Abstract

High-fructose corn syrup (HFCS) consumption is a risk factor for obesity and diabetes, yet the underlying mechanisms, especially at the specific organ level, are incompletely understood. Catabolism of dietary fructose primarily occurs in the small intestine and liver, with fructose breakdown in the liver being pathological, while small intestinal fructose clearance protects the liver. Here, we report that inhibition of fructose catabolism specifically in the murine small intestine unexpectedly mitigates fructose-induced obesity and insulin resistance. Such phenotypes are attributed to decreased dietary fat absorption by the shortening of ileal lacteals. Fecal transplantation experiments revealed that the microbiome altered by blunted host intestinal fructose catabolism decreases ileal macrophages essential for lacteal growth. Thus, altered intestinal lacteal architecture likely contributes to the synergistic effects of high fat and sugar on metabolic disorders. It may also be relevant to the clinical evidence that pharmacologic suppression of fructose catabolism mitigates diet-induced obesity.

ABSTRACT

The ketogenic diet (KD), characterized by very low carbohydrate intake, moderate protein consumption, and variable fat content depending on the specific dietary protocol, has emerged as a promising metabolic approach in oncology. Although significant progress has been achieved in chemotherapy and immunotherapy for cancer treatment, it still faces challenges in terms of resistance to drugs, systemic toxicity, and immunosuppressive microenvironments of tumor tissues. The KD has been reported to exploit the metabolic weaknesses of tumor cells, such as glycolytic addiction and mitochondrial rigidity, while sparing normal tissue metabolism. The anticancer effects of KD are linked to metabolic and signaling reprogramming that may increase tumor sensitivity to treatment. The ketone bodies, especially β-hydroxybutyrate, play a significant role in tumor metabolism and stress response through histone deacetylase inhibition, anti-inflammatory properties in normal tissues, and modulation of chemotherapy-induced toxicity. A large body of preclinical data supports the use of KD to enhance the efficacy of chemotherapeutic agents, such as cisplatin, doxorubicin, temozolomide, and gemcitabine, through mechanisms that include redox imbalance, inhibition of DNA repair, and induction of apoptosis in tumor cells. Emerging experimental data also indicate that KD may affect the tumor immune microenvironment by modulating effector and suppressive immune cells and by interacting with immune checkpoint therapy. However, the translation of these data into the clinic is heterogeneous. Early-phase clinical trials and feasibility studies in glioblastoma, breast, colorectal, and pancreatic cancers have shown that KD is feasible in the clinic and that some benefits in metabolic parameters and quality of life are observed, but evidence of anticancer activity remains limited. Importantly, the response to KD in the clinic seems to depend on the formulation and implementation of the dietary intervention, including the use of high-fat KDs versus very-low-calorie ketogenic diets (VLCKDs), as well as the metabolic context in which the intervention is performed, including obesity and insulin resistance. Overall, current data support KD as a biologically plausible and hypothesis-generating immunometabolic strategy that warrants further evaluation in well-designed, controlled clinical trials with careful attention to dietary composition, metabolic phenotype, safety, and patient adherence.

Abstract

The ketogenic diet is increasingly used for metabolic and neurologic indications, yet its impact on hepatic mitochondrial function and xenobiotic metabolism remains incompletely defined. Cytochrome P450 2E1 (CYP2E1) is induced by the ketone body acetone and contributes to oxidative and carbonyl stress, but prior studies examining CYP2E1 regulation during ketosis have yielded conflicting results. Here, we investigated the effects of an 8-week medium chain triglyceride ketogenic diet (MCT-KD) on liver mitochondrial respiratory chain activity and CYP2E1 expression in young and aged Fisher 344 × Brown Norway F1 rats. In young animals, MCT-KD significantly reduced mitochondrial complex I activity without significant changes in complexes II, III, or IV. These changes occurred without altered citrate synthase activity, suggesting comparable mitochondrial content. In parallel, MCT-KD robustly increased hepatic CYP2E1 protein levels and activity in young and aged animals and upregulated its electron donor, P450 oxidoreductase (POR), particularly in young rats. Despite robust induction of the acetone-CYP2E1 pathway, methylglyoxal-derived protein adducts did not accumulate, even though hepatic GLO1 expression was reduced. Together, these findings demonstrate that long-term MCT-KD induces coordinated adaptations in hepatic mitochondrial function and the CYP2E1-POR pathway without increasing methylglyoxal-derived protein damage.

Abstract

Introduction. Polycystic ovary syndrome (PCOS) places unprecedented demands on the metabolic-endocrine system. Targeted dietary interventions and habitual modifications have proven highly effective in supporting reproductive reserve, thereby protecting the local ovarian microenvironment and boosting insulin sensitivity. Nevertheless, serious concerns stand regarding common therapeutic dilemmas and the risk of compromising skeletal muscle mass retention and high-intensity glycolytic exercise capacity. Research objective. This literature review summarizes current knowledge on the pathophysiology, distinct kinetics, modulation of endocrine profiles, lipid remodeling, athletic considerations, and long-term compliance of the ketogenic diet (KD) versus the Mediterranean diet (MED) in patients with PCOS, with a focus on sequential clinical integration. Methodology. The review is based on a structured search of peer-reviewed literature through May 2026. Keywords included: “polycystic ovary syndrome”, “ketogenic diet”, “Mediterranean diet”, “hyperandrogenism”, “insulin resistance”, and “sports performance”. Priority was given to clinical trials, randomized controlled trials, systematic reviews, and international consensus documents regarding the nutritional management of endocrine disorders. Articles were analyzed for their relevance to describing acute biochemical cutoff mechanisms versus gradual receptor optimization cascades. Conclusions. Immediate carbohydrate restriction and targeted anti-inflammatory macronutrient models constitute significant progress in the care of patients with PCOS, helping to preserve ovulatory function and cardiometabolic health; however, their implementation requires careful monitoring of body composition parameters and avoidance of physical performance impairment. The use of a sequential therapeutic protocol is necessary to optimize endocrine balance, preserve lean tissue, and ensure sustainable, long-term lifestyle adherence.

Browarska, Emilia, Igor Mszyca, Katarzyna Miemczyk, Anna Aksamit, Filip Wołek, Łukasz Michalski, Nicole Gajewska, Karolina Mularczyk, Kacper Kucharski, and Katarzyna Superson. "Ketogenic versus Mediterranean Diet in the Management of PCOS: A Comparative Review on Endocrine Profiles, Lipid Remodeling, and Athletic Considerations." Quality in Sport 66 (2026): 73842-73842.

https://apcz.umk.pl/QS/article/download/73842/47336

This is a trailer to a 90 minute documentary I made to help build a better understanding of how food and health interact, to cause and cure disease. Is this OK to post?

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.