Transition from fetal to postnatal state in the heart: Crosstalk between metabolism and regeneration.

Cardiovascular disease is the leading cause of mortality worldwide. Myocardial injury resulting from ischemia can be fatal because of the limited regenerative capacity of adult myocardium. Mammalian cardiomyocytes rapidly lose their proliferative capacities, with only a small fraction of adult myocardium remaining proliferative, which is insufficient to support post-injury recovery. Recent investigations have revealed that this decline in myocardial proliferative capacity is closely linked to perinatal metabolic shifts. Predominantly glycolytic fetal myocardial metabolism transitions towards mitochondrial fatty acid oxidation postnatally, which not only enables efficient production of ATP but also causes a dramatic reduction in cardiomyocyte proliferative capacity. Extensive research has elucidated the mechanisms behind this metabolic shift, as well as methods to modulate these metabolic pathways. Some of these methods have been successfully applied to enhance metabolic reprogramming and myocardial regeneration. This review discusses recently acquired insights into the interplay between metabolism and myocardial proliferation, emphasizing postnatal metabolic transitions.

Liver protects neuron viability and electrocortical activity in post-cardiac arrest brain injury.

Brain injury is the leading cause of mortality among patients who survive cardiac arrest (CA). Clinical studies have shown that the presence of post-CA hypoxic hepatitis or pre-CA liver disease is associated with increased mortality and inferior neurological recovery. In our in vivo global cerebral ischemia model, we observed a larger infarct area, elevated tissue injury scores, and increased intravascular CD45+ cell adhesion in reperfused brains with simultaneous hepatic ischemia than in those without it. In the ex vivo brain normothermic machine perfusion (NMP) model, we demonstrated that addition of a functioning liver to the brain NMP circuit significantly reduced post-CA brain injury, increased neuronal viability, and improved electrocortical activity. Furthermore, significant alterations were observed in both the transcriptome and metabolome in the presence or absence of hepatic ischemia. Our study highlights the crucial role of the liver in the pathogenesis of post-CA brain injury.

Hyperglycemia Stimulates the Irreversible Catabolism of Branched-Chain Amino Acids and Generation of Ketone Bodies by Cultured Human Astrocytes.

Astrocytes are considered to possess a noticeable role in brain metabolism and, as a partners in neuron-glia cooperation, to contribute to the synthesis, bioconversion, and regulation of the flux of substrates for neuronal metabolism. With the aim of investigating to what extent human astrocytes are metabolizing amino acids and by which compounds are they enriching their surroundings, we employed a metabolomics analysis of their culture media by 1H-NMR. In addition, we compared the composition of media with either 5 mM or 25 mM glucose. The quantitative analysis of culture media by 1H-NMR revealed that astrocytes readily dispose from their milieu glutamine, branched-chain amino acids, and pyruvate with significantly high rates, while they enrich the culture media with lactate, branched-chain keto acids, citrate, acetate, ketone bodies, and alanine. Hyperglycemia suppressed the capacity of astrocytes to release branched-chain 2-oxo acids, while stimulating the generation of ketone bodies. Our results highlight the active involvement of astrocytes in the metabolism of several amino acids and the regulation of key metabolic intermediates. The observed metabolic activities of astrocytes provide valuable insights into their roles in supporting neuronal function, brain metabolism, and intercellular metabolic interactions within the brain. Understanding the complex metabolic interactions between astrocytes and neurons is essential for elucidating brain homeostasis and the pathophysiology of neurological disorders. The observed metabolic activities of astrocytes provide hints about their putative metabolic roles in brain metabolism.

Possible Extracellular Signals to Ameliorate Sarcopenia in Response to Medium-Chain Triglycerides (8:0 and 10:0) in Frail Older Adults.

In frail older adults (mean age 85 years old), a 3-month supplementation with a low dose (6 g/day) of medium-chain triglycerides (MCTs; C8:0 and C10:0) given at a meal increased muscle mass and function, relative to supplementation with long-chain triglycerides (LCTs), but it decreased fat mass. The reduction in fat mass was partly due to increased postprandial energy expenditure by stimulation of the sympathetic nervous system (SNS). However, the extracellular signals to ameliorate sarcopenia are unclear. The following three potential extracellular signals to increase muscle mass and function after MCT supplementation are discussed: (1) Activating SNS-the hypothesis for this is based on evidence that a beta2-adrenergic receptor agonist acutely (1-24 h) markedly upregulates isoforms of peroxisomal proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) mRNAs, promotes mitochondrial biogenesis, and chronically (~1 month) induces muscle hypertrophy. (2) An increased concentration of plasma acyl-ghrelin stimulates growth hormone secretion. (3) A nitrogen-sparing effect of ketone bodies, which fuel skeletal muscle, may promote muscle protein synthesis and prevent muscle protein breakdown. This review will help guide clinical trials of using MCTs to treat primary (age-related) sarcopenia.

Effects of angiotensin receptor-neprilysin inhibitor on ketone body metabolism in pre-heart failure/heart failure patients.

Recently, a mild elevation of the blood ketone levels was found to exert multifaceted cardioprotective effects. To investigate the effect of angiotensin receptor neprilysin inhibitors (ARNIs) on the blood ketone body levels, 46 stable pre-heart failure (HF)/HF patients were studied, including 23 who switched from angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) to ARNIs (ARNI group) and 23 who continued treatment with ACE inhibitors or ARBs (control group). At baseline, there were no significant differences in the total ketone body (TKB) levels between the two groups. Three months later, the TKB levels in the ARNI group were higher than the baseline values (baseline to 3 months: 71 [51, 122] to 92 [61, 270] µmol/L, P < 0.01). In the control group, no significant change was observed between the baseline and 3 months later. A multiple regression analysis demonstrated that the initiation of ARNI and an increase in the blood non-esterified fatty acid (NEFA) levels at 3 months increased the percentage changes in the TKB levels from baseline to 3 months (%ΔTKB level) (initiation of ARNI: P = 0.017, NEFA level at 3 months: P < 0.001). These results indicate that ARNI administration induces a mild elevation of the blood TKB levels in pre-HF/HF patients.

Empagliflozin alters lipid metabolism in the myocardium and liver in a prediabetes model with severe dyslipidemia.

Background and aims: Recent studies suggest that empagliflozin reduces total and cardiovascular mortality in both diabetic and nondiabetic subjects. Although the exact mechanism is unclear, it is understood to positively affect myocardial energetics, including the metabolism of ketone bodies, lipids, and fatty acids. In this study, we compared empagliflozin effects on lipid metabolism in the heart and liver in a prediabetic rat model with severe dyslipidemia. Materials and methods: Wistar rats served as the control group, while hereditary hypertriglyceridemic (HHTg) rats were used as a nonobese, prediabetic model. Rats were treated with or without empagliflozin at a dose of 10 mg/kg body weight (BW) for 8 weeks. Results: In HHTg rats, empagliflozin decreased body weight and adiposity, improved glucose tolerance, and decreased serum triacylglycerols (TAGs) (p < 0.001). Empagliflozin decreased the activity and gene expression of the lipogenic enzyme SCD-1 (p < 0.001) in the myocardium, which may have led to a decrease in the ectopic accumulation of TAGs and lipotoxic diacylglycerols and lysophosphatidylcholines (p < 0.001). Changes in the myocardial phosphatidylcholine/phosphatidylethanolamine ratio (p < 0.01) and in the fatty acid profile of myocardial phospholipids may have contributed to the antifibrotic effects of empagliflozin. The anti-inflammatory effects of empagliflozin were evidenced by an increased IL-10/TNFα ratio (p < 0.001), a marked decrease in arachidonic acid metabolites (20-HETE, p < 0.001), and an increase in PUFA metabolites (14,15-EETs, p < 0.001) in the myocardium. However, empagliflozin did not significantly affect either the concentration or utilization of ketone bodies. In the liver, empagliflozin decreased lipogenesis and the accumulation of TAGs and lipotoxic intermediates. Its effect on arachidonic acid metabolites and alterations in n-3 PUFA metabolism was less pronounced than in the myocardium. Conclusion: Our findings suggest that empagliflozin treatment in the heart and liver reduced the accumulation of neutral lipids and lipotoxic intermediates and altered the metabolism of n-3 PUFA. In the heart, empagliflozin altered arachidonic acid metabolism, which is likely associated with the anti-inflammatory and antifibrotic effects of the drug. We assume that these alterations in lipid metabolism contribute to the cardioprotective effects of empagliflozin in prediabetic states with severe dyslipidemia.

Determination of the safety of Halomonas sp. KM-1-derived d-ß-hydroxybutyric acid and its fermentation-derived impurities in mice and Japanese adults.

The use of halophilic bacteria in industrial chemical and food production has received great interest because of the unique properties of these bacteria; however, their safety remains under investigation. Halomonas sp. KM-1 intracellularly stores poly-D-ß-hydroxybutyric acid under aerobic conditions and successively secretes D-ß-hydroxybutyric acid (D-BHB) under microaerobic conditions. Therefore, we tested the safety of Halomonas sp. KM-1-derived D-BHB and the impurities generated during D-BHB manufacturing at a 100-fold increased concentration in acute tests using mice and daily intake of 16.0 g D-BHB in Japanese adults for 12 weeks. In the mice test, there were no abnormalities in the body weights or health of mice fed the purified D-BHB or its impurities. In the Japanese adult test, blood parameters and body condition showed no medically problematic fluctuations. These findings indicate that Halomonas sp. KM-1 is safe and can be used for commercial production of D-BHB and its derivatives.

Both Enantiomers of 2-Hydroxyglutarate Modulate the Metabolism of Cultured Human Neuroblastoma Cells.

Elevated levels of D-2-hydroxyglutarate (D-2HG) and L-2-hydroxyglutarate (L-2HG) in the brain are associated with various pathological conditions, potentially contributing to neurological symptoms and neurodegeneration. Previous studies on animal models have revealed their capability to interfere with several cellular processes, including mitochondrial metabolism. Both enantiomers competitively inhibit the enzymatic activity of 2-oxoglutarate-dependent dioxygenases. These enzymes also execute several signaling cascades and regulate the level of covalent modifications on nucleic acids or proteins, e.g., methylation, hydroxylation, or ubiquitination, with an effect on epigenetic regulation of gene expression, protein stability, and intracellular signaling. To investigate the potential impact of 2HG enantiomers on human neuronal cells, we utilized the SH-SY5Y human neuroblastoma cell line as a model. We employed proton nuclear magnetic resonance (1H-NMR) spectroscopy of culture media that provided high-resolution insights into the changes in the content of metabolites. Concurrently, we performed biochemical assays to complement the 1H-NMR findings and to estimate the activities of lactate and 3-hydroxybutyrate dehydrogenases. Our results reveal that both 2HG enantiomers can influence the cellular metabolism of human neuroblastoma cells on multiple levels. Specifically, both enantiomers of 2HG comparably stimulate anaerobic metabolism of glucose and inhibit the uptake of several essential amino acids from the culture media. In this respect, both 2HG enantiomers decreased the catabolism capability of cells to incorporate the leucine-derived carbon atoms into their metabolism and to generate the ketone bodies. These results provide evidence that both enantiomers of 2HG have the potential to influence the metabolic and molecular aspects of human cells. Furthermore, we may propose that increased levels of 2HG enantiomers in the brain parenchyma may alter brain metabolism features, potentially contributing to the etiology of neurological symptoms in patients.

Relationships Between Changes in Serum Ketone Body Levels and Metabolic Effects in Patients with Severe Obesity Who Underwent Laparoscopic Sleeve Gastrectomy.

BACKGROUND: Serum ketone bodies increase due to dynamic changes in the lipid metabolisms of patients undergoing bariatric surgery. However, there have been few studies on the role of ketone bodies after bariatric surgery. We aimed to clarify the role of and relationship between the changes in serum ketone bodies and weight loss, as well as between those changes and the metabolic effects after laparoscopic sleeve gastrectomy (LSG). METHODS: We recruited 52 patients with severe obesity who underwent LSG. We measured acetoacetic acid (AcAc) and ß-hydroxybutyric acid (ß-OHB) at the baseline, 1 month, and 6 months after LSG. Subsequently, we compared the changes in the serum ketone bodies with weight-loss effects and various metabolic parameters. RESULTS: At 1 month after LSG, ß-OHB significantly increased (p = 0.009), then significantly decreased 6 months after LSG (p = 0.002). In addition, ß-OHB in patients without Type 2 diabetes (T2D) and metabolic dysfunction-associated steatohepatitis (MASH) was notably higher than in patients with T2D at 1 month after LSG (p < 0.001). In the early phase, both AcAc and ß-OHB mainly had strong positive correlations with changes in T2D- and MASH-related parameters. In the middle term after LSG, changes in both AcAc and ß-OHB were positively correlated with changes in lipid parameters and chronic kidney disease-related parameters. CONCLUSION: We demonstrated that the postoperative surge of ketone bodies plays a crucial function in controlling metabolic effects after LSG. These findings suggest the cause- and consequence-related roles of ketone bodies in the metabolic benefits of bariatric surgery.

Pioglitazone reduces serum ketone bodies in sodium-glucose cotransporter-2 inhibitor-treated non-obese type 2 diabetes: A single-centre, randomized, crossover trial.

AIM: To examine the effects of the thiazolidinedione (TZD) pioglitazone on reducing ketone bodies in non-obese patients with T2DM treated with the sodium-glucose cotransporter-2 (SGLT2) inhibitor canagliflozin. METHODS: Crossover trials with two periods, each treatment period lasting 4 weeks, with a 4-week washout period, were conducted. Participants were randomly assigned in a 1:1 ratio to receive pioglitazone combined with canagliflozin (PIOG + CANA group) versus canagliflozin monotherapy (CANA group). The primary outcome was change (Δ) in ß-hydroxybutyric acid (ß-HBA) before and after the CANA or PIOG + CANA treatments. The secondary outcomes were Δchanges in serum acetoacetate and acetone, the rate of conversion into urinary ketones, and Δchanges in factors related to SGLT2 inhibitor-induced ketone body production including non-esterified fatty acids (NEFAs), glucagon, glucagon to insulin ratio, and noradrenaline (NA). Analyses were performed in accordance with the intention-to-treat principle. RESULTS: Twenty-five patients with a mean age of 49 ± 7.97 years and a body mass index of 25.35 ± 2.22 kg/m2 were included. One patient discontinued the study during the washout period. Analyses revealed a significant increase in the levels of serum ketone bodies and an elevation in the rate of conversion into urinary ketones after both interventions. However, differernces in levels of ketone bodies (except for acetoacetate) in the PIOG + CANA group were significantly smaller than in the CANA group (219.84 ± 80.21 µmol/L vs. 317.69 ± 83.07 µmol/L, p < 0.001 in ß-HBA; 8.98 ± 4.17 µmol/L vs. 12.29 ± 5.27 µmol/L, p = 0.018 in acetone). NEFA, glucagon, glucagon to insulin ratio, and NA were also significantly increased after both CANA and PIOG + CANA treatments; while only NEFAs demonstrated a significant difference between the two groups. Correlation analyses revealed a significant association between the difference in Δchanges in serum NEFA levels with the differences in Δchanges in ketones of ß-HBA and acetoacetate. CONCLUSION: Supplementation of pioglitazone could alleviate canagliflozin-induced ketone bodies. This benefit may be closely associated with decreased substrate NEFAs rather than other factors including glucagon, fasting insulin and NA.

Adaptive Metabolic Responses Facilitate Blood-Brain Barrier Repair in Ischemic Stroke via BHB-Mediated Epigenetic Modification of ZO-1 Expression.

Adaptive metabolic responses and innate metabolites hold promising therapeutic potential for stroke, while targeted interventions require a thorough understanding of underlying mechanisms. Adiposity is a noted modifiable metabolic risk factor for stroke, and recent research suggests that it benefits neurological rehabilitation. During the early phase of experimental stroke, the lipidomic results showed that fat depots underwent pronounced lipolysis and released fatty acids (FAs) that feed into consequent hepatic FA oxidation and ketogenesis. Systemic supplementation with the predominant ketone beta-hydroxybutyrate (BHB) is found to exert discernible effects on preserving blood-brain barrier (BBB) integrity and facilitating neuroinflammation resolution. Meanwhile, blocking FAO-ketogenesis processes by administration of CPT1α antagonist or shRNA targeting HMGCS2 exacerbated endothelial damage and aggravated stroke severity, whereas BHB supplementation blunted these injuries. Mechanistically, it is unveiled that BHB infusion is taken up by monocarboxylic acid transporter 1 (MCT1) specifically expressed in cerebral endothelium and upregulated the expression of tight junction protein ZO-1 by enhancing local ß-hydroxybutyrylation of H3K9 at the promoter of TJP1 gene. Conclusively, an adaptive metabolic mechanism is elucidated by which acute lipolysis stimulates FAO-ketogenesis processes to restore BBB integrity after stroke. Ketogenesis functions as an early metabolic responder to restrain stroke progression, providing novel prospectives for clinical translation.

Ketone body levels and its associations with cardiac markers following an acute myocardial infarction: a post hoc analysis of the EMMY trial.

BACKGROUND: Sodium-glucose co-transporter 2 inhibitors (SGLT2i) have been suggested to exert cardioprotective effects in patients with heart failure, possibly by improving the metabolism of ketone bodies in the myocardium. METHODS: This post hoc analysis of the EMMY trial investigated the changes in serum ß-hydroxybutyrate (3-ßOHB) levels after acute myocardial infarction (AMI) in response to 26-week of Empagliflozin therapy compared to the usual post-MI treatment. In addition, the association of baseline and repeated measurements of 3-ßOHB with cardiac parameters and the interaction effects of Empagliflozin were investigated. Cardiac parameters included N-terminal pro-B-type natriuretic peptide (NT-proBNP), left ventricular ejection fraction (LVEF), left ventricle end-systolic volume (LVESV), left ventricle end-diastolic volume (LVEDV), and left ventricular filling pressure (E/é ratio). RESULTS: The mean 3-ßOHB levels increased from baseline (46.2 ± 3.0 vs. 51.7 ± 2.7) to 6 weeks (48.8 ± 2.2 vs. 42.0 ± 2.3) and 26 weeks (49.3 ± 2.2 vs. 35.8 ± 1.9) in the Empagliflozin group compared to a consistent decline in placebo over 26 weeks (pinteraction < 0.001). Baseline and longitudinal measurements of 3-ßOHB were not significantly associated with NT-proBNP and E/é ratio. Baseline 3-ßOHB value was negatively associated with LVEF (coefficient: - 0.464, 95%CI - 0.863;- 0.065, p = 0.023), while an increase in its levels over time was positively associated with LVEF (0.595, 0.156;1.035, 0.008). The baseline 3-ßOHB was positively associated with LVESV (1.409, 0.186;2.632, 0.024) and LVEDV (0.640, - 1.170;- 2.449, 0.488), while an increase in its levels over time was negatively associated with these cardiac parameters (LVESV: - 2.099, - 3.443;- 0.755, 0.002; LVEDV: - 2.406, - 4.341;- 0.472, 0.015). Empagliflozin therapy appears to modify the association between 3-ßOHB, LVEF (pinteraction = 0.090), LVESV (pinteraction = 0.134), and LVEDV (pinteraction = 0.168), particularly at 26 weeks; however, the results were not statistically significant. CONCLUSION: This post hoc analysis showed that SGLT2i increased 3-ßOHB levels after AMI compared to placebo. Higher baseline 3-ßOHB levels were inversely associated with cardiac function at follow-up, whereas a sustained increase in 3-ßOHB levels over time improved these markers. This highlights the importance of investigating ketone body metabolism in different post-MI phases. Although more pronounced effect of 3-ßOHB on cardiac markers was observed in the SGLT2i group, further research is required to explore this interaction effect.

Prognostic role of urinary ketone body in patients with sepsis-associated encephalopathy without hepatic failure: a retrospective cohort study.

Sepsis-associated encephalopathy (SAE) is defined as a dysfunction of the central nervous system experienced during sepsis with variable clinical features. The study aims to identify the prognostic role of urinary ketone bodies in relation to clinical outcomes in patients with SAE. The Medical Information Mart for Intensive Care III (MIMIC-III) database was used to conduct a retrospective cohort study. We recruited 427 patients with SAE admitted to the intensive care unit (ICU) from the MIMIC-III database. Patients with SAE were divided into a survival group (380 patients) and a non-survival group (47 patients). We used the Wilcoxon signed-rank test and the multivariate logistic regression analysis to analyze the relationship between the level of urinary ketone bodies and the clinical prognosis in patients with SAE. The primary outcome was the relationship between urinary ketone body levels and 28-day mortality of SAE. The secondary outcomes were the relationship between urinary ketone body levels and length of ICU stays, Simplified Acute Physiology Score II, Sequential Organ Failure Assessment (SOFA), Glasgow Coma Scale, mechanical ventilation, renal replacement therapy, and the use of vasopressors. The 28-day mortality of patients with SAE was 11.0%. Urinary ketone body levels were not significantly associated with the 28-day mortality of patients with SAE. Urinary ketone body levels were associated with SOFA score and the use of vasopressors in patients with SAE. The SOFA score was an independent risk factor for the 28-day mortality in patients with SAE. Urinary ketone body levels were significantly associated with SOFA score and the use of vasopressors in patients with SAE. Furthermore, the SOFA score can predict the prognosis of short-term outcomes of patients with SAE. Therefore, we should closely monitor the changes of urinary ketone bodies and SOFA score and intervene in time.

Association of ketone bodies with incident CKD and death: A UK Biobank study.

AIMS: Although cellular and animal models have suggested a protective effect of ketone bodies (KBs), clinical data are still lacking to support these findings. This study aimed to investigate the association of KB levels with incident chronic kidney disease (CKD) and death. METHODS: This was a prospective cohort study of 87,899 UK Biobank participants without baseline CKD who had plasma levels of ß-hydroxybutyrate, acetoacetate, and acetone levels measured at the time of enrollment. The main predictor was plasma total KB, which was the sum of the aforementioned three KBs. The primary outcome was a composite of incident CKD, or all-cause mortality. Secondary outcomes included the individual components of the primary outcome. RESULTS: During a median follow-up of 11.9 years, a total of 8,145 primary outcome events occurred (incidence rate 8.0/1,000 person-years). In the multivariable Cox model, a 1-standard deviation increase in log total KB was associated with a 7 % [adjusted hazard ratio (aHR), 1.07; 95 % confidence interval (CI), 1.05-1.10] higher risk of the primary outcome. When stratified into quartiles, the aHR (95 % CI) for Q4 versus Q1 was 1.18 (1.11-1.27). This association was consistent for incident CKD (aHR, 1.04; 95 % CI, 1.01-1.07), and all-cause mortality (aHR, 1.10; 95 % CI, 1.07-1.13). Compared with Q1, Q4 was associated with a 12 % (aHR 1.12; 95 % CI 1.02-1.24) and 26 % (aHR 1.26; 95 % CI 1.15-1.37) higher risk of incident CKD and all-cause mortality, respectively. CONCLUSIONS: Higher KB levels were independently associated with higher risk of incident CKD and death.

Cardiac mitochondrial metabolism during pregnancy and the postpartum period.

The goal of the present study was to characterize changes in mitochondrial respiration in the maternal heart during pregnancy and after birth. Timed pregnancy studies were performed in 12-wk-old female FVB/NJ mice, and cardiac mitochondria were isolated from the following groups of mice: nonpregnant (NP), midpregnancy (MP), late pregnancy (LP), and 1-wk postbirth (PB). Similar to our previous studies, we observed increased heart size during all stages of pregnancy (e.g., MP and LP) and postbirth (e.g., PB) compared with NP mice. Differential cardiac gene and protein expression analyses revealed changes in several mitochondrial transcripts at LP and PB, including several mitochondrial complex subunits and members of the Slc family, important for mitochondrial substrate transport. Respirometry revealed that pyruvate- and glutamate-supported state 3 respiration was significantly higher in PB vs. LP mitochondria, with respiratory control ratio (RCR) values higher in PB mitochondria. In addition, we found that PB mitochondria respired more avidly when given 3-hydroxybutyrate (3-OHB) than mitochondria from NP, MP, and LP hearts, with no differences in RCR. These increases in respiration in PB hearts occurred independent of changes in mitochondrial yield but were associated with higher abundance of 3-hydroxybutyrate dehydrogenase 1. Collectively, these findings suggest that, after birth, maternal cardiac mitochondria have an increased capacity to use 3-OHB, pyruvate, and glutamate as energy sources; however, increases in mitochondrial efficiency in the postpartum heart appear limited to carbohydrate and amino acid metabolism.NEW & NOTEWORTHY Few studies have detailed the physiological adaptations that occur in the maternal heart. We and others have shown that pregnancy-induced cardiac growth is associated with significant changes in cardiac metabolism. Here, we examined mitochondrial respiration and substrate preference in isolated mitochondria from the maternal heart. We show that following birth, cardiac mitochondria are "primed" to respire on carbohydrate, amino acid, and ketone bodies. However, heightened respiratory efficiency is observed only with carbohydrate and amino acid sources. These results suggest that significant changes in mitochondrial respiration occur in the maternal heart in the postpartum period.

Effect of Ketogenic Diet on Obesity and Other Metabolic Disorders: Narrative Review.

Obesity is defined as an abnormal or excessive accumulation of fat that increases the burden of different chronic diseases in the population. It has reached epidemic proportions and is a major risk factor for a variety of diseases, including hypertension, cardiovascular disease, type 2 diabetes, dyslipidaemia, atherosclerosis, and some malignancies. Weight gain is a result of excessive energy intake compared to energy expenditure (energy loss from metabolism and physical exercise). A ketogenic diet has a more useful effect on obesity than other diets. A ketogenic diet is a low-carbohydrate, high-fat, moderate-protein diet that induces the production of ketone bodies by mimicking the breakdown of a fasting state. The mechanism behind the ketogenic diet is still unknown, although it obviously helps people with obesity lose weight. Several pathways for the ketogenic diet effect on weight loss have been hypothesized by researchers, including reduced appetite due to effects on appetite control hormones and a possible direct appetite suppressant action of ketone bodies; reduced lipogenesis and increased lipolysis; greater metabolic efficiency; and increased metabolic costs.

Offspring of women with hyperemesis gravidarum are more likely to have cardiovascular abnormalities.

BACKGROUND: Hyperemesis gravidarum (HG) is a severe form of pregnancy-related nausea and vomiting affecting 0.3-2.3% of pregnancies, which can lead to fluid, electrolyte, and acid-base imbalances, nutritional deficiencies, and weight loss, and is usually severe enough to require hospitalization. Abnormally elevated urinary ketones are commonly seen in patients with HG, and ketone bodies are free to pass through the placenta, and maternal hyperketonemia, with or without acidosis, is associated with an increased rate of stillbirth, an increased incidence of congenital anomalies, and impaired neurophysiologic development of the infant. This study investigates the obstetric outcomes of patients with HG and whether HG increases the incidence of cardiovascular disease in the offspring. METHODS: This study included 1020 pregnant women who were hospitalized in our hospital for HG and ultimately delivered in our hospital as well as pregnant women without HG in early gestation and delivered in our hospital from January 2019-January 2020, and we collected and followed up the clinical information of the pregnant women and their offspring. RESULTS: Pregnant women with HG were more likely to have severe urinary ketones, the rate of early miscarriage and mid-term miscarriage was significantly higher in women with HG compared to pregnant women without HG. Fetal and neonatal head and abdominal circumferences were smaller in HG group than in control group. Neonatal birth weight and length were also lower in the HG group and cardiovascular anomalies were more likely to occur in the offspring of women with HG when all births were followed up for 3 years. CONCLUSIONS: HG may cause poor obstetric outcomes and was associated with the development of cardiovascular disease in the offspring of women with HG.

Medium- and Long-Chain Triacylglycerol: Preparation, Health Benefits, and Food Utilization.

Medium- and long-chain triacylglycerol (MLCT) is a structured lipid with both medium- and long-chain fatty acids in one triacylglycerol molecule. Compared with long-chain triacylglycerol (LCT), which is mainly present in common edible oils, and the physical blend of medium-chain triacylglycerol with LCT (MCT/LCT), MLCT has different physicochemical properties, metabolic characteristics, and nutritional values. In this article, the recent advances in the use of MLCT in food formulations are reviewed. The natural sources and preparation of MLCT are discussed. A comprehensive summary of MLCT digestion, absorption, transport, and oxidation is provided as well as its health benefits, including reducing the risk of overweight, hypolipidemic and hypoglycemic effects, etc. The potential MLCT uses in food formulations, such as infant formulas, healthy foods for weight loss, and sports foods, are summarized. Finally, the current safety assessment and regulatory status of MLCT in food formulations are reviewed.

A novel therapeutic target for kidney diseases: Lessons learned from starvation response.

The prevalence of chronic kidney disease (CKD) is increasing worldwide, making the disease an urgent clinical challenge. Caloric restriction has various anti-aging and organ-protective effects, and unraveling its molecular mechanisms may provide insight into the pathophysiology of CKD. In response to changes in nutritional status, intracellular nutrient signaling pathways show adaptive changes. When nutrients are abundant, signals such as mechanistic target of rapamycin complex 1 (mTORC1) are activated, driving cell proliferation and other processes. Conversely, others, such as sirtuins and AMP-activated protein kinase, are activated during energy scarcity, in an attempt to compensate. Autophagy, a cellular self-maintenance mechanism that is regulated by such signals, has also been reported to contribute to the progression of various kidney diseases. Furthermore, in recent years, ketone bodies, which have long been considered to be detrimental, have been reported to play a role as starvation signals, and thereby to have renoprotective effects, via the inhibition of mTORC1. Therefore, in this review, we discuss the role of mTORC1, which is one of the most extensively studied nutrient-related signals associated with kidney diseases, autophagy, and ketone body metabolism; and kidney energy metabolism as a novel therapeutic target for CKD.

Global Energy Metabolism Deficit in Alzheimer Disease Brain.

BACKGROUND: The understanding of Alzheimer's disease (AD) has been dominated by the amyloid hypothesis. However, therapies targeting beta-amyloid have largely failed, generating interest in other potential pathogenic factors including energy metabolism. OBJECTIVES: To interrogate canonical energy metabolism pathways from human prefrontal cortical tissue samples obtained from necropsy comparing AD and control. DESIGN, SETTING, AND PARTICIPANTS: Postmortem pre-frontal cortical tissue from 10 subjects histologically diagnosed with AD and 10 control (CTRL) subjects was subjected to untargeted metabolomics to interrogate energy metabolism pathways. The samples were matched by age, sex, and post-mortem interval. Metabolite Measurements: Untargeted metabolomics analyses were via Metabolon®. RESULTS: Glucose-derived energy metabolites in the glycolytic and pentose phosphate pathway and the ketone body ß-hydroxybutyrate were uniformly decreased in AD brain vs. CTRL brain. CONCLUSION: This pilot study aimed to identify energy metabolism abnormalities using untargeted brain metabolomics in two independent subject cohorts. Our study revealed a pattern of global energy deficit in AD brain, supporting a growing body of evidence of deficient energy metabolism in AD.