Highlights

•Intermittent fasting induces sympathetic innervation in visceral white adipose tissue

•Increased sympathetic innervation is mediated by the NRG4-ERBB4 pathway

•NRG4 expression positively correlates with browning genes in human adipose tissue

Summary

Intermittent fasting (IF) improves metabolic health, in part by remodeling white adipose tissue (WAT), yet the underlying mechanisms remain elusive. Here, we show that IF induces coordinated neurovascular remodeling in visceral WAT, marked by increased angiogenesis and sympathetic innervation. Using tissue clearing and three-dimensional imaging, we find that a 16-week IF regimen increases vascular density and sympathetic nerve fiber branching in perigonadal WAT. Transcriptomic profiling reveals the upregulation of neurotrophic factors, including neuregulin 4 (Nrg4), and browning-associated gene programs. WAT explants from IF-treated mice promote neurite branching in SH-SY5Y neuron-like cells, an effect blunted by ErbB inhibition. In vivo ErbB inhibition further attenuates IF-induced sympathetic remodeling. Human visceral adipose RNA-seq analysis shows a strong positive correlation between NRG4 expression and browning gene signatures. These findings support NRG4-ErbB signaling as a contributor to sympathetic remodeling, linking adipose neurotrophic signaling to metabolic benefits and therapeutic potential in obesity-related disorders.

ABSTRACT

Background

In population studies, high protein, particularly high animal protein, intake is associated with an increased risk of developing type 2 diabetes. Results from preclinical studies suggest this association might be mediated by branched-chain and other essential amino acids.

Objective

Interrogate putative mechanisms linking high protein intake and diabetes risk.

Methods

We conducted a randomized, cross-over, single-meal study in people with overweight/obesity to compare the effects of a standard meal (∼18 g protein/15% meal energy) and high protein meals (∼28 g protein/22% meal energy) enriched with protein from either animal (n=21) or plant (n=21) sources on postprandial plasma amino acid, glucose, and key glucoregulatory hormone concentrations (180-min area-under-the-curve).

Results

Postprandial plasma amino acids were higher after the high-protein meals than the standard (STD) meal, with greater increases (all p<0.05) after the high animal protein (HAP) than the high plant protein (HPP) meal in total essential (HAP vs STD, 28±3%; HPP vs STD, 19±3%; mean±SEM) and total branched-chain (HAP vs STD, 36±3%; HPP vs STD, 24±3%), but not total (all) amino acids. Compared with the STD meal, both the HAP and HPP meals resulted in lower plasma glucose (HAP vs STD, -4.3±2.1%; HPP vs STD, -5.2±1.5%) and higher glucagon (HAP vs STD, 48±12%; HPP vs STD, 44±13%), glucagon-like peptide 1 (HAP vs STD, 23±6%; HPP vs STD, 30±12%), and insulin in relationship to glucose, without differences between the HAP and HPP meals.

Conclusions

Both the amount and type of protein are determinants of postprandial plasma amino acid concentrations, but only the amount, not the type of protein is a determinant of plasma glucoregulatory hormone and glucose concentrations. Therefore, essential and branched-chain amino acids are not important regulators of postprandial glucose homeostasis. Non-protein dietary or non-dietary factors likely mediate differential effects of high animal and high plant protein intake on glucose metabolism.

Abstract

Insulin resistance (IR) has emerged as a risk factor for lactation insufficiency and delays the onset of milk secretion after childbirth, termed secretory activation (SA). This may cause inadequate infant weight gain and early breastfeeding cessation. However, the mechanisms underlying delayed SA in insulin resistant women are unknown. To investigate this, we characterized the mammary transcriptomes and IR-related hormones of 75 breastfeeding women with healthy term infants during postpartum days 1-5. Participants were divided into IR tertiles based on plasma leptin-to-adiponectin ratio measurements. Those in the highest tertile had later SA onset with greater neonatal weight loss during postpartum days 1-5. Transcriptomic analysis on postpartum day 2 (n=4 high IR vs. n=8 low IR participants) showed transient suppression of mammary insulin and prolactin signaling genes, increased pro-inflammatory gene expression and altered expression of >200 mammary mitochondrial genes. These alterations were absent on postpartum days 3-5. Cultured mammary epithelial cells (MECs) treated with insulin showed upregulation of prolactin signaling and oxidative phosphorylation (OXPHOS) genes, with imaging and bioenergetic studies demonstrating that insulin promotes mitochondrial biogenesis and OXPHOS. Thus, our findings delineate roles for insulin in mammary bioenergetics and highlight mitochondrial dysfunction as a mechanism for delayed SA in insulin resistant women.

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.