bims-kimdis Biomed News
on Ketones, inflammation and mitochondria in disease
Issue of 2024‒06‒09
ten papers selected by
Matías Javier Monsalves Álvarez, Universidad Andrés Bello
  1. The use of ketogenic diets in children living with drug-resistant epilepsy, glucose transporter 1 deficiency syndrome and pyruvate dehydrogenase deficiency: A scoping review.
  2. Ketogenic diet administration later in life improves memory by modifying the synaptic cortical proteome via the PKA signaling pathway in aging mice.
  3. The ketogenic diet and hypoxia promote mitophagy in the context of glaucoma.
  4. Ketogenic diet enhances the anti-cancer effects of PD-L1 blockade in renal cell carcinoma.
  5. Multifunctional Dopamine-Based Hydrogel Microneedle Electrode for Continuous Ketone Sensing.
  6. Effects of endurance training under calorie restriction on energy substrate metabolism in mouse skeletal muscle and liver.
  7. The ketogenic diet is unable to improve cardiac function in ischemic heart failure: an unexpected result?
  8. Acute effect of an exogenous ketone monoester supplement on appetite and food intake in adults with type 2 diabetes.
  9. Skeletal muscle PGC-1α remodels mitochondrial phospholipidome but does not alter energy efficiency for ATP synthesis.
  10. Quantifying fecal and plasma short-chain fatty acids in healthy Thai individuals.
  1. J Hum Nutr Diet. 2024 Jun 04.
    The use of ketogenic diets in children living with drug-resistant epilepsy, glucose transporter 1 deficiency syndrome and pyruvate dehydrogenase deficiency: A scoping review.
    Tracy Cameron, Karen Allan, Kay Cooper.
      BACKGROUND: The ketogenic diet (KD) is a high fat, moderate protein and very low carbohydrate diet. It can be used as a medical treatment for drug-resistant epilepsy (DRE), glucose transporter 1 deficiency syndrome and pyruvate dehydrogenase deficiency. The aim of this scoping review was to map the KD literature, with a focus on epilepsy and associated metabolic conditions, to summarise the current evidence-base and identify any gaps.METHODS: This review was conducted using JBI scoping review methodological guidance and the PRISMA extension for scoping reviews reporting guidance. A comprehensive literature search was conducted in September 2021 and updated in February 2024 using MEDLINE, CINAHL, AMED, EmBASE, CAB Abstracts, Scopus and Food Science Source databases.
    RESULTS: The initial search yielded 2721 studies and ultimately, data were extracted from 320 studies that fulfilled inclusion criteria for the review. There were five qualitative studies, and the remainder were quantitative, including 23 randomised controlled trials (RCTs) and seven quasi-experimental studies. The USA published the highest number of KD studies followed by China, South Korea and the UK. Most studies focused on the classical KD and DRE. The studies key findings suggest that the KD is efficacious, safe and tolerable.
    CONCLUSIONS: There are opportunities available to expand the scope of future KD research, particularly to conduct high-quality RCTs and further qualitative research focused on the child's needs and family support to improve the effectiveness of KDs.
    Keywords:  children; epilepsy; glucose transporter 1 deficiency syndrome; ketogenic diet; pyruvate dehydrogenase deficiency; scoping review
    DOI:  https://doi.org/10.1111/jhn.13324
  2. Cell Rep Med. 2024 Jun 03. pii: S2666-3791(24)00285-4. [Epub ahead of print] 101593
    Ketogenic diet administration later in life improves memory by modifying the synaptic cortical proteome via the PKA signaling pathway in aging mice.
    Diego Acuña-Catalán, Samah Shah, Cameron Wehrfritz, Mitsunori Nomura, Alejandro Acevedo, Cristina Olmos, Gabriel Quiroz, Hernán Huerta, Joanna Bons, Estibaliz Ampuero, Ursula Wyneken, Magdalena Sanhueza, Felipe Arancibia, Darwin Contreras, Julio César Cárdenas, Bernardo Morales, Birgit Schilling, John C Newman, Christian González-Billault.
      Aging compromises brain function leading to cognitive decline. A cyclic ketogenic diet (KD) improves memory in aged mice after long-term administration; however, short-term effects later in life and the molecular mechanisms that govern such changes remain unclear. Here, we explore the impact of a short-term KD treatment starting at elderly stage on brain function of aged mice. Behavioral testing and long-term potentiation (LTP) recordings reveal that KD improves working memory and hippocampal LTP. Furthermore, the synaptosome proteome of aged mice fed a KD long-term evidence changes predominantly at the presynaptic compartment associated to the protein kinase A (PKA) signaling pathway. These findings were corroborated in vivo by western blot analysis, with high BDNF abundance and PKA substrate phosphorylation. Overall, we show that a KD modifies brain function even when it is administered later in life and recapitulates molecular features of long-term administration, including the PKA signaling pathway, thus promoting synaptic plasticity at advanced age.
    Keywords:  BDNF; LTP; PKA; aging; brain-derived neurotrophic factor; ketogenic diet; long-term potentiation; protein kinase A; proteomics; β-hydroxybutyrate
    DOI:  https://doi.org/10.1016/j.xcrm.2024.101593
  3. Front Cell Neurosci. 2024 ;18 1409717
    The ketogenic diet and hypoxia promote mitophagy in the context of glaucoma.
    Autumn B Morgan, Yan Fan, Denise M Inman.
      Mitochondrial homeostasis includes balancing organelle biogenesis with recycling (mitophagy). The ketogenic diet protects retinal ganglion cells (RGCs) from glaucoma-associated neurodegeneration, with a concomitant increase in mitochondrial biogenesis. This study aimed to determine if the ketogenic diet also promoted mitophagy. MitoQC mice that carry a pH-sensitive mCherry-GFP tag on the outer mitochondrial membrane were placed on a ketogenic diet or standard rodent chow for 5 weeks; ocular hypertension (OHT) was induced via magnetic microbead injection in a subset of control or ketogenic diet animals 1 week after the diet began. As a measure of mitophagy, mitolysosomes were quantified in sectioned retina immunolabeled with RBPMS for RGCs or vimentin for Müller glia. Mitolysosomes were significantly increased as a result of OHT and the ketogenic diet (KD) in RGCs. Interestingly, the ketogenic diet increased mitolysosome number significantly higher than OHT alone. In contrast, OHT and the ketogenic diet both increased mitolysosome number in Müller glia to a similar degree. To understand if hypoxia could be a stimulus for mitophagy, we quantified mitolysosomes after acute OHT, finding significantly greater mitolysosome number in cells positive for pimonidazole, an adduct formed in cells exposed to hypoxia. Retinal protein analysis for BNIP3 and NIX showed no differences across groups, suggesting that these receptors were equivocal for mitophagy in this model of OHT. Our data indicate that OHT and hypoxia stimulate mitophagy and that the ketogenic diet is an additive for mitophagy in RGCs. The different response across RGCs and Müller glia to the ketogenic diet may reflect the different metabolic needs of these cell types.
    Keywords:  BNIP; Müller glia; PGC1 α; glaucoma; hypoxia; mitophagy; retinal ganglion cell
    DOI:  https://doi.org/10.3389/fncel.2024.1409717
  4. Front Endocrinol (Lausanne). 2024 ;15 1344891
    Ketogenic diet enhances the anti-cancer effects of PD-L1 blockade in renal cell carcinoma.
    Jeremy Richard, Céline Beauvillain, Maxime Benoit, Magalie Barth, Cécile Aubert, Cyrielle Rolley, Sarah Bellal, Jennifer Bourreau, Matthieu Ferragu, Souhil Lebdai, Arnaud Chevrollier, Daniel Henrion, Vincent Procaccio, Pierre Bigot.
      Introduction: Clear cell renal cell carcinoma (ccRCC) is characterized by a predominant metabolic reprogramming triggering energy production by anaerobic glycolysis at the expense of oxydative phosphorylation. Ketogenic diet (KD), which consists of high fat and low carbohydrate intake, could bring required energy substrates to healthy cells while depriving tumor cells of glucose. Our objective was to evaluate the effect of KD on renal cancer cell tumor metabolism and growth proliferation.Methods: Growth cell proliferation and mitochondrial metabolism of ACHN and Renca renal carcinoma cells were evaluated under ketone bodies (KB) exposure. In vivo studies were performed with mice (nude or Balb/c) receiving a xenograft of ACHN cells or Renca cells, respectively, and were then split into 2 feeding groups, fed either with standard diet or a 2:1 KD ad libitum. To test the effect of KD associated to immunotherapy, Balb/c mice were treated with anti-PDL1 mAb. Tumor growth was monitored.
    Results: In vitro, KB exposure was associated with a significant reduction of ACHN and Renca cell proliferation and viability, while increasing mitochondrial metabolism. In mice, KD was associated with tumor growth reduction and PDL-1 gene expression up-regulation. In Balb/c mice adjuvant KD was associated to a better response to anti-PDL-1 mAb treatment.
    Conclusion: KB reduced the renal tumor cell growth proliferation and improved mitochondrial respiration and biogenesis. KD also slowed down tumor growth of ACHN and Renca in vivo. We observed that PDL-1 was significantly overexpressed in tumor in mice under KD. Response to anti-PDL-1 mAb was improved in mice under KD. Further studies are needed to confirm the therapeutic benefit of adjuvant KD combined with immunotherapy in patients with kidney cancer.
    Keywords:  PDL1; adjuvant ketogenic diet; immunotherapy; metabolic reprogramming; mitochondrial biogenesis; renal cell carcinoma
    DOI:  https://doi.org/10.3389/fendo.2024.1344891
  5. Adv Mater. 2024 Jun 07. e2402009
    Multifunctional Dopamine-Based Hydrogel Microneedle Electrode for Continuous Ketone Sensing.
    Irfani Rahmi Ausri, Sadegh Sadeghzadeh, Subhamoy Biswas, Hanjia Zheng, Peyman GhavamiNejad, Michelle Dieu Thao Huynh, Fatemeh Keyvani, Erfan Shirzadi, Fasih A Rahman, Joe Quadrilatero, Amin GhavamiNejad, Mahla Poudineh.
      Diabetic ketoacidosis (DKA), a severe complication of type 1 diabetes (T1D) is triggered by production of large quantities of ketone bodies, requiring patients with T1D to constantly monitor their ketone levels. Here, we report a skin compatible hydrogel microneedle (HMN)-continuous ketone monitoring (HMN-CKM) device. The sensing mechanism relies on the catechol-quinone chemistry inherent to the dopamine (DA) molecules that are covalently linked to the polymer structure of the HMN patch. The DA serves the dual-purpose of acting as a redox mediator for measuring the byproduct of oxidation of 3-beta-hydroxybutyrate (β-HB), the primary ketone bodies, while also facilitating the formation of a crosslinked HMN patch. A universal approach involving pre-oxidation and detection of the generated catechol compounds was introduced to correlate the sensor response to the β-HB concentrations. We further showed that real-time tracking of a decrease in ketone levels of T1D rat model is possible using the HMN-CKM device in conjunction with a data-driven machine learning model that considers potential time delays. This article is protected by copyright. All rights reserved.
    Keywords:  catechol‐quinone redox mediators; electrochemistry; hydrogel microneedles; interstitial fluid; wearable biosensors
    DOI:  https://doi.org/10.1002/adma.202402009
  6. J Physiol Sci. 2024 Jun 07. 74(1): 32
    Effects of endurance training under calorie restriction on energy substrate metabolism in mouse skeletal muscle and liver.
    Kenya Takahashi, Yu Kitaoka, Hideo Hatta.
      We investigated whether calorie restriction (CR) enhances metabolic adaptations to endurance training (ET). Ten-week-old male Institute of Cancer Research (ICR) mice were fed ad libitum or subjected to 30% CR. The mice were subdivided into sedentary and ET groups. The ET group performed treadmill running (20-25 m/min, 30 min, 5 days/week) for 5 weeks. We found that CR decreased glycolytic enzyme activity and monocarboxylate transporter (MCT) 4 protein content, while enhancing glucose transporter 4 protein content in the plantaris and soleus muscles. Although ET and CR individually increased citrate synthase activity in the plantaris muscle, the ET-induced increase in respiratory chain complex I protein content was counteracted by CR. In the soleus muscle, mitochondrial enzyme activity and protein levels were increased by ET, but decreased by CR. It has been suggested that CR partially interferes with skeletal muscle adaptation to ET.
    Keywords:  Calorie restriction; Endurance training; Enzyme; Gluconeogenesis; Liver; Mitochondria; Skeletal muscle; Transporter
    DOI:  https://doi.org/10.1186/s12576-024-00924-5
  7. Cardiovasc Res. 2024 Jun 06. pii: cvae126. [Epub ahead of print]
    The ketogenic diet is unable to improve cardiac function in ischemic heart failure: an unexpected result?
    Carolina Magdalen Greco, Enzo Nisoli.
      
    DOI:  https://doi.org/10.1093/cvr/cvae126
  8. Appl Physiol Nutr Metab. 2024 Jun 03.
    Acute effect of an exogenous ketone monoester supplement on appetite and food intake in adults with type 2 diabetes.
    Barbara Oliveira, Kaja Falkenhain, Brenda M Davy, Kevin P Davy, Jonathan P Little.
      The effects of exogenous ketones on appetite and food intake remain elusive, especially for people with type 2 diabetes (T2D). This study aimed to determine whether acute ingestion of an oral ketone monoester supplement (KME) affected appetite sensations, prospective food consumption and intake in T2D. Results showed that acute KME ingestion did not significantly alter appetite scores. However, there was a tendency for lower energy intake during an ad libitum meal three hours following ketone ingestion compared to non-energetic placebo. Further research is warranted to understand the long-term effects of exogenous ketones for energy and macronutrient intake in T2D.
    DOI:  https://doi.org/10.1139/apnm-2023-0568
  9. bioRxiv. 2024 May 26. pii: 2024.05.22.595374. [Epub ahead of print]
    Skeletal muscle PGC-1α remodels mitochondrial phospholipidome but does not alter energy efficiency for ATP synthesis.
    Takuya Karasawa, Ran Hee Choi, Cesar A Meza, J Alan Maschek, James E Cox, Katsuhiko Funai.
      Background: Exercise training is thought to improve the mitochondrial energy efficiency of skeletal muscle. Some studies suggest exercise training increases the efficiency for ATP synthesis by oxidative phosphorylation (OXPHOS), but the molecular mechanisms are unclear. We have previously shown that exercise remodels the lipid composition of mitochondrial membranes, and some of these changes could contribute to improved OXPHOS efficiency (ATP produced by O2 consumed or P/O). Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) is a transcriptional co-activator that coordinately regulates exercise-induced adaptations including mitochondria. We hypothesized that increased PGC-1α activity is sufficient to remodel mitochondrial membrane lipids and promote energy efficiency.Methods: Mice with skeletal muscle-specific overexpression of PGC-1α (MCK-PGC-1α) and their wildtype littermates were used for this study. Lipid mass spectrometry and quantitative PCR were used to assess muscle mitochondrial lipid composition and their biosynthesis pathway. The abundance of OXPHOS enzymes was determined by western blot assay. High-resolution respirometry and fluorometry analysis were used to characterize mitochondrial bioenergetics (ATP production, O2 consumption, and P/O) for permeabilized fibers and isolated mitochondria.
    Results: Lipidomic analyses of skeletal muscle mitochondria from wildtype and MCK-PGC-1α mice revealed that PGC-1α increases the concentrations of cone-shaped lipids such as phosphatidylethanolamine (PE), cardiolipin (CL), and lysophospholipids, while decreases the concentrations of phosphatidylcholine (PC), phosphatidylinositol (PI) and phosphatidic acid (PA). However, while PGC-1α overexpression increased the abundance of OXPHOS enzymes in skeletal muscle and the rate of O2 consumption (JO2), P/O values were unaffected with PGC-1α in permeabilized fibers or isolated mitochondria.
    Conclusions: Collectively, overexpression of PGC-1α promotes the biosynthesis of mitochondrial PE and CL but neither PGC-1α nor the mitochondrial membrane lipid remodeling induced in MCK-PGC-1α mice is sufficient to increase the efficiency for mitochondrial ATP synthesis. These findings suggest that exercise training may increase OXPHOS efficiency by a PGC-1α-independent mechanism, and question the hypothesis that mitochondrial lipids directly affect OXPHOS enzymes to improve efficiency for ATP synthesis.
    Keywords:  exercise; mitochondria; phospholipids; skeletal muscle
    DOI:  https://doi.org/10.1101/2024.05.22.595374
  10. Comput Struct Biotechnol J. 2024 Dec;23 2163-2172
    Quantifying fecal and plasma short-chain fatty acids in healthy Thai individuals.
    Weerawan Manokasemsan, Narumol Jariyasopit, Patcha Poungsombat, Khwanta Kaewnarin, Kwanjeera Wanichthanarak, Alongkorn Kurilung, Kassaporn Duangkumpha, Suphitcha Limjiasahapong, Yotsawat Pomyen, Roongruedee Chaiteerakij, Rossarin Tansawat, Chatchawan Srisawat, Yongyut Sirivatanauksorn, Vorapan Sirivatanauksorn, Sakda Khoomrung.
      Short-chain fatty acids (SCFAs) are involved in important physiological processes such as gut health and immune response, and changes in SCFA levels can be indicative of disease. Despite the importance of SCFAs in human health and disease, reference values for fecal and plasma SCFA concentrations in healthy individuals are scarce. To address this gap in current knowledge, we developed a simple and reliable derivatization-free GC-TOFMS method for quantifying fecal and plasma SCFAs in healthy individuals. We targeted six linear- and seven branched-SCFAs, obtaining method recoveries of 73-88% and 83-134% in fecal and plasma matrices, respectively. The developed methods are simpler, faster, and more sensitive than previously published methods and are well suited for large-scale studies. Analysis of samples from 157 medically confirmed healthy individuals showed that the total SCFAs in the feces and plasma were 34.1 ± 15.3 µmol/g and 60.0 ± 45.9 µM, respectively. In fecal samples, acetic acid (Ace), propionic acid (Pro), and butanoic acid (But) were all significant, collectively accounting for 89% of the total SCFAs, whereas the only major SCFA in plasma samples was Ace, constituting of 93% of the total plasma SCFAs. There were no statistically significant differences in the total fecal and plasma SCFA concentrations between sexes or among age groups. The data revealed, however, a positive correlation for several nutrients, such as carbohydrate, fat, iron from vegetables, and water, to most of the targeted SCFAs. This is the first large-scale study to report SCFA reference intervals in the plasma and feces of healthy individuals, and thereby delivers valuable data for microbiome, metabolomics, and biomarker research.
    Keywords:  Feces; Gas chromatography-mass spectrometry; Gut microbial metabolite; Plasma; Quantitative analysis; Short-Chain Fatty Acids
    DOI:  https://doi.org/10.1016/j.csbj.2024.05.007
This page is being maintained by Thomas Krichel. It was last updated on 2024‒09‒09 at 14:21.