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Fasting has long-lasting effects on the daily rhythmicity in spontaneous locomotor activity. a Experimental timeline. b Weight change (%) before (pre-fasting) and after 48 h fasting (post-fasting), and during the refeeding phase at two different time points: 5 days after the refeeding (refeeding T1), 10 days after the refeeding (refeeding T2) (AL N = 6, F N = 6, two-way RM ANOVA time*treatment, interaction F3,30 = 78.35 p < 0.0001, post-hoc Sidak, AL vs F (post-fasting) t40 = 12.7 p < 0.0001. Gray square represents the fasting period. c Representative trace of the locomotor activity of a single mouse in the time domain (top) and in the frequency domain (bottom). c Relative power of the circadian oscillation (total power between 0.9 and 1.1 cycles per day) in AL and FAST mice in three epochs: before fasting (Pre-fast), first 5 days of refeeding (T1) and second 5 days of refeeding (T2). (N = 6 per condition, two-way RM ANOVA time*treatment, interaction F2,20 = 4.11 p = 0.032, post-hoc Holm Sidak, AL vs FAST (Pre-fast) T30 = 0.598 p = 0.555, AL vs FAST (T1) T30 = 3.768 p = 0.002, AL vs FAST (T2) T30 = 3.274 p = 0.005). Error bars represent SEM
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Little is known about the impact of metabolic stimuli on brain tissue at a molecular level. The ketone body beta-hydroxybutyrate (BHB) can be a signaling molecule regulating gene transcription. Thus, we assessed lysine beta-hydroxybutyrylation (K-bhb) levels in proteins extracted from the cerebral cortex of mice undergoing a ketogenic metabolic cha...
Citations
... Interestingly, no changes in cortical expression of these genes were observed compared to the control group after re-feeding. Thus, results suggest that BHB plays a powerful epigenetic molecular role through direct and specific histone markers in nervous tissue [72]. ...
Previous studies have found that β-Hydroxybutyrate (BHB), the main component of ketone bodies, is of physiological importance as a backup energy source during starvation or induces diabetic ketoacidosis when insulin deficiency occurs. Ketogenic diets (KD) have been used as metabolic therapy for over a hundred years, it is well known that ketone bodies and BHB not only serve as ancillary fuel substituting for glucose but also induce anti-oxidative, anti-inflammatory, and cardioprotective features via binding to several target proteins, including histone deacetylase (HDAC), or G protein-coupled receptors (GPCRs). Recent advances in epigenetics, especially novel histone post-translational modifications (HPTMs), have continuously updated our understanding of BHB, which also acts as a signal transduction molecule and modification substrate to regulate a series of epigenetic phenomena, such as histone acetylation, histone β-hydroxybutyrylation, histone methylation, DNA methylation, and microRNAs. These epigenetic events alter the activity of genes without changing the DNA structure and further participate in the pathogenesis of related diseases. This review focuses on the metabolic process of BHB and BHB-mediated epigenetics in cardiovascular diseases, diabetes and complications of diabetes, neuropsychiatric diseases, cancers, osteoporosis, liver and kidney injury, embryonic and fetal development, and intestinal homeostasis, and discusses potential molecular mechanisms, drug targets, and application prospects.
... The liver simultaneously releases antiinflammatory substances under certain conditions. For example, in animals that butyrate, one of the ketone bodies released by the liver of animals after a fasting period, reaches the brain and binds to numerous gene sites with anti-inflammatory effects (Cornuti et al., 2023). ...
... The rise of the physiological levels of ketone bodies whether induced by KD, starvation or the administration of BHB or its derivatives, has an impact in genome regulation and therefore in the protein content (Xie et al., 2016;Cornuti et al., 2023). ...
... The β-hydroxybutyrylation of lysine 9 in histone 3 (H3K9bhb) is the most extensively studied Kbhb mark, known to be highly responsive to changes in BHB levels (Terranova et al., 2021). It is enriched in response to high KBs levels in the liver, kidney, brain, heart and the cell lines HEK293T and MEF (Xie et al., 2016;Huang et al., 2021;Koronowski et al., 2021;Hou et al., 2022;Cornuti et al., 2023;Luo et al., 2023). H3K9bhb has been related to the upregulation of a vast set of genes specific of each cell type or tissue. ...
... When endogenous ketosis is induced in mice by 2-days starvation after post-weaning, H3K9bhb is increased in the cerebral cortex, where it changes the expression of genes related to circadian rhythms, neurogenesis, dendrite morphogenesis, chromatin remodeling, and synaptic transmission, among others. Furthermore, the changes in clock-core genes are correlated with altered locomotor circadian rhythmicity (Cornuti et al., 2023), suggesting that fasting can alter circadian rhythmicity of locomotor activity. ...
A growing body of evidence supports the beneficial effects of the ketone bodies (KBs), acetoacetate and β-hydroxybutyrate (BHB), on diverse physiological processes and diseases. Hence, KBs have been suggested as therapeutic tools for neurodegenerative diseases. KBs are an alternative fuel during fasting and starvation as they can be converted to Ac-CoA to produce ATP. A ketogenic diet (KD), enriched in fats and low in carbohydrates, induces KB production in the liver and favors their use in the brain. BHB is the most abundant KB in the circulation; in addition to its role as energy fuel, it exerts many actions that impact the set of proteins in the cell and tissue. BHB can covalently bind to proteins in lysine residues as a new post-translational modification (PTM) named β-hydroxybutyrylation (Kbhb). Kbhb has been identified in many proteins where Kbhb sites can be critical for binding to other proteins or cofactors. Kbhb is mostly found in proteins involved in chromatin structure, DNA repair, regulation of spliceosome, transcription, and oxidative phosphorylation. Histones are the most studied family of proteins with this PTM, and H3K9bhb is the best studied histone mark. Their target genes are mainly related to cell metabolism, chromatin remodeling and the control of circadian rhythms. The role of Kbhb on physiological processes is poorly known, but it might link KB metabolism to cell signaling and genome regulation. BHB also impacts the proteome by influencing proteostasis. This KB can modulate the Unfolded Protein Response (UPR) and autophagy, two processes involved in the maintenance of protein homeostasis through the clearance of accumulated unfolded and damaged proteins. BHB can support proteostasis and regulate the UPR to promote metabolism adaptation in the liver and prevent cell damage in the brain. Also, BHB stimulates autophagy aiding to the degradation of accumulated proteins. Protein aggregation is common to proteinopathies like Alzheimer’s (AD) and Parkinson’s (PD) diseases, where the KD and BHB treatment have shown favorable effects. In the present review, the current literature supporting the effects of KBs on proteome conformation and proteostasis is discussed, as well as its possible impact on AD and PD.
... Among the most studied Kbhb residues is histone 3 lysine 9 (H3K9) based on its association with active gene expression when it is acetylated (H3K9ac) at promoter regions 14 . To date, several studies have used H3K9bhb chromatin immunoprecipitation (ChIP) assays to identify BHB-regulated genes in the context of BHB-treatment, starvation, or ketogenic diet 10,[15][16][17][18][19][20]. ...
Ketone bodies are short chain fatty acids produced in the liver during periods of limited glucose availability that provide an alternative source of energy for the brain, heart, and skeletal muscle. Beyond this classical metabolic role, β-hydroxybutyrate (BHB), is gaining recognition as a pleiotropic signaling molecule. Lysine β-hydroxybutyrylation (Kbhb) is a newly discovered post-translational modification in which BHB is covalently attached to lysine ε-amino groups. This novel protein adduct is metabolically sensitive, dependent on BHB concentration, and found on proteins in multiple intracellular compartments, including the mitochondria and nucleus. Therefore, Kbhb is hypothesized to be an important component of ketone body-regulated physiology. Kbhb on histones is proposed to be an epigenetic regulator, which links metabolic alterations to gene expression. However, we found that the widely used antibody against the β-hydroxybutyrylated lysine 9 on histone H3 (H3K9bhb) also recognizes other modification(s), which are increased by deacetylation inhibition and include likely acetylations. Therefore, caution must be used when interpreting gene regulation data acquired with the H3K9bhb antibody.
Ketone bodies (KBs), such as acetoacetate and β-hydroxybutyrate, serve as crucial alternative energy sources during glucose deficiency. KBs, generated through ketogenesis in the liver, are metabolized into acetyl-CoA in extrahepatic tissues, entering the tricarboxylic acid cycle and electron transport chain for ATP production. Reduced glucose metabolism and mitochondrial dysfunction correlate with increased neuronal death and brain damage during cerebral ischemia and neurodegeneration. Both KBs and the ketogenic diet (KD) demonstrate neuroprotective effects by orchestrating various cellular processes through metabolic and signaling functions. They enhance mitochondrial function, mitigate oxidative stress and apoptosis, and regulate epigenetic and post-translational modifications of histones and non-histone proteins. Additionally, KBs and KD contribute to reducing neuroinflammation and modulating autophagy, neurotransmission systems, and gut microbiome. This review aims to explore the current understanding of the molecular mechanisms underpinning the neuroprotective effects of KBs and KD against brain damage in cerebral ischemia and neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease.
Parkinson’s disease (PD) is an age-related neurodegenerative disorder characterized by the degeneration of the nigrostriatal dopaminergic neurons, and by intraneuronal accumulation of aggregated α-synuclein (aSyn). Environmental factors contribute significantly to neurodegeneration in patients, and non-pharmacological interventions are increasingly explored. Among these, caloric restriction and time-restricted feeding have demonstrated beneficial effects in animal models of neurodegenerative diseases. The ketone body β-hydroxybutyrate (BHB) has been suggested to mediate some of these effects.
In this study, we tested the therapeutic potential of intermittent fasting (IF, every other day feeding) in an aSyn-based mouse model of PD. IF was initiated four weeks after induction of aSyn pathology. Four weeks of IF mitigated the aSyn-induced degeneration of dopaminergic neurons and axon terminals. IF also reduced aSyn pathology as reported by staining for phosphorylated aSyn and Triton X-100 solubility. IF mitigated the aSyn-induced motor phenotype, the decrease in striatal dopamine and the decrease in synaptic markers. Mechanistically, we observed an increased expression of the neurotrophin BDNF in the striatum and a shift in microglia activation towards an anti-inflammatory phenotype. In addition, IF induced neuronal autophagy, and we observed more aSyn in the expanded autolysosomal compartment. Furthermore, both starvation and BHB, but not BDNF, induced autophagy and reduced αSyn pathology in primary mouse neurons.
Taken together, IF might constitute a plausible neuroprotective strategy for patients with Parkinson’s diseases. BHB-induced autophagy and altered neuroinflammation are pathways that potentially contribute to the protective effect.
Ketone bodies are short-chain fatty acids produced in the liver during periods of limited glucose availability that provide an alternative energy source for the brain, heart, and skeletal muscle. Beyond this metabolic role, β-hydroxybutyrate (BHB), is gaining recognition as a signaling molecule. Lysine β-hydroxybutyrylation (Kbhb) is a newly discovered post-translational modification in which BHB is covalently attached to lysine ε-amino groups. This protein adduct is metabolically sensitive, dependent on BHB concentration, and found on proteins in multiple intracellular compartments. Therefore, Kbhb is hypothesized to be an important component of ketone body-regulated physiology. Kbhb on histones is proposed to be an epigenetic regulator, which links metabolic alterations to gene expression. However, we found that the widely used antibody against β-hydroxybutyrylated lysine 9 on histone H3 (H3K9bhb) also recognizes other modification(s) that likely include acetylation. Therefore, caution must be used when interpreting gene regulation data acquired with the H3K9bhb antibody.
Gli ultimi dieci anni di ricerca epigenetica possono essere sintetizzati in tre filoni principali. Abbiamo avanzamenti nella conoscenza: 1) dei meccanismi epigenetici, soprattutto dell'immenso mondo degli RNA non codificanti; 2) dell'epigenetica delle prime fasi della vita, inclusa l'epige- netica transgenerazionale; 3) degli effetti molecolari degli stati mentali e delle terapie non farmacologiche (come la psicoterapia e le tecniche di gestione dello stress) e dei comportamenti (nutrizione e attività fisica). L'articolo, che si basa sulla seconda edizione del libro Epigenetica e Psi- coneuroendocrinoimmunologia, scritto dagli Autori, passerà in rassegna questi argomenti con lo scopo di fornire una visione d'assieme dello stato della ricerca nel campo dell'epigenetica.
