bims-medica 2025-12-21 papers

bims-medica

Biomed News

on Metabolism and diet in cancer

Issue of 2025–12–21
twelve papers selected by
Brett Chrest, Wake Forest University

Combined ketone body and glutamine supplementation restores aerobic energy production in AGC1-deficient neuronal progenitors.
The fate of pyruvate dictates cell growth by modulating cellular redox potential.
Redox-dependent protein S-glutathionylation governs azacitidine sensitivity and resistance in AML.
Survival outcomes of rectal and head and neck cancer patients receiving radio(chemo)therapy with a ketogenic diet. A post-hoc analysis from the KETOCOMP trial.
Reductive death is averted by an ancient metabolic switch.
Biomarkers of glycolysis and the tricarboxylic acid (TCA) cycle in youth with and without obesity.
Metabolism Meets Epigenetics: β-Hydroxybutyrate-Driven Lysine β-Hydroxybutyrylation Bridging Energy Metabolism With Transcription and Protein Functional Remodeling.
Niclosamide nanoparticles enhance pancreatic cancer sensitivity to gemcitabine via HIF-1α inhibition.
NAMPT inhibition uncovers therapeutic vulnerabilities to venetoclax and chemotherapy in acute myelogenous leukemia.
Proton MRI and MRSI as a Superior Methodology to Assess Oxidative Phosphorylation.
A green lifetime biosensor for calcium that remains bright over its full dynamic range.
Succinate Modulation as a Biochemical Correlate of Metabolic and Neurobehavioral Changes Associated With Intermittent Fasting in Obesity.

Cell Death Dis. 2025 Dec 15.

Combined ketone body and glutamine supplementation restores aerobic energy production in AGC1-deficient neuronal progenitors.

Simona Nicole Barile, Maria Chiara Magnifico, Eleonora Poeta, Felix Distelmaier, Luigi Viggiano, Nicola Balboni, Michele Protti, Sabrina Petralla, Antonella Pignataro, Giacomo Volpe, Monica De Luise, Massimo Bonora, Marica Antonicelli, Giorgia Babini, Francesca Massenzio, Vito Porcelli, Eleonora Lama, Roberto Arrigoni, Isabella Pisano, Veronica Addabbo, Anna Campana, Francesca Begnozzi, Stewart A Anderson, Giuseppe Fiermonte, Federico Manuel Giorgi, Paolo Pinton, Ferdinando Palmieri, Giuseppe Gasparre, Laura Mercolini, Luigi Palmieri, Douglas C Wallace, Julia Hentschel, Barbara Monti, Francesco Massimo Lasorsa.

AGC1 deficiency is a rare, early-onset encephalopathy caused by mutations in the SLC25A12 gene, encoding the mitochondrial aspartate/glutamate carrier isoform 1 (AGC1). Patients exhibit epileptic encephalopathy, cerebral hypomyelination, severe hypotonia, and global developmental delay. A hallmark biochemical feature of AGC1 deficiency is reduced brain N-acetylaspartate (NAA), a key metabolite involved in myelin lipid synthesis. However, the underlying mechanisms leading to the hypomyelinating phenotype remain unclear. In this study, we generated neuronal progenitors (NPs) derived from human-induced pluripotent stem cells (hiPSCs) of AGC1-deficient patients to investigate the metabolic and bioenergetic consequences of AGC1 loss. We demonstrated that AGC1-deficient NPs exhibit impaired proliferation, increased apoptosis, and a metabolic shift toward a hyperglycolytic phenotype due to defective mitochondrial pyruvate oxidation. RNA sequencing revealed downregulation of mitochondrial pyruvate carrier MPC1/2, limiting pyruvate-driven oxidative phosphorylation (OXPHOS) and reinforcing glycolysis as the primary energy source. Despite this metabolic shift, AGC1-deficient mitochondria retained the potential for OXPHOS when alternative anaplerotic substrates were provided. Notably, the administration of ketone bodies, in combination with glutamine, fully restored mitochondrial respiration, suggesting a mechanistic basis for the clinical improvements observed in AGC1-deficient patients undergoing ketogenic diet therapy. Our study highlights the importance of alternative metabolic pathways in maintaining neuronal energy homeostasis in AGC1 deficiency and offers insights into potential therapeutic strategies aimed at bypassing the mitochondrial pyruvate oxidation defect.

DOI: https://doi.org/10.1038/s41419-025-08314-4
Elife. 2025 Dec 16. pii: RP103705. [Epub ahead of print]13

The fate of pyruvate dictates cell growth by modulating cellular redox potential.

Ashish G Toshniwal, Geanette Lam, Alex J Bott, Ahmad A Cluntun, Rachel Skabelund, Hyuck-Jin Nam, Dona R Wisidagama, Carl S Thummel, Jared Rutter.

  Pyruvate occupies a central node in carbohydrate metabolism such that how it is produced and consumed can optimize a cell for energy production or biosynthetic capacity. This has been primarily studied in proliferating cells, but observations from the post-mitotic Drosophila fat body led us to hypothesize that pyruvate fate might dictate the rapid cell growth observed in this organ during development. Indeed, we demonstrate that augmented mitochondrial pyruvate import prevented cell growth in fat body cells in vivo as well as in cultured mammalian hepatocytes and human hepatocyte-derived cells in vitro. We hypothesize that this effect on cell size was caused by an increase in the NADH/NAD+ ratio, which rewired metabolism toward gluconeogenesis and suppressed the biomass-supporting glycolytic pathway. Amino acid synthesis was decreased, and the resulting loss of protein synthesis prevented cell growth. Surprisingly, this all occurred in the face of activated pro-growth signaling pathways, including mTORC1, Myc, and PI3K/Akt. These observations highlight the evolutionarily conserved role of pyruvate metabolism in setting the balance between energy extraction and biomass production in specialized post-mitotic cells.

Keywords:  D. melanogaster; cell biology; cell growth; genetics; hepatocytes; human; pyruvate metabolism; redox state; translation

DOI:  https://doi.org/10.7554/eLife.103705
Redox Biol. 2025 Dec 04. pii: S2213-2317(25)00471-9. [Epub ahead of print]89 103958

Redox-dependent protein S-glutathionylation governs azacitidine sensitivity and resistance in AML.

Dušan Nemes, Michaela Myšáková, Lubomír Minařík, Anna Jonášová, Tomáš Stopka, Kristýna Gloc Pimková.

  Disruption of redox metabolism is a hallmark of drug-resistant cancer cells, representing a major obstacle to the effective treatment of acute myeloid leukemia (AML). While recent studies have highlighted the importance of redox balance in AML therapy, the specific contribution of protein redox signaling to resistance remains poorly understood. Defining these mechanisms could uncover therapeutic vulnerabilities of resistant AML cells and guide the development of novel combination strategies. Here, we performed comprehensive mass spectrometry-based redox and quantitative proteomic profiling of AML cell lines and patient samples sensitive or resistant to the hypomethylating agent azacitidine (AZA). We demonstrate that AZA disrupts redox homeostasis, which inactivates the glyoxalase system and DNA damage response, and thereby induces cell death. In contrast, AZA resistance is associated with a redox reset characterized by elevated glutathione levels and diminished protein S-glutathionylation. Importantly, AZA failed to induce oxidation of proteins in these pathways in resistant cells and patient-derived AML samples. Pharmacological inhibition of glutathione synthesis restored protein S-glutathionylation and resensitized resistant AML cells to AZA.

Keywords:  Acute myeloid leukemia; Azacitidine; Cysteine oxidation; DNA damage; Drug resistance; Glyoxalase system; Hypomethylation therapy; Redox proteomics; S-glutathionylation

DOI:  https://doi.org/10.1016/j.redox.2025.103958
Strahlenther Onkol. 2025 Dec 17.

Survival outcomes of rectal and head and neck cancer patients receiving radio(chemo)therapy with a ketogenic diet. A post-hoc analysis from the KETOCOMP trial.

Rainer J Klement, Reinhart A Sweeney.

   PURPOSE: Ketogenic diets (KDs) have been proposed to target glycolytic cancer metabolism and synergize with radio- and chemotherapy. We herein report survival outcomes of rectal and head and neck cancer (HNC) patients who followed a KD during radio(chemo)therapy.
METHODS: Thirty-five patients on a KD during radiotherapy and 46 patients on a standard diet were prospectively followed. Overall (OS), progression-free (PFS), and locoregional recurrence-free survival (RFS) were analyzed with the Kaplan-Meier method and by computing restricted mean survival times. Acute radiotherapy-induced side effects were compared using Fisher's exact test. In an exploratory analysis, patients in the KD group were matched to control patients with propensity score matching, and survival analysis was performed.
RESULTS: Median follow-up was 77.4 (range 12.1-107.9; HNC) and 71.3 (1.5-127.1) months (rectal cancer), respectively. There were no significant differences in any survival outcome between the KD and control groups in either cohort. A numerically longer restricted mean RFS time for HNC patients did not reach the statistical significance threshold (KD: 100.5 months, 0 events; control group: 87.3 ± 7.0 months, 3 events; p = 0.059). In the propensity score-matched HNC sample, patients on a KD exhibited numerically longer OS (log-rank test: p = 0.084) and RFS (p = 0.064); however, these differences were not statistically significant. Acute skin toxicity was less severe in HNC patients on a KD (p = 0.063), which became significant in intention-to-treat analysis (p = 0.0495); all other acute toxicities were without significant differences between the groups.
CONCLUSION: Our analysis failed to detect a significant survival benefit of a KD during radio(chemo)therapy in HNC and rectal cancer patients, but provides further evidence for the safety of this approach.

Keywords:  Kaplan–Meier; Ketogenic metabolic therapy; Ketone bodies; Radiotherapy; Survival analysis

DOI:  https://doi.org/10.1007/s00066-025-02499-5
bioRxiv. 2025 Nov 25. pii: 2025.11.24.690166. [Epub ahead of print]

Reductive death is averted by an ancient metabolic switch.

Fasih M Ahsan, Jen F Rotti, Armen I Yerevanian, Sinclair W Emans, Nicole L Stuhr, Jose A Aceves-Salvador, Wei Wang, Daniel J Baker, Dimitra Pouli, Owen S Skinner, Michael D Blower, Alexander A Soukas.

Biguanides, including metformin, the world's most prescribed oral hypoglycemic, extend health-span and lifespan in vertebrates and invertebrates. Given the widespread use and apparent safety of metformin, it is assumed that its effects are not associated with toxicity, except when in marked excess. Here we determine that accumulation of damaging reducing equivalents is an unanticipated toxicity associated with biguanides, the defense against which requires post-transcriptional protection of de novo fatty acid biosynthesis. We demonstrate that biguanide treatment during impaired fatty acid biosynthesis drives NADPH toxicity, leading to catastrophic elevation of NADH/GSH reducing equivalents and accelerated death across metazoans. Multiple NADPH-generating interventions require fatty acid biosynthesis to prevent markedly shortened survival, indicating that this defense mechanism is broadly leveraged. We propose that fatty acid biosynthesis is a tunable rheostat which can minimize biguanide-induced reductive stress whilst maximizing its pro-longevity outcomes and serve as an exploitable vulnerability in reductive stress sensitive cancers.
HIGHLIGHTS: Biguanides inhibit cytosolic mRNA translation to extend lifespan in C. elegans . Fatty acid synthesis is translationally protected by eIF3 complex subunits. pod-2 / fasn-1 inactivation amplifies biguanide-induced reductive stress and death. NADPH-generating insults require fatty acid synthesis to buffer reductive stress.

DOI: https://doi.org/10.1101/2025.11.24.690166
Horm Res Paediatr. 2025 Dec 18. 1-13

Biomarkers of glycolysis and the tricarboxylic acid (TCA) cycle in youth with and without obesity.

Ermena Refugjati, Zhongyao Li, Giuseppina Rosaria Umano, Brittany Galuppo, Michelle Van Name, Stephanie Samuels, Gloria Kang, Emiliano Barbieri, Janice J Hwang, Nicola Santoro.

Given the rising prevalence of childhood obesity, it is critical to understand the metabolic consequences of excess adiposity in youth. In particular, investigating alterations in glycolysis and the tricarboxylic acid (TCA) cycle in youth with obesity is essential for elucidating the underlying mechanisms contributing to metabolic dysregulation in this population. Forty-eight adolescents and young adults aged 15-24 years had plasma obtained after a 12-hour fasting to measure levels of glucose, insulin, and TCA cycle intermediates: pyruvate, lactate, fumarate, malate, α-ketoglutarate, cis/trans aconitate, and isocitrate. Additionally, participants underwent an assessment of liver proton-density fat fraction (PDFF) and a 3-hour oral glucose tolerance test (OGTT). Nineteen youth without obesity (BMI 21.5 ± 0.5 Kg/m2) and twenty-nine youth with obesity (BMI 37.3 ± 1.7 Kg/m2) were enrolled in the study. Youth with obesity showed higher plasma concentrations of lactate (P=0.009) and pyruvate (P=0.096) and lower plasma concentrations of fumarate (P=0.022), malate (P=0.009), cis/trans aconitate (P=0.03), and citrate/isocitrate (P=0.012). PDFF was also directly correlated with lactate (r=0.46, P=0.027). Adipose tissue insulin resistance was not associated with biomarkers of glycolysis. The metabolomic analysis revealed distinct characteristics between adolescents with and without obesity, thus demonstrating lower rates of aerobic glucose utilization in youth with obesity, which may contribute to the development of insulin resistance, type 2 diabetes, and cardiovascular disease.

DOI: https://doi.org/10.1159/000548624
Nutr Rev. 2025 Dec 19. pii: nuaf258. [Epub ahead of print]

Metabolism Meets Epigenetics: β-Hydroxybutyrate-Driven Lysine β-Hydroxybutyrylation Bridging Energy Metabolism With Transcription and Protein Functional Remodeling.

Shaoqi Cheng, Chao Cheng, Jiaxin Zhou, Yun Ji, Yujun Liu, Wenliang Jiang, Cuixia Liu, Honggang Wang.

  β-Hydroxybutyrate (BHB) is the primary product of ketone body metabolism. Beyond serving as an energy source, BHB plays a crucial role in metabolic regulation, anti-inflammatory and antioxidative responses, immune modulation, and neuroprotection. Circulating BHB levels are closely linked to dietary composition and lifestyle. Medium-chain fatty acids, fasting, ketogenic diets, and moderate exercise promote BHB production, and exogenous ketone supplements can rapidly elevate BHB without the need for carbohydrate restriction. Studies have shown that BHB can regulate gene expression through epigenetic modifications, with lysine β-hydroxybutyrylation (Kbhb) establishing a crucial link between ketone body metabolism and gene regulation. Kbhb modulates chromatin accessibility, gene transcription, and cellular metabolism, and its substrates extend beyond histones to include non-histone proteins. Consequently, this modification is essential for maintaining physiological homeostasis and regulating disease processes. Despite substantial progress in Kbhb research, its precise regulatory mechanisms remain incompletely understood. Histone deacetylases (HDACs) and the sirtuin (SIRT) family function as "erasers" (enzymes that catalyze the removal of specific post-translational modifications from histone and non-histone proteins), whereas E1A-binding protein p300 and its homolog CREB-binding protein (p300/CBP) act as "writers" (enzymes that catalyze the addition of specific post-translational modifications to histone and non-histone proteins), both playing pivotal roles in the dynamic regulation of Kbhb modification. This review summarizes the biological functions of BHB and Kbhb, emphasizing their roles in metabolic regulation, their nutritional connections, epigenetic modifications, and disease development.

Keywords:  Lysine β-hydroxybutyrylation; disease; epigenetics; β-Hydroxybutyrate; β-Hydroxybutyrate in nutrition

DOI:  https://doi.org/10.1093/nutrit/nuaf258
iScience. 2025 Dec 19. 28(12): 114088

Niclosamide nanoparticles enhance pancreatic cancer sensitivity to gemcitabine via HIF-1α inhibition.

Susheel Kumar Nethi, Venugopal Gunda, Nagabhishek Sirpu Natesh, Brianna M White, Adam S Mullis, Balaji Narasimhan, Surinder K Batra, Surya K Mallapragada, Satyanarayana Rachagani.

  Pancreatic cancer (PC) exhibits profound metabolic adaptations that support tumor progression, survival, and therapy resistance. Hypoxia-inducible factor-1α (HIF-1α) is a key regulator of these processes, promoting metabolic reprogramming and chemoresistance. Given that mitochondrial metabolites modulate HIF-1α stability, targeting mitochondrial metabolism offers a promising therapeutic strategy. Niclosamide (Nic), a clinically approved anthelmintic, disrupts mitochondrial function but is limited by poor bioavailability. To overcome this, we developed polyanhydride-based Nic nanoparticles (NicNps) to enhance bioavailability and efficacy. NicNps impaired mitochondrial function, suppressed metabolism, downregulated HIF-1α, and inhibited growth of PC cells and orthotopic gemcitabine (Gem)-resistant mouse tumor models. Notably, NicNps combined with Gem overcame therapy resistance by synergistically reducing tumor hypoxia and HIF-1α-driven metabolic reprogramming. These findings highlight NicNps as a mitochondria-targeted, nanoparticle-based therapy that enhances Nic's bioavailability while suppressing HIF-1α-driven adaptations. NicNps in combination with Gem offer a promising strategy to overcome therapy resistance and improve treatment outcomes in patients with pancreatic cancer.

Keywords:  Cancer; Metabolomics; Pharmacology

DOI:  https://doi.org/10.1016/j.isci.2025.114088
Leuk Lymphoma. 2025 Dec 16. 1-11

NAMPT inhibition uncovers therapeutic vulnerabilities to venetoclax and chemotherapy in acute myelogenous leukemia.

John R Sanchez, Chaomei Liu, Vishakha Pawar, Yanqing Huang, Daisy Diaz-Rohena, Jyotsana Singh, Priya Koppikar, Tzung-Huei Lai, Lisa St John, Vinay Puduvalli, Jeffrey Molldrem, Palaniraja Thandapani, Nitin Jain, Rosa Lapalombella, Deepa Sampath.

  Acute myeloid leukemia (AML) cells depend on nicotinamide adenine dinucleotide (NAD+) biosynthesis via nicotinamide phosphoribosyltransferase (NAMPT) for survival. Single-cell RNA sequencing revealed robust NAMPT expression across diverse AML subtypes. Proteomic profiling showed that NAMPT inhibition with KPT-9274 induced adaptive upregulation of BCL2, an anti-apoptotic protein, highlighting a survival mechanism. BH3 profiling confirmed that AML cells hierarchically depend on BCL2, followed by MCL1 and BCLxL, for survival. Combining KPT9274 with the BCL2 inhibitor venetoclax synergistically enhanced mitochondrial dysfunction, cytochrome C release, and apoptotic death in AML blasts. Additionally, NAMPT inhibition reduced PARP activity and impaired DNA repair pathways, sensitizing AML cells to cytarabine and hypomethylating agents. Together, these results demonstrate that NAMPT inhibition both potentiates venetoclax activity and enhances the cytotoxic effects of standard chemotherapies by targeting metabolic and DNA repair vulnerabilities. These findings provide strong preclinical support for evaluating NAMPT and BCL2 dual inhibition strategies in future AML clinical trials.

Keywords:  AML; BCL-2 dependency; DNA repair impairment; KPT-9274; NAMPT inhibition; metabolic vulnerability

DOI:  https://doi.org/10.1080/10428194.2025.2571199
Acad Radiol. 2025 Dec 16. pii: S1076-6332(25)01117-1. [Epub ahead of print]

Proton MRI and MRSI as a Superior Methodology to Assess Oxidative Phosphorylation.

Ryan R Armbruster, Dushyant Kumar, Neil E Wilson, Ravinder Reddy.

   RATIONALE AND OBJECTIVES: Accurate determination of energy metabolism is crucial for disease indication and measurement of tissue health in disease conditions. Creatine recovery kinetics following exercise correlates to oxidative phosphorylation (OXPHOS) in tissues and can be used as a marker for understanding energy metabolism. In this study, we demonstrate that creatine chemical exchange saturation transfer (CrCEST), when combined with proton magnetic resonance spectroscopic imaging (1H-MRSI), provides a more accurate assessment of creatine recovery kinetics in a muscle-specific manner when compared to the traditional approach, 31P spectroscopy.
MATERIAL AND METHODS: Three male subjects were scanned on a 7T MRI scanner using either a dual-tuned 1H-31P surface coil or a 1H 28-channel knee coil. Each scan session included baseline, in-magnet plantar flexion, and post-exercise acquisitions, with protocols tailored for mild or intense exercise.
RESULTS: Using 31P-MRS, signal from different muscle components cannot be separated in phosphocreatine dynamics (Fig 1) and the Pi peak displays broad signal changes between 4-4.8 ppm (Fig 4). In contrast, 1H-based CrCEST and MRSI techniques provide spatially localized, muscle-specific information to detect creatine dynamics (Figs. 2, 3) and pH variations after exercise (Fig 5). Importantly, 1H-MRSI allows confirmation that mild exercise was performed by revealing minimal pH changes (e.g., <0.1 shift), ensuring CrCEST signal detection without acidosis for assessment of mitochondrial function (Fig 6).
CONCLUSION: This combined approach enables precise, muscle-specific detection of creatine recovery kinetics. CrCEST provides accurate measurement of creatine recovery time and thus OXPHOS, while rapid 1H-MRSI acquisition captures muscle-specific pH variations to track acidosis.
CATEGORY: Metabolic Imaging and Spectroscopy, Chemical Exchange Saturation Transfer, Creatine, pH.

Keywords:  Chemical Exchange Saturation Transfer; Creatine; In-vivo; Metabolic Imaging; Spectroscopy

DOI:  https://doi.org/10.1016/j.acra.2025.11.034
Elife. 2025 Dec 19. pii: RP105086. [Epub ahead of print]14

A green lifetime biosensor for calcium that remains bright over its full dynamic range.

Franka H van der Linden, Stephen C Thornquist, Rick M Ter Beek, Jelle Y Huijts, Mark A Hink, Theodorus W J Gadella, Gaby Maimon, Joachim Goedhart.

  Fluorescent biosensors toggle between two states, and for the vast majority of biosensors, one state is bright and the other state is dim. As a consequence, there is a substantial difference in the signal-to-noise ratio (SNR) for the two states. The dim state has a low SNR, which is problematic when precise, quantitative measurements are needed. During the engineering of a red-shifted variant of an mTurquoise-based calcium sensor, we serendipitously generated a green-emitting sensor that shows high brightness in both the calcium-bound and -unbound state, while still showing a calcium-dependent lifetime change of >1 ns. This sensor, named G-Ca-FLITS, is comparable in brightness to the bright state of GCaMP3 and jGCaMP7c in mammalian cells. The calcium-induced loss in fluorescence intensity is only around 30% and therefore we observe little variation in the SNR when calcium levels change. G-Ca-FLITS shows negligible sensitivity to pH in the physiological range, like its turquoise parent. Using fluorescence lifetime imaging (FLIM), we measured the calcium concentration with G-Ca-FLITS in various organelles and observed in HeLa cells transient and spatially heterogeneous calcium elevations in mitochondria. Finally, we evaluated the use of G-Ca-FLITS and its turquoise predecessor for two-photon FLIM in Drosophila brains.

Keywords:  D. melanogaster; FLIM; GFP; biochemistry; biosensor; calcium; chemical biology; human; lifetime; mitochondria

DOI:  https://doi.org/10.7554/eLife.105086
Acta Physiol (Oxf). 2026 Jan;242(1): e70143

Succinate Modulation as a Biochemical Correlate of Metabolic and Neurobehavioral Changes Associated With Intermittent Fasting in Obesity.

Andrea Tognozzi, Fabrizia Carli, Sherif Abdelkarim, Sara Cornuti, Francesca Damiani, Maria Grazia Giuliano, Alice Miniati, Martina Nasisi, Lia De Benedictis, Kousha Changizi Ashtiani, Gaia Scabia, Margherita Maffei, Pierre Baldi, Amalia Gastaldelli, Paola Tognini.

   AIM: Obesity significantly impacts the central nervous system (CNS), increasing the risks of neuropsychiatric disorders and dementia. Intermittent fasting (IF) shows promise for improving peripheral and CNS health, but its mechanisms are unclear.
METHODS: Using a diet-induced obesity mouse model [10 weeks high fat diet (HFD), then 4 weeks intervention], we compared HFD, HFD-IF, ad libitum control chow (CC), and CC-IF groups.
RESULTS: Switching to CC or IF reduced body weight, fat mass, and improved glucose tolerance. Notably, CC-IF uniquely enhanced exploration and reduced anxiety-like behavior. Transcriptomics revealed HFD-induced hippocampal neuroinflammation, whereas metabolomics identified a specific succinate signature in CC-IF mice: plasma concentration decreased, whereas liver and brown adipose tissue (BAT) levels increased. Succinate supplementation mimicked CC-IF metabolic and behavioral benefits and reduced hippocampal inflammation.
CONCLUSION: These findings suggest that regulating plasma succinate and its metabolism in liver and BAT may represent a novel biochemical correlate underlying the metabolic, neuroinflammatory, and behavioral improvements induced by IF.

Keywords:  behavior; high fat diet; hippocampus; intermittent fasting; neuroinflammation; obesity; succinate

DOI:  https://doi.org/10.1111/apha.70143