrated and analysed using in silico and data modelling approaches. We used both unsupervised and supervised multivariate analysis techniques to investigate structures within the time series and associations with patient outcome. FINDINGS: The multivariate metabolite time series exhibited two characteristic brain metabolic states that were attributed to changes in key metabolites: valine, 4-methyl-2-oxovaleric acid (4-MOV), isobeta-hydroxybutyrate (iso-bHB), tyrosyine, and 2-ketoisovaleric acid (2-KIV). These identified cerebral metabolic states differed significantly with respect to standard clinical values. We validated our findings in a second cohort using a classification model trained on the cerebral metabolic states. We demonstrated that short-term (therapeutic intensity level (TIL)) and mid-term patient outcome (6-month Glasgow Outcome Score (GOS)) can be predicted from the time series characteristics. INTERPRETATION: We identified two specific cerebral metabolic patterns that are closely linked to ketometabolism and were associated with both TIL and GOS. Our findings support the view that advanced metabolomics approaches combined with CMD may be applied in real-time to predict short-term treatment intensity and long-term patient outcome.


Assuntos
Lesões Encefálicas Traumáticas/metabolismo , Encéfalo/metabolismo , Corpos Cetônicos/metabolismo , Adulto , Biomarcadores , Lesões Encefálicas Traumáticas/líquido cefalorraquidiano , Lesões Encefálicas Traumáticas/diagnóstico , Lesões Encefálicas Traumáticas/terapia , Cromatografia Líquida , Biologia Computacional/métodos , Feminino , Escala de Coma de Glasgow , Humanos , Pressão Intracraniana , Masculino , Metaboloma , Metabolômica/métodos , Microdiálise , Pessoa de Meia-Idade , Avaliação de Resultados da Assistência ao Paciente , Prognóstico , Curva ROC , Estudos Retrospectivos , Espectrometria de Massas em Tandem
20.
Cardiovasc Res ; 115(11): 1567-1569, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-30989167
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