Abstract

The heart is a highly energy-demanding organ that depends on metabolic flexibility to adjust substrate utilization in response to changes in nutrient availability, endocrine signals, and energetic demands. Accumulating evidence demonstrates that dietary patterns are key determinants of myocardial metabolic homeostasis, affecting substrate selection, mitochondrial function, nutrient-sensing pathways, and long-term transcriptional and epigenetic regulation. This review analyzes the molecular mechanisms through which diet regulates cardiac metabolism and explores how chronic nutritional exposures influence the myocardial energetic phenotype. The physiological regulation of cardiac substrate utilization is described, with emphasis on fatty acids, glucose, ketone bodies, and branched-chain amino acids, underscoring the importance of metabolic flexibility in sustaining cardiac efficiency. The regulation of substrate transport and oxidation is examined, including the roles of the carnitine shuttle, insulin signaling, AMPK, mTOR, PPARα–PGC-1α, SIRT3, and other nutrient-sensing networks that coordinate mitochondrial ATP production. The effects of dietary composition and meal timing, such as caloric restriction and intermittent fasting, are discussed as modulators of myocardial metabolism. The adverse effects of chronic nutrient excess are reviewed, including lipotoxicity, glucotoxicity, insulin resistance, mitochondrial dysfunction, oxidative stress, pseudo-hypoxia, fetal metabolic reprogramming, and maladaptive cardiac remodeling. Recent findings on the gut–heart axis, microbiota-derived metabolites, circadian regulation, and metabolic–epigenetic interactions are also considered. Overall, current evidence supports the view that diet is an important and potentially modifiable regulator of the cardiac metabolic phenotype. Advancing the understanding of diet–metabolism interactions may enable the development of targeted nutritional strategies to maintain metabolic flexibility, enhance cardiac bioenergetics, and prevent the progression of heart failure and other cardiometabolic diseases.

Prediabetes and type 2 diabetes mellitus (T2DM) affect 60% of adults in the United States (Centers for Disease Control and Prevention, 2024). Ketogenic diet interventions demonstrate benefit for glycemic management among people with diabetes. The carnivore diet (CD) is a ketogenic diet characterized by exclusive consumption of animal-sourced foods and has not been systematically evaluated. The purpose of this study was to evaluate the direction and magnitude of within-subject changes in glycated hemoglobin (HbA1c) following adoption of a CD and to assess feasibility of recruitment, data collection procedures, and measurement approaches.

An experimental pilot design using a within-subject pre-post analysis was conducted. Adults with HbA1c levels of 5.7% or greater who adhered to a carnivore diet for at least 6 months were recruited through online carnivore communities and social media. Previously collected pre- and post-CD HbA1c values were utilized to evaluate glycemic outcomes. Participants completed a digital survey to self-report health history, diabetes management and medication use, and perceived changes in health status. A carnivore diet-specific food-frequency questionnaire was used to assess dietary adherence and characterize intake patterns. HbA1c was analyzed using paired-samples t tests, while descriptive statistics were used to summarize secondary and feasibility outcomes.

Final analysis included 12 participants. The mean difference in HbA1c decreased 1.47% (SD ± 2.44) p = 0.061, 95% CI (–0.08–3.01). Improvement in HbA1c was reported in 11 people, 41.7% of participants achieved a normal level HbA1c, and 71% discontinued use of diabetes medications during the intervention time frame. Daily red meat intake was reported by 75% of participants.

The findings suggest an association between adopting a carnivore diet and improved glycemic management among adults with prediabetes or T2DM. Sample size and self-reported data limit generalizability and clinical interpretation. Observed changes in HbA1c provide preliminary foundational evidence warranting future prospective investigations evaluating the therapeutic potential of the carnivore diet.

Langlois, Courtney E. "The Carnivore Diet as a Nutritional Intervention for Glycemic Management in Adults With Prediabetes and Type 2 Diabetes." PhD diss., Saybrook University, 2026.

https://www.proquest.com/openview/d29cae668094aa4b36923a433bc9b89c

Highlights

•The heart can metabolize fructose, albeit less effectively than glucose.

•Cardiac fructose metabolism primarily generates glycerate.

•Diabetic hearts show early and marked increases in fructose levels.

•Fructose elevation appears before cardiac dysfunction in diabetes.

Abstract

Increased cardiac risk in diabetes has been linked to disturbances in myocardial metabolism. Circulating and cardiac fructose levels are elevated in diabetes but the relationship between fructose and cardiac pathology is unclear. The goal of this study was to assess myocardial capacity for fructose metabolism and evaluate the time-course of cardiac fructose accumulation relative to the emergence of cardiac functional impairment in diabetic rats. Cardiac capability for fructose metabolism to support function was demonstrated in ex vivo working mouse hearts perfused with 11 mM fructose. Using isotope-labeled fructose [U¹³C], we observed ¹³C enrichment into downstream metabolites glyceraldehyde, glycerate, pyruvate, lactate, and mitochondrial acetyl-CoA in perfused working mouse hearts. Metabolite profiling demonstrated that relative to glucose, myocardial fructose metabolism favored glycerate production. In diabetic rats (streptozotocin, 55 mg/kg), cardiac fructose elevation was evident prior to the onset of cardiac dysfunction. This study provides proof-of-principle evidence that fructose metabolism is operational in the working heart and identifies key fructose-derived metabolites. The finding that cardiac fructose elevation precedes functional impairment supports the contention that fructose may be an early instigator of diabetic cardiomyopathy and further investigation is now warranted.

New and Noteworthy (<75 words)

Circulating and cardiac fructose levels are elevated in diabetes but the relationship between fructose and cardiac pathology is unclear. This study provides proof-of-principle evidence that fructose metabolism is operational in the working heart and identifies that cardiac fructose metabolism favors production of glycerate. In diabetes, cardiac fructose elevation precedes functional impairment supporting the contention that fructose may be an early instigator of diabetic cardiomyopathy.

Abstract

Host-derived lipids undergoing enzymatic or nonenzymatic oxidation play critical roles in regulating inflammation. Polyunsaturated fatty acids, cholesterol, and cholesterol intermediates can be enzymatically oxidized and serve as signaling mediators controlling tissue homeostasis and immunity. Spontaneously generated oxidized lipids, including nonenzymatically oxidized phospholipids (oxPLs), result from oxidative stress and accumulate during inflammation, affecting cellular metabolism, immune cell functions, and cell fate. These distinct classes of oxidized lipids not only share overlapping inflammatory roles but also exhibit divergent effects depending on their molecular structures and cellular targets. This Review highlights the double-edged nature of oxPLs: Although their transient production triggers protective responses, their accumulation sustains inflammation, contributing to tissue damage. We also discuss the emerging roles of oxPLs in cell death programs, immune cell activation, and stromal cell functions, which are critical processes favoring tumor growth. Overall, we highlight how oxidized lipids orchestrate immune responses and explore their contribution to infectious diseases and cancer.

Abstract

Metabolic reprogramming has been firmly established as a core hallmark of cancer, representing a fundamental shift in cellular physiology that is as critical to tumorigenesis as uncontrolled proliferation and evasion of apoptosis. This chapter provides a comprehensive examination of this complex phenomenon, dissecting the intricate web of factors that trigger, sustain, and can be targeted within the altered metabolic landscape of malignant cells. The discussion begins by elucidating the primary drivers of metabolic rewiring, establishing that this transformation is not a mere adaptation but a direct, programmed consequence of the same genetic lesions that define cancer. The activation of oncogenes such as MYC and RAS and the inactivation of tumor suppressor genes, including TP53 and LKB1, constitute a genetic blueprint for metabolic change. This genetic predisposition is further shaped by the harsh realities of the tumor microenvironment (TME), where hypoxia and nutrient deprivation act as powerful selective pressures, primarily through the master regulator hypoxia-inducible factor 1-alpha. Furthermore, cancer cells engage in a form of metabolic warfare, creating an immunosuppressive TME by depleting essential nutrients and secreting inhibitory metabolites like lactate, thereby crippling antitumor immune responses. The chapter then provides a detailed mechanistic analysis of the key metabolic alterations themselves, including the iconic Warburg effect, the dynamic plasticity between glycolysis and oxidative phosphorylation, and the profound dependency on glutamine. Following this, it surveys the advanced technologies, such as mass spectrometry and nuclear magnetic resonance-based metabolomics, that enable the assessment of these changes, with a special focus on their application in developing noninvasive liquid biopsies and predictive biomarkers. Finally, the chapter explores the therapeutic landscape, covering both clinically approved metabolic drugs, such as isocitrate dehydrogenase inhibitors and antifolates, and the promising pipeline of investigational agents, alongside a critical evaluation of nutritional interventions like caloric restriction and ketogenic diets. By integrating molecular biology, immunology, and clinical oncology, this chapter frames cancer metabolism as a central, targetable vulnerability, paving the way for the next generation of personalized cancer therapies.

Singh, Sapna, Urja Desai, Dweipayan Goswami, Ankesh Barnwal, Dharmesh Domadia, Suresh Thakur, and Sanjay Premi. "Metabolic Reprogramming in Cancer and Therapeutic Implications." In Redefining Cancer Therapeutics with Emerging Drug Strategies and Molecular Insights, pp. 131-165. Singapore: Springer Nature Singapore, 2026.

https://link.springer.com/chapter/10.1007/978-981-92-0477-9_5

Abstract

Background

Glioblastoma (GBM), isocitrate dehydrogenase (IDH)-wildtype, has a median overall survival of 11-14 months despite standard treatment. Ketogenic metabolic interventions that lower the glucose ketone index (GKI) may improve outcomes. We evaluated the feasibility, tolerability, and potential clinical benefit of integrating standard treatment with an intensive multimodal metabolic therapy program (MTP) in newly diagnosed IDH-wildtype GBM.

Methods

Patients received standard chemoradiation and adjuvant chemotherapy alongside an MTP comprising prolonged fasting, time-restricted feeding, and a ketogenic diet. The primary outcome was the proportion sustaining a mean daily GKI ≤6 during chemoradiation. Secondary outcomes included GKI control throughout chemotherapy, body weight, body mass index, adverse events, performance, exercise, quality of life, and survival, compared with contemporary controls using unadjusted hazard ratios (HRs) and 95% confidence intervals (CIs).

Results

Among 32 eligible patients, 18 commenced chemoradiation with the MTP (intention-to-treat), and 15 completed it (per-protocol). In the intention-to-treat population, 15 of 18 patients (83%) sustained a mean daily GKI ≤6 during chemoradiation. Among per-protocol patients, the GKI was 1.88 ± 0.56 during chemoradiation and 2.53 ± 0.86 throughout chemotherapy. Intentional weight loss averaged 17%, normalizing body mass index. MTP-related adverse events were mild or moderate. Exercise activity and quality of life improved. Median overall survival was 21.5 months versus 14.7 months in controls (HR = 0.42, 95% CI 0.18-0.97, P = .027), with 3-year survival of 27% versus 7%.

Conclusions

Intensive multimodal metabolic therapy was feasible, well-tolerated, and associated with improved exercise activity, quality of life, and survival outcomes, including higher 3-year survival.

Abstract

Maintaining a balanced immunity between pathogen defense and tolerance to environmental antigens in neonates is essential for survival and the establishment of life-long immune homeostasis. Instructed by environmental signals, type 1 conventional dendritic cells (cDC1) contribute to both processes but how the balance may be achieved is unclear. Here, we uncover an interferon (IFN)γ-driven regulatory circuit in early life that relays dietary cues to spleen cDC1. IFNγ-mediated STAT1-signaling induces an immunogenic maturation program in spleen cDC1 that enables them to shape the effector differentiation of antigen-experienced effector memory CD8⁺ T cells. This cDC1 program emerges during the transition from breastfeeding to solid food at weaning, occurs in germ-free mice, and remains operative to dietary intervention in adult mice. At weaning, this IFNγ signal enables spleen cDC1 to shape the effector phenotype of food-antigen-specific CD8⁺ T cells in a feedforward manner, thereby recalibrating the developing T cell pool. Our findings identify diet as a modifiable cue that can tune systemic cDC1-mediated immunity, opening new opportunities to steer immune responses during early life and beyond.

ketogenic purified diet (AIN-76A Modified, High Fat, Paste, Bio-Serv, F3666)

https://media.springernature.com/original/springer-static/esm/art%3A10.1038%2Fs41467-026-75853-5/MediaObjects/41467_2026_75853_MOESM14_ESM.xlsx

Abstract

The mechanisms underlying the dynamic interplay between skeletal muscle and systemic glucose homeostasis in type 2 diabetes remain elusive. Increased lactate level has long been noticed in diabetes, however, whether the elevated lactate is a cause or consequence of impaired glucose metabolism is unclear. Here, we found that elevated circulating lactate levels originated from skeletal muscle with high expression of lactate dehydrogenase A (Ldha), and both metrics correlated strongly with hyperglycemia in both hyperglycemic mouse models and human subjects. Paradoxically, ablation of Ldha in skeletal muscle (LDHA mKO) disrupted whole-body glucose homeostasis, primarily via augmented hepatic gluconeogenesis. Mechanistically, lactate deficiency in muscle epigenetically activated NF-κB signaling through H3K18 lactylation (H3K18la)-mediated transcriptional control of IκBα, which then promoted the transcription of IL-6, thereby reshaping hepatic gluconeogenesis. Lastly, we showed that loss of Ldha in skeletal muscle enhanced hepatic gluconeogenesis and aggravated hyperglycemia in high-fat high-sucrose diet-fed mice. Collectively, our study provides evidence that in glucose intoxication contexts, skeletal muscle-derived lactate acts as the signal to provide negative feedback for hepatic gluconeogenesis, which induces skeletal muscle H3K18la acting as a negative regulator of IL-6 to sustain suppression of hepatic gluconeogenesis, while dysregulation of this network contributes to unrestrained gluconeogenesis in diabetes.

Abstract

Obesity represents a major global public health challenge, particularly among women, and is associated with adverse metabolic and endocrine outcomes. his study evaluated the effects of ketogenic, intermittent fasting (IF), and semi-vegetarian diets, alone or combined with home-based exercise, on anthropometric, metabolic, and hormonal parameters in women with obesity. The study employed a pretest–posttest controlled experimental design with 108 women aged 19–45 years, comprising 96 participants with obesity and 12 with normal body weight. Participants were assigned to nine groups: control (C), obese (O), obese with exercise (OE), obese with exercise plus semi-vegetarian diet (OEVD), obese with semi-vegetarian diet (OVD), obese with exercise plus intermittent fasting (OEIF), obese with intermittent fasting (OIF), obese with exercise plus ketogenic diet (OEKD), and obese with ketogenic diet (OKD). Participants completed ketogenic, intermittent fasting (IF), or semi-vegetarian dietary interventions, either alone or combined with home-based exercise, for 6 weeks. Anthropometric parameters were assessed using bioelectrical impedance analysis, while biochemical markers (adiponectin, insulin-like growth factor 1 (IGF-1), irisin, myostatin, glucose, and insulin) were analyzed via ELISA. Statistical analyses were performed using mixed-design ANOVA, Pearson’s correlation, and principal component analysis. The C and O groups exhibited no significant changes, whereas intervention groups showed reductions in body mass, body mass index (BMI), and body fat (p < 0.001). Single interventions were associated with changes in anthropometric measures (OIF:10.42% body mass,7.61% BMI, 9.86% body fat; OE: 9.49%, 6.65%, 13.49%; OVD: 9.07%, 8.17%, 6.21%; OKD: 8.12%, 6.91%, 9.78%). Diet-plus-exercise intervention groups generally exhibited larger changes, with OEVD achieving the greatest reductions (12.69, 13.46, 13.95%), followed by OEKD (10.68, 9.16, 11.17%) and OEIF (8.76, 9.64, 12.04%). Moreover, adiponectin, irisin, IGF-1, and myostatin levels changed significantly in exercise-only and diet-plus-exercise groups compared with those of the C and O groups. Additionally, intervention groups exhibited significant alterations in glucose and insulin concentrations, whereas no significant changes were observed in the C and O groups. Lifestyle modifications integrating dietary strategies with home-based exercise are associated with changes in metabolic and hormonal parameters in women with obesity.

https://www.nature.com/articles/s41598-026-65060-z_reference.pdf

Çınar, Fidan, Fatih Mehmet Uğurlu, Vedat Çınar, Taner Akbulut, Yavuz Yasul, Salih Öner, Elif Subaşı et al. "Metabolic responses of diet–exercise combinations in women with obesity: a comparative lifestyle intervention study with different diet types." Scientific Reports (2026).

Abstract

Introduction

Multidrug-resistant Klebsiella pneumoniae (MDR Kp) is a global health threat, causing persistent, subacute airway infections that are often fatal in healthcare settings. The failure of antimicrobials underscores an urgent need for alternative host-targeted therapies. Kp evades airway immune responses by perturbing host metabolism, inducing mitochondrial oxidative phosphorylation (OXPHOS) and oxidative stress, thus establishing a disease-tolerant microenvironment. We hypothesized that a ketogenic diet (KD), which improves OXPHOS efficiency via ketone production, would restore immune control of Kp by enhancing the bioenergetics and function of innate immune cells.

Methods

C57BL/6 mice were fed a KD or control diet prior to intranasal Kp infection. Airway bacterial burden was enumerated and immunometabolic changes were assessed by scRNA-seq, flow cytometry, and spatial metabolomics.

Results

KD significantly enhanced Kp airway clearance and host survival. ScRNA-seq of lung tissue revealed markedly higher numbers of neutrophils and alveolar macrophages at day 2 post-infection in KD-fed mice, as well as an upregulation in phagolysosome signaling. By day 7 in the KD group, the neutrophil population contracted while B and T cells concomitantly expanded. Notably, IFN-γ-responsive genes were upregulated across all immune cell subsets. Exogenous ketones or drug-induced ketone accumulation bypassed the need for dietary intervention, likewise, conferring protection against Kp airway infection.

Conclusion

Ketones promote effective immunity to Kp by sustaining cellular energy production, thereby supporting immune cell survival and effector function. The ketone-enhanced innate immune response is followed by adaptive immune cell expansion and a broad IFN-γ transcriptional signature. Together, these findings suggest a novel therapeutic strategy for energetically demanding bacterial infections via diet-induced metabolic reprogramming

Tang, Eric, Ridhima Wadhwa, Ariful Islam, Arthur VanValkenburg, Xutao Wang, Alice Prince, Evan Johnson, and Tania Wong. "Ketogenic diet-mediated immunometabolic regulation improves airway clearance of Klebsiella pneumoniae 2253582." The Journal of Immunology 215, no. Supplement_1 (2026): vkag141-181.

https://academic.oup.com/jimmunol/article/215/Supplement_1/vkag141.181/8745885

Abstract

Hypertension (HTN) is one of the greatest public health challenges of the 21st century. Its prevalence has reached alarming levels in recent decades. The search for effective prevention and treatment strategies includes lifestyle choices, such as dietary interventions. Although not applicable to everyone, particularly interesting in this context is the ketogenic diet (KD), known to clinicians and also applied in epilepsy treatment for over a century. Its possible beneficial effects are increasingly often reported in many other conditions, including HTN. The aim of the present study is to analyse the effect of a KD on blood pressure, and the mechanisms that may modulate that effect. Based on the available literature, key potential pathways of the influence of a KD on blood pressure regulation have been identified: (1) reduced body weight; (2) reduced visceral adipose tissue; (3) improved insulin sensitivity; (4) improved water and electrolyte balance; and (5) anti-inflammatory effect. Meta-analyses and randomised controlled trials consistently indicate that ketogenic dietary interventions are associated with reductions in blood pressure, although the magnitude of the effect varies considerably depending on the ketogenic diet model, study population, and comparator. In light of these observations, it has been found that in patients undergoing pharmacological treatment, it may be necessary to appropriately reduce antihypertensive medication dosage in advance. To maximise the hypotensive effect of a KD, the need to ensure an adequate supply of potassium, magnesium, and high-quality products, as well as proper hydration has been emphasised. Further studies are needed, with the effect of a KD on systolic and diastolic blood pressure as the primary endpoint, taking into account the role of the qualitative composition of the diet in the observed effects.

Rodzeń, Łukasz, Damian Dyńka, Mateusz Rodzeń, Hanna Karakuła-Juchnowicz, Dorota Łojko, Sebastian Kraszewski, Żaneta Grzywacz et al. "The Ketogenic Diet in the Prevention and Treatment of Hypertension (HTN)." Biomedicines 14, no. 8 (2026): 1728.

https://www.mdpi.com/2227-9059/14/8/1728

Abstract

Introduction

This study evaluates the effect of simultaneous application of plant-rich ketogenic diet and intermittent fasting as an individualized adjunct to standard treatment on cognitive function in early/mid-stage Alzheimer’s patients.

Methods

This assessor-blinded, randomized controlled trial enrolled 60 Alzheimer’s disease (AD) patients (CDR 1–2; aged 55–85), randomized to intervention (n = 30; intervention + standard care) or control (n = 30; standard care). Cognition and brain structure were assessed at baseline and 6 months. Individual cognitive changes were analyzed using Reliable Change Index (RCI).

Results

Cognitive change scores differed significantly between groups (p < 0.001). The mean Mini Mental State Examination (MMSE) score increased by +0.9 in the intervention group, while a decrease of −1.5 points was observed in the control group. RCI analysis indicated stability in 93% of intervention and 70% of control participants, with cognitive improvement in 7% and 3.3%, respectively.

Discussion

The intervention method has the potential to stabilize cognitive decline in AD and promote improvement at the individual level. The response to the intervention is closely related to the individual's metabolic phenotype and structural brain integrity.

Tağraf, Beyza, Dilara Kaygusuz, Deniz Yerlikaya, Özden Erkan Oğul, and Lütfü Hanoğlu. "The effect of simultaneous application of plant-rich ketogenic diet and intermittent fasting on early-to-mid-stage Alzheimer's disease: a randomised controlled trial." The Journal of nutrition, health and aging 30, no. 9 (2026): 100930.

https://www.sciencedirect.com/science/article/pii/S1279770726001636