bims-kimdis Biomed News
on Ketones, inflammation and mitochondria in disease
Issue of 2023–09–10
twenty papers selected by
Matías Javier Monsalves Álvarez, Universidad de O’Higgins
  1. The Influence of Ketogenic Diet on Gut Microbiota: Potential Benefits, Risks and Indications.
  2. Potential benefits of medium chain fatty acids in aging and neurodegenerative disease.
  3. Keto Menu-Effect of Ketogenic Menu and Intermittent Fasting on the Biochemical Markers and Body Composition in a Physically Active Man-A Controlled Case Study.
  4. Ketogenic diets in children with intractable epilepsy and its effects on gastrointestinal function, gut microbiome, inflammation, and quality of life.
  5. D - β -hydroxybutyrate stabilizes the hippocampal CA3-CA1 circuit during acute insulin resistance.
  6. The impact of ketogenic diet on the onset and progression of multiple sclerosis.
  7. Triangulating evidence from observational and Mendelian randomization studies of ketone bodies for cognitive performance.
  8. Mitochondrial Dysfunction and Sarcopenic Obesity: The Role of Exercise.
  9. Targeting NLRP3 inflammasome for neurodegenerative disorders.
  10. Metabolic intervention by low carbohydrate diet suppresses the onset and progression of neuroendocrine tumors.
  11. Sodium Butyrate as Key Regulator of Mitochondrial Function and Barrier Integrity of Human Glomerular Endothelial Cells.
  12. Mitochondrial Properties in Skeletal Muscle Fiber.
  13. Mitochondrial dynamics in health and disease: mechanisms and potential targets.
  14. Carbohydrate-insulin model: does the conventional view of obesity reverse cause and effect?
  15. Effect of mitochondrial circulation on mitochondrial age density distribution.
  16. Reduced Expression of Septin7 Hinders Skeletal Muscle Regeneration.
  17. Validation of an Italian Questionnaire of Adherence to the Ketogenic Dietary Therapies: iKetoCheck.
  18. HMGCS2 serves as a potential biomarker for inhibition of renal clear cell carcinoma growth.
  19. Fatty acid oxidation regulates cellular senescence by modulating the autophagy-SIRT1 axis.
  20. Recent Advances in Nutraceuticals for the Treatment of Sarcopenic Obesity.
  1. Nutrients. 2023 Aug 22. pii: 3680. [Epub ahead of print]15(17):
    The Influence of Ketogenic Diet on Gut Microbiota: Potential Benefits, Risks and Indications.
    Andrea Santangelo, Antonio Corsello, Giulia Carla Immacolata Spolidoro, Chiara Maria Trovato, Carlo Agostoni, Alessandro Orsini, Gregorio Paolo Milani, Diego Giampietro Peroni.
      The ketogenic diet (KD) restricts carbohydrate consumption, leading to an increase in ketone bodies, such as acetoacetate, β-hydroxybutyrate, and acetone, which are utilized as energy substrates. This dietary approach impacts several biochemical processes, resulting in improved clinical management of various disorders, particularly in childhood. However, the exact mechanisms underlying the efficacy of KD remain unclear. Interestingly, KD may also impact the gut microbiota, which plays a pivotal role in metabolism, nutrition, and the development of the immune and nervous systems. KD has gained popularity for its potential benefits in weight loss, blood sugar control, and certain neurological conditions. This narrative review sums up KD-related studies published over 30 years. While short-term studies have provided valuable insights into the effects of KD on the gut microbiota, persistent uncertainties surround its long-term efficacy and potential for inducing dysbiosis. The significant influence of KD on epigenetic mechanisms, intracellular pathways, and gut microbial composition underscores its potential as a therapeutic choice. However, a judicious consideration of the potential risks associated with the strict adherence to a low-carbohydrate, high-fat, and high-protein regimen over prolonged periods is imperative. As KDs gain popularity among the adolescent and young adult demographic for weight management, it becomes imperative to undertake additional research to comprehensively assess their impact on nutritional status and gut microbiota, ensuring a holistic and sustainable approach to medical nutrition.
    Keywords:  children microbiome; drug-resistant epilepsy; gut microbiota; gut–brain axis; ketogenic diet; ketones and cancer; obesity treatment
    DOI:  https://doi.org/10.3390/nu15173680
  2. Front Aging Neurosci. 2023 ;15 1230467
    Potential benefits of medium chain fatty acids in aging and neurodegenerative disease.
    Ella Dunn, Biqin Zhang, Virender K Sahota, Hrvoje Augustin.
      Neurodegenerative diseases are a large class of neurological disorders characterized by progressive dysfunction and death of neurones. Examples include Alzheimer's disease, Parkinson's disease, frontotemporal dementia, and amyotrophic lateral sclerosis. Aging is the primary risk factor for neurodegeneration; individuals over 65 are more likely to suffer from a neurodegenerative disease, with prevalence increasing with age. As the population ages, the social and economic burden caused by these diseases will increase. Therefore, new therapies that address both aging and neurodegeneration are imperative. Ketogenic diets (KDs) are low carbohydrate, high-fat diets developed initially as an alternative treatment for epilepsy. The classic ketogenic diet provides energy via long-chain fatty acids (LCFAs); naturally occurring medium chain fatty acids (MCFAs), on the other hand, are the main components of the medium-chain triglyceride (MCT) ketogenic diet. MCT-based diets are more efficient at generating the ketone bodies that are used as a secondary energy source for neurones and astrocytes. However, ketone levels alone do not closely correlate with improved clinical symptoms. Recent findings suggest an alternative mode of action for the MCFAs, e.g., via improving mitochondrial biogenesis and glutamate receptor inhibition. MCFAs have been linked to the treatment of both aging and neurodegenerative disease via their effects on metabolism. Through action on multiple disease-related pathways, MCFAs are emerging as compounds with notable potential to promote healthy aging and ameliorate neurodegeneration. MCFAs have been shown to stimulate autophagy and restore mitochondrial function, which are found to be disrupted in aging and neurodegeneration. This review aims to provide insight into the metabolic benefits of MCFAs in neurodegenerative disease and healthy aging. We will discuss the use of MCFAs to combat dysregulation of autophagy and mitochondrial function in the context of "normal" aging, Parkinson's disease, amyotrophic lateral sclerosis and Alzheimer's disease.
    Keywords:  Alzheimer’s disease; Parkinson’ s disease; ageing; amyotrophic lateral sclerosis; autophagy; ketogenic diet (KD); medium chain fatty acid (MCFA); mitochondria
    DOI:  https://doi.org/10.3389/fnagi.2023.1230467
  3. Foods. 2023 Aug 26. pii: 3219. [Epub ahead of print]12(17):
    Keto Menu-Effect of Ketogenic Menu and Intermittent Fasting on the Biochemical Markers and Body Composition in a Physically Active Man-A Controlled Case Study.
    Damian Dyńka, Agnieszka Paziewska, Katarzyna Kowalcze.
      The combination of ketogenic diet (KD) with intermittent fasting (IF) has, for years, aroused a great interest in the scientific world and among healthy lifestyle enthusiasts. Its importance is even greater when the study subjects are physically active individuals. The aim of the study was a determination of the effect of strict calculated ketogenic menu combined with IF and with caloric deficit on the selected biochemical markers and body composition in a 23-year-old man performing strength training. At the same time, we decided to conduct the first so-deeply investigated and controlled case study in this respect. The study protocol included a 13-week-long ketogenic diet with intermittent fasting (of delayed time-restricted eating 16:8 type) and caloric deficit. A detailed menu was designed and was used by the man throughout the whole study duration. A number of blood tests were performed before and after the implemented dietary intervention. Additionally, body composition was determined weekly and the concentrations of glucose and ketone bodies, as well as pulse rate and arterial pressure, were measured daily. The most important changes noted included a significant increase in testosterone and vitamin D concentrations and significant reduction in the HOMA-IR index and concentrations of hepatic enzymes, insulin, glucose, iron, urea, and free triiodothyronine (FT3). Moreover, a significant improvement of body composition occurred (the ratio of total body mass to the adipose and muscular tissue and water mass improved). Favourable changes were also noted in heart rate and arterial pressure values. In view of that, the KD with IF and caloric deficit exerted favourable effects on most biochemical parameters and on body composition and caused an almost twofold increase in serum testosterone concentration.
    Keywords:  anthropometric parameters; biochemical markers; body composition; caloric restriction; high fat; intermittent fasting; ketogenic diet; ketogenic foods; ketogenic menu; ketone bodies; lipid profile; low carb; physical activity; testosterone
    DOI:  https://doi.org/10.3390/foods12173219
  4. J Pediatr Gastroenterol Nutr. 2023 Sep 08.
    Ketogenic diets in children with intractable epilepsy and its effects on gastrointestinal function, gut microbiome, inflammation, and quality of life.
    Jessica Menzies, Alamelu Sundararaj, Michael Cardamone, Alexandra McHarg, Steven T Leach, Usha Krishnan.
       OBJECTIVES: The ketogenic diet (KD) is a treatment for children with intractable epilepsy (IE), it can cause gastrointestinal symptoms, and have an adverse effect on growth, nutrition and quality of life (QOL). This study investigated the extent of these side-effects by comparing children with IE on KDs to their counterparts on normal diets.
    METHODS: Patients with IE were categorised into patients with KD or control groups. Gastrointestinal side effects and QOL were assessed using the PedsQL™ Gastrointestinal Symptoms Module. Cross sectional growth, gut microbiome compositions and inflammation levels were also analysed.
    RESULTS: Fourteen patients on the KD and 13 control patients were enrolled. Patients had been on KD for a median duration of 15 months (Interquartile range (IQR): 9.8 to 60 months). The patients on the KD reported a trend to lower total gastrointestinal symptoms scores (more symptoms) compared to control patients, at 71.1 and 84.9 respectively (p=0.06, not significant). Patients on the KD had significantly lower QOL scores compared to control patients(p=0.01). Patients on the KD were found to have consistently lower median height/length, weight and Body mass index (BMI) z scores compared to the controls although these were not statistically significant. Patients on the KD had a lower microbial diversity, Both groups had a normal level of S100A12, a marker of gut inflammation.
    CONCLUSIONS: Patients on the KD reported a trend to more gastrointestinal symptoms and more QOL concerns compared to controls. Although microbial differences were noted in patients on the KD, this did not result in detectable gut inflammation.
    DOI:  https://doi.org/10.1097/MPG.0000000000003928
  5. bioRxiv. 2023 Aug 24. pii: 2023.08.23.554428. [Epub ahead of print]
    D - β -hydroxybutyrate stabilizes the hippocampal CA3-CA1 circuit during acute insulin resistance.
    Bartosz Kula, Botond Antal, Corey Weistuch, Florian Gackière, Alexander Barre, Victor Velado, Jeffrey M Hubbard, Maria Kukley, Lilianne R Mujica-Parodi, Nathan A Smith.
      The brain primarily relies on glycolysis for mitochondrial respiration but switches to alternative fuels such as ketone bodies (KB) during low glucose availability. Neuronal KB uptake, which does not rely on the glucose transporter 4 (GLUT4) and insulin, has shown promising clinical applications in alleviating the neurological and cognitive effects of disorders with hypometabolic components. However, the specific mechanisms by which such interventions affect neuronal functions are poorly understood. In this study, we pharmacologically blocked GLUT4 to investigate the effects of the exogenous KB D-β-hydroxybutyrate (D-βHb) on mouse brain metabolism during acute insulin resistance (AIR). We found the impacts of AIR and D-βHb to be qualitatively distinct across neuronal compartments: AIR decreased synaptic activity and LTP, and impaired axonal conduction, synchronization, and action potential (AP) properties. D-βHb rescued neuronal functions connected to axonal conduction and synchronization but did not rescue synaptic activity. While D-βHB failed to rescue synaptic activity, it successfully rescued neuronal functions associated with axonal conduction and synchronization. Teaser: D-βHb reverses detrimental effects of acute insulin resistance in the hippocampus, with distinct effects on soma, dendrites, and axons.
    DOI:  https://doi.org/10.1101/2023.08.23.554428
  6. Eur J Microbiol Immunol (Bp). 2023 Sep 04.
    The impact of ketogenic diet on the onset and progression of multiple sclerosis.
    Jurij D Brockhoff, Stefan Bereswill, Markus M Heimesaat.
      Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) characterized by inflammation and neurodegeneration. Current research suggests that diet may influence disease course, severity of symptoms, and quality of life in MS patients. The ketogenic diet (KD) has been used for more than a century as a therapeutic approach for various medical conditions. It was originally developed in the 1920s as a treatment option for epilepsy, and especially in the last 30 years, has gained popularity for its potential benefits in a variety of neurological conditions other than epilepsy. This prompted us to perform a literature survey regarding the effect of KD on the onset and progression of MS. The here reviewed 15 original research articles including in vitro, preclinical, and clinical studies provide evidence for the safety and feasibility of the KD in MS, showing potential neuroprotective effects and positive impacts on cellular metabolism and disease outcome. Since the literature is limited and most studies were conducted with low numbers of MS patients and rather exploratory in nature, further studies with larger cohorts are needed to gain a better understanding of the mechanisms by which the improvements of the MS disease course are achieved.
    Keywords:  Ketogenic diet; cuprizone (CPZ) model; demyelinating autoimmune diseases in CNS; experimental autoimmune encephalomyelitis (EAE) model; multiple sclerosis; neuroprotective effects
    DOI:  https://doi.org/10.1556/1886.2023.00020
  7. BMC Med. 2023 Sep 04. 21(1): 340
    Triangulating evidence from observational and Mendelian randomization studies of ketone bodies for cognitive performance.
    UCLEB Consortium
       BACKGROUND: Ketone bodies (KBs) are an alternative energy supply for brain functions when glucose is limited. The most abundant ketone metabolite, 3-β-hydroxybutyrate (BOHBUT), has been suggested to prevent or delay cognitive impairment, but the evidence remains unclear. We triangulated observational and Mendelian randomization (MR) studies to investigate the association and causation between KBs and cognitive function.
    METHODS: In observational analyses of 5506 participants aged ≥ 45 years from the Whitehall II study, we used multiple linear regression to investigate the associations between categorized KBs and cognitive function scores. Two-sample MR was carried out using summary statistics from an in-house KBs meta-analysis between the University College London-London School of Hygiene and Tropical Medicine-Edinburgh-Bristol (UCLEB) Consortium and Kettunen et al. (N = 45,031), and publicly available summary statistics of cognitive performance and Alzheimer's disease (AD) from the Social Science Genetic Association Consortium (N = 257,841), and the International Genomics of Alzheimer's Project (N = 54,162), respectively. Both strong (P < 5 × 10-8) and suggestive (P < 1 × 10-5) sets of instrumental variables for BOHBUT were applied. Finally, we performed cis-MR on OXCT1, a well-known gene for KB catabolism.
    RESULTS: BOHBUT was positively associated with general cognitive function (β = 0.26, P = 9.74 × 10-3). In MR analyses, we observed a protective effect of BOHBUT on cognitive performance (inverse variance weighted: βIVW = 7.89 × 10-2, PIVW = 1.03 × 10-2; weighted median: βW-Median = 8.65 × 10-2, PW-Median = 9.60 × 10-3) and a protective effect on AD (βIVW =  - 0.31, odds ratio: OR = 0.74, PIVW = 3.06 × 10-2). Cis-MR showed little evidence of therapeutic modulation of OXCT1 on cognitive impairment.
    CONCLUSIONS: Triangulation of evidence suggests that BOHBUT has a beneficial effect on cognitive performance. Our findings raise the hypothesis that increased BOHBUT may improve general cognitive functions, delaying cognitive impairment and reducing the risk of AD.
    Keywords:  Alzheimer’s disease; Cognitive performance; Ketone bodies; Mendelian randomization
    DOI:  https://doi.org/10.1186/s12916-023-03047-7
  8. J Clin Med. 2023 Aug 29. pii: 5628. [Epub ahead of print]12(17):
    Mitochondrial Dysfunction and Sarcopenic Obesity: The Role of Exercise.
    Spyridon Hadjispyrou, Antonios Giannopoulos, Anastassios Philippou, Apostolos Theos.
      Sarcopenic obesity (SO) constitutes the coexistence of skeletal muscle mass loss (sarcopenia) and excess adiposity (obesity). It is mainly considered as a condition in the elderly with health-threatening impacts ranging from frailty to mortality. Mitochondrial dysfunction consists one of the basic pathophysiological mechanisms leading to the development of SO and its consequences. Indirect indicators of mitochondrial function, such as VO2max and exercise capacity, have been demonstrated to be negatively affected in individuals with SO, while the positive effect of exercise on mitochondrial function has been widely proved; thus, in this review, we aimed at investigating the effects of endurance, resistance, and concurrent exercise training on indexes of mitochondrial dysfunction in SO patients. The results of the clinical trials evaluated reveal positive effects of chronic exercise on VO2max and physical capacity, as well as mitochondrial biogenesis and activity. It has been concluded that utilizing a systematic exercise training program that includes both aerobic and strength exercises can be an effective strategy for managing SO and promoting overall health in these patients.
    Keywords:  VO2max; mitochondria; physical capacity; sarcopenia; training
    DOI:  https://doi.org/10.3390/jcm12175628
  9. Mol Psychiatry. 2023 Sep 05.
    Targeting NLRP3 inflammasome for neurodegenerative disorders.
    Jing Yao, Zhe Wang, Weihong Song, Yun Zhang.
      Neuroinflammation is a key pathological feature in neurological diseases, including Alzheimer's disease (AD). The nucleotide-binding domain leucine-rich repeat-containing proteins (NLRs) belong to the pattern recognition receptors (PRRs) family that sense stress signals, which play an important role in inflammation. As a member of NLRs, the NACHT, LRR and PYD domains-containing protein 3 (NLRP3) is predominantly expressed in microglia, the principal innate immune cells in the central nervous system (CNS). Microglia release proinflammatory cytokines to cause pyroptosis through activating NLRP3 inflammasome. The active NLRP3 inflammasome is involved in a variety of neurodegenerative diseases (NDs). Recent studies also indicate the key role of neuronal NLRP3 in the pathogenesis of neurological disorders. In this article, we reviewed the mechanisms of NLRP3 expression and activation and discussed the role of active NLRP3 inflammasome in the pathogenesis of NDs, particularly focusing on AD. The studies suggest that targeting NLRP3 inflammasome could be a novel approach for the disease modification.
    DOI:  https://doi.org/10.1038/s41380-023-02239-0
  10. Cell Death Dis. 2023 Sep 07. 14(9): 597
    Metabolic intervention by low carbohydrate diet suppresses the onset and progression of neuroendocrine tumors.
    Yu Chen, Tatsuki Yamamoto, Yura Takahashi, Tomoka Moro, Tomoko Tajima, Yukiko Sakaguchi, Naoaki Sakata, Akihiko Yokoyama, Susumu Hijioka, Akane Sada, Yuko Tabata, Rieko Ohki.
      Insulin signaling often plays a role in the regulation of cancer, including tumor initiation, progression, and response to treatment. In addition, the insulin-regulated PI3K-Akt-mTOR pathway plays an important role in the regulation of islet cell proliferation, and this pathway is hyperactivated in human non-functional pancreatic neuroendocrine tumors (PanNETs). We, therefore, investigated the effect of a very low carbohydrate diet (ketogenic diet) on a mouse model that develops non-functional PanNETs to ask how reduced PI3K-Akt-mTOR signaling might affect the development and progression of non-functional PanNET. We found that this dietary intervention resulted in lower PI3K-Akt-mTOR signaling in islet cells and a significant reduction in PanNET formation and progression. We also found that this treatment had a significant effect on the suppression of pituitary NET development. Furthermore, we found that non-functional PanNET patients with lower blood glucose levels tend to have a better prognosis than patients with higher blood glucose levels. This preclinical study shows that a dietary intervention that results in lower serum insulin levels leads to lower insulin signals within the neuroendocrine cells and has a striking suppressive effect on the development and progression of both pancreatic and pituitary NETs.
    DOI:  https://doi.org/10.1038/s41419-023-06123-1
  11. Int J Mol Sci. 2023 Aug 23. pii: 13090. [Epub ahead of print]24(17):
    Sodium Butyrate as Key Regulator of Mitochondrial Function and Barrier Integrity of Human Glomerular Endothelial Cells.
    Maria Novella Nicese, Roel Bijkerk, Anton Jan Van Zonneveld, Bernard M Van den Berg, Joris I Rotmans.
      The gut microbiota has emerged as an important modulator of cardiovascular and renal homeostasis. The composition of gut microbiota in patients suffering from chronic kidney disease (CKD) is altered, where a lower number of bacteria producing short chain fatty acids (SCFAs) is observed. It is known that SCFAs, such as butyrate and acetate, have protective effects against cardiovascular diseases and CKD but their mechanisms of action remain largely unexplored. In the present study, we investigated the effect of butyrate and acetate on glomerular endothelial cells. Human glomerular microvascular endothelial cells (hgMVECs) were cultured and exposed to butyrate and acetate and their effects on cellular proliferation, mitochondrial mass and metabolism, as well as monolayer integrity were studied. While acetate did not show any effects on hgMVECs, our results revealed that butyrate reduces the proliferation of hgMVECs, strengthens the endothelial barrier through increased expression of VE-cadherin and Claudin-5 and promotes mitochondrial biogenesis. Moreover, butyrate reduces the increase in oxygen consumption induced by lipopolysaccharides (LPS), revealing a protective effect of butyrate against the detrimental effects of LPS. Taken together, our data show that butyrate is a key player in endothelial integrity and metabolic homeostasis.
    Keywords:  LPS; butyrate; endothelial barrier; glomerular endothelial cells; mitochondria; proliferation; seahorse; short chain fatty acids
    DOI:  https://doi.org/10.3390/ijms241713090
  12. Cells. 2023 Aug 30. pii: 2183. [Epub ahead of print]12(17):
    Mitochondrial Properties in Skeletal Muscle Fiber.
    Han Dong, Shih-Yin Tsai.
      Mitochondria are the primary source of energy production and are implicated in a wide range of biological processes in most eukaryotic cells. Skeletal muscle heavily relies on mitochondria for energy supplements. In addition to being a powerhouse, mitochondria evoke many functions in skeletal muscle, including regulating calcium and reactive oxygen species levels. A healthy mitochondria population is necessary for the preservation of skeletal muscle homeostasis, while mitochondria dysregulation is linked to numerous myopathies. In this review, we summarize the recent studies on mitochondria function and quality control in skeletal muscle, focusing mainly on in vivo studies of rodents and human subjects. With an emphasis on the interplay between mitochondrial functions concerning the muscle fiber type-specific phenotypes, we also discuss the effect of aging and exercise on the remodeling of skeletal muscle and mitochondria properties.
    Keywords:  mitochondria; skeletal muscle physiology
    DOI:  https://doi.org/10.3390/cells12172183
  13. Signal Transduct Target Ther. 2023 Sep 06. 8(1): 333
    Mitochondrial dynamics in health and disease: mechanisms and potential targets.
    Wen Chen, Huakan Zhao, Yongsheng Li.
      Mitochondria are organelles that are able to adjust and respond to different stressors and metabolic needs within a cell, showcasing their plasticity and dynamic nature. These abilities allow them to effectively coordinate various cellular functions. Mitochondrial dynamics refers to the changing process of fission, fusion, mitophagy and transport, which is crucial for optimal function in signal transduction and metabolism. An imbalance in mitochondrial dynamics can disrupt mitochondrial function, leading to abnormal cellular fate, and a range of diseases, including neurodegenerative disorders, metabolic diseases, cardiovascular diseases and cancers. Herein, we review the mechanism of mitochondrial dynamics, and its impacts on cellular function. We also delve into the changes that occur in mitochondrial dynamics during health and disease, and offer novel perspectives on how to target the modulation of mitochondrial dynamics.
    DOI:  https://doi.org/10.1038/s41392-023-01547-9
  14. Philos Trans R Soc Lond B Biol Sci. 2023 Oct 23. 378(1888): 20220211
    Carbohydrate-insulin model: does the conventional view of obesity reverse cause and effect?
    David S Ludwig.
      Conventional obesity treatment, based on the First Law of Thermodynamics, assumes that excess body fat gain is driven by overeating, and that all calories are metabolically alike in this regard. Hence, to lose weight one must ultimately eat less and move more. However, this prescription rarely succeeds over the long term, in part because calorie restriction elicits predictable biological responses that oppose ongoing weight loss. The carbohydrate-insulin model posits the opposite causal direction: overeating doesn't drive body fat increase; instead, the process of storing excess fat drives overeating. A diet high in rapidly digestible carbohydrates raises the insulin-to-glucagon ratio, shifting energy partitioning towards storage in adipose, leaving fewer calories for metabolically active and fuel sensing tissues. Consequently, hunger increases, and metabolic rate slows in the body's attempt to conserve energy. A small shift in substrate partitioning though this mechanism could account for the slow but progressive weight gain characteristic of common forms of obesity. From this perspective, the conventional calorie-restricted, low-fat diet amounts to symptomatic treatment, failing to target the underlying predisposition towards excess fat deposition. A dietary strategy to lower insulin secretion may increase the effectiveness of long-term weight management and chronic disease prevention. This article is part of a discussion meeting issue 'Causes of obesity: theories, conjectures and evidence (Part II)'.
    Keywords:  carbohydrate; diet; insulin; macronutrients; obesity; scientific models
    DOI:  https://doi.org/10.1098/rstb.2022.0211
  15. Int J Numer Method Biomed Eng. 2023 Sep 09. e3770
    Effect of mitochondrial circulation on mitochondrial age density distribution.
    Ivan A Kuznetsov, Andrey V Kuznetsov.
      Recent publications report that although the mitochondria population in an axon can be quickly replaced by a combination of retrograde and anterograde axonal transport (often within less than 24 hours), the axon contains much older mitochondria. This suggests that not all mitochondria that reach the soma are degraded and that some are recirculating back into the axon. To explain this, we developed a model that simulates mitochondria distribution when a portion of mitochondria that return to the soma are redirected back to the axon rather than being destroyed in somatic lysosomes. Utilizing the developed model, we studied how the percentage of returning mitochondria affects the mean age and age density distributions of mitochondria at different distances from the soma. We also investigated whether turning off the mitochondrial anchoring switch can reduce the mean age of mitochondria. For this purpose, we studied the effect of reducing the value of a parameter that characterizes the probability of mitochondria transition to the stationary (anchored) state. The reduction in mitochondria mean age observed when the anchoring probability is reduced suggests that some injured neurons may be saved if the percentage of stationary mitochondria is decreased. The replacement of possibly damaged stationary mitochondria with newly synthesized ones may restore the energy supply in an injured axon. We also performed a sensitivity study of the mean age of stationary mitochondria to the parameter that determines what portion of mitochondria re-enter the axon and the parameter that determines the probability of mitochondria transition to the stationary state. The sensitivity of the mean age of stationary mitochondria to the mitochondria stopping probability increases linearly with the number of compartments in the axon. High stopping probability in long axons can significantly increase mitochondrial age.
    Keywords:  age density distribution; axonal transport; mathematical modeling; mean age; neurons
    DOI:  https://doi.org/10.1002/cnm.3770
  16. Int J Mol Sci. 2023 Aug 31. pii: 13536. [Epub ahead of print]24(17):
    Reduced Expression of Septin7 Hinders Skeletal Muscle Regeneration.
    László Szabó, Andrea Telek, János Fodor, Nóra Dobrosi, Klaudia Dócs, Zoltán Hegyi, Mónika Gönczi, László Csernoch, Beatrix Dienes.
      Septins are considered the fourth component of the cytoskeleton with the septin7 isoform playing a critical role in the formation of diffusion barriers in phospholipid bilayers and intra- and extracellular scaffolds. While its importance has already been confirmed in different intracellular processes, very little is known about its role in skeletal muscle. Muscle regeneration was studied in a Sept7 conditional knock-down mouse model to prove the possible role of septin7 in this process. Sterile inflammation in skeletal muscle was induced which was followed by regeneration resulting in the upregulation of septin7 expression. Partial knock-down of Sept7 resulted in an increased number of inflammatory cells and myofibers containing central nuclei. Taken together, our data suggest that partial knock-down of Sept7 hinders the kinetics of muscle regeneration, indicating its crucial role in skeletal muscle functions.
    Keywords:  central nuclei; muscle injury; regeneration; septin7; skeletal muscle
    DOI:  https://doi.org/10.3390/ijms241713536
  17. Foods. 2023 Aug 26. pii: 3214. [Epub ahead of print]12(17):
    Validation of an Italian Questionnaire of Adherence to the Ketogenic Dietary Therapies: iKetoCheck.
    Lenycia de Cassya Lopes Neri, Monica Guglielmetti, Valentina De Giorgis, Ludovica Pasca, Martina Paola Zanaboni, Claudia Trentani, Elena Ballante, Serena Grumi, Cinzia Ferraris, Anna Tagliabue, On Behalf Of The KDTs Delphi Validation Study Group.
      Ketogenic dietary therapies (KDTs) are an effective and safe non-pharmacological treatment for drug-resistant epilepsy, but adherence can be challenging for both patients and caregivers. In Europe, there are no adequate tools to measure it other than monitoring ketosis. This study aimed to adapt and validate the Brazilian adherence questionnaire, Keto-check, into the Italian version: iKetoCheck. Using the Delphi technique, 12 judges validated the contents through agreement rates and the Content Validity Index (CVI). The iKetocheck was self-completed electronically by 61 drug-resistant epilepsy or GLUT1 deficiency patients within an interval of 15 days to measure its reproducibility. The test-retest reliability was evaluated using Pearson's correlation and relative significance test. Exploratory and confirmatory factorial analyses were made using Factor software version 12.03.02. The final tool, iKetoCheck, consists of 10 questions with 5-point Likert scale answers. It evaluates various aspects such as informing caregivers about the diet, organization of meals, measurement of ketosis, weighing food consumed, diet negligence, use of carbohydrate-free medications, attending follow-up visits, reading food labels, consulting an expert for dietary concerns, and cooking at home. The factorial analysis resulted in three factors: "attention," "organization," and "precision," with satisfactory results for indices in exploratory and confirmatory analyses. Although higher mean values of ketonemia measurement were observed in patients with a higher adherence score, these values were not statistically significant (p = 0.284). In conclusion, despite the small sample size, iKetoCheck is a valid tool for evaluating KDTs' adherence in Italian drug-resistant epilepsy or GLUT1 deficiency patients. It can provide valuable information to improve patient management and optimize the effectiveness of KDTs.
    Keywords:  GLUT1 deficiency; adherence; epilepsy; ketogenic diet; patient compliance; treatment adherence and compliance
    DOI:  https://doi.org/10.3390/foods12173214
  18. Sci Rep. 2023 Sep 05. 13(1): 14629
    HMGCS2 serves as a potential biomarker for inhibition of renal clear cell carcinoma growth.
    Huajie Mao, Runzhi Wang, Fengling Shao, Ming Zhao, Dayu Tian, Hua Xia, Ya Zhao.
      3-Hydroxymethylglutaryl-CoA synthase 2 (HMGCS2) is the rate-limiting enzyme for ketone body synthesis, and most current studies focus on mitochondrial maturation and metabolic reprogramming. The role of HMGCS2 was evaluated in a pan-cancer multi-database using R language, and HMGCS2 was lowly expressed or not differentially expressed in all tumor tissues compared with normal tissues. Correlation analysis of clinical case characteristics, genomic heterogeneity, tumor stemness, and overall survival revealed that HMGCS2 is closely related to clear cell renal cell carcinoma (KIRC). Single-cell sequencing data from normal human kidneys revealed that HMGCS2 is specifically expressed in proximal tubular cells of normal adults. In addition, HMGCS2 is associated with tumor immune infiltration and microenvironment, and KIRC patients with low expression of HMGCS2 have worse prognosis. Finally, the results of cell counting kit 8 assays, colony formation assays, flow cytometry, and Western blot analysis suggested that upregulation of HMGCS2 increased the expression of key tumor suppressor proteins, inhibited the proliferation of clear cell renal cell carcinoma cells and promoted cell apoptosis. In conclusion, HMGCS2 is abnormally expressed in pan-cancer, may play an important role in anti-tumor immunity, and is expected to be a potential tumor prognostic marker, especially in clear cell renal cell carcinoma.
    DOI:  https://doi.org/10.1038/s41598-023-41343-7
  19. BMB Rep. 2023 Sep 08. pii: 5938. [Epub ahead of print]
    Fatty acid oxidation regulates cellular senescence by modulating the autophagy-SIRT1 axis.
    Seungyeon Yang, Subin Moon, Soojung Claire Hur, Seung Min Jeong.
      Senescence, a cellular process through which damaged or dysfunctional cells suppress their cell cycle, contributes to aging or age-related functional declines. Cell metabolism has been closely correlated with aging processes and it is widely recognized that metabolic changes underlie cellular alterations with aging. Here, we report that fatty acid oxidation (FAO) serves as a critical regulator of cellular senescence and uncover the underlying mechanism by which FAO inhibition induces senescence. Pharmacological or genetic ablation of FAO results in a p53-dependent induction of cellular senescence in human fibroblasts, whereas enhancing FAO suppresses replicative senescence. We find that FAO inhibition promotes cellular senescence through acetyl-CoA, independent of energy depletion. Mechanistically, the increased formation of autophagosome following FAO inhibition leads to a reduction in SIRT1 protein levels, thereby contributing to senescence induction. Finally, we find that the inhibition of autophagy or the enforced expression of SIRT1 can rescue the induction of senescence as a result of FAO inhibition. Collectively, our study reveals a distinctive role for the FAO-autophagy-SIRT1 axis in the regulation of cellular senescence.
  20. Nutrients. 2023 Sep 04. pii: 3854. [Epub ahead of print]15(17):
    Recent Advances in Nutraceuticals for the Treatment of Sarcopenic Obesity.
    Young-Chan Kim, Sang-Woo Ki, Hannah Kim, Sumin Kang, Hayoon Kim, Gwang-Woong Go.
      Sarcopenic obesity, low muscle mass, and high body fat are growing health concerns in the aging population. This review highlights the need for standardized criteria and explores nutraceuticals as potential therapeutic agents. Sarcopenic obesity is associated with insulin resistance, inflammation, hormonal changes, and reduced physical activity. These factors lead to impaired muscle activity, intramuscular fat accumulation, and reduced protein synthesis, resulting in muscle catabolism and increased fat mass. Myostatin and irisin are myokines that regulate muscle synthesis and energy expenditure, respectively. Nutritional supplementation with vitamin D and calcium is recommended for increasing muscle mass and reducing body fat content. Testosterone therapy decreases fat mass and improves muscle strength. Vitamin K, specifically menaquinone-4 (MK-4), improves mitochondrial function and reduces muscle damage. Irisin is a hormone secreted during exercise that enhances oxidative metabolism, prevents insulin resistance and obesity, and improves bone quality. Low-glycemic-index diets and green cardamom are potential methods for managing sarcopenic obesity. In conclusion, along with exercise and dietary support, nutraceuticals, such as vitamin D, calcium, vitamin K, and natural agonists of irisin or testosterone, can serve as promising future therapeutic alternatives.
    Keywords:  irisin; mitochondrial function; nutraceutical; sarcopenic obesity
    DOI:  https://doi.org/10.3390/nu15173854
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