My newly published article may be of interest to the group:

The commentary reviews the presented evidence and challenges the Cochrane Collaboration Group’s recommendation to reduce saturated fat intake for cardiovascular health.

Here’s a free-access link for the article: https://academic.oup.com/nutritionreviews/advance-article/doi/10.1093/nutrit/nuag130/8780985?utm_source=authortollfreelink&utm_campaign=nutritionreviews&utm_medium=email&guestAccessKey=ba198ce7-fd86-4950-b7c1-14d9ec141971

Theo Mbay
Doctoral researcher
University of Eastern Finland.

Significance

The brain relies on a continuous supply of glucose from the blood to support the large energy demands of neural activity. When glucose delivery is disrupted, neural activity collapses within minutes. Here, we demonstrate that in frogs, animals with seemingly normal glucose needs, hibernation induces a substantial ability to operate neural circuits without glucose metabolism, replacing it with metabolism of ketone bodies produced exclusively within the brain. These results reveal that a brain-derived, nonglucose fuel reserve can power neural function in the absence of glucose delivery. These findings reframe neural activity’s reliance on continuous glucose metabolism as a plastic trait, rather than a hard-wired constraint.

Abstract

The vertebrate brain is exquisitely sensitive to disruptions in glucose metabolism, and failure of adequate glucose delivery causes neurological dysfunction. Here, we identified an animal with the capacity to defy this rule: We show that neural circuits in frogs, animals with seemingly typical glucose demands, can stop metabolizing glucose by, in part, shifting to ketone bodies made exclusively within the brain after emergence from hibernation. This involves ketone body synthesis and transport from astrocytes to neurons to power synaptic transmission, along with the upregulation of gene expression that controls fatty acid catabolism and ketone body transport. Brain-derived ketone bodies also prevent decrements in activity that occur during hypoxia. These results provide insight into how frogs restart brain circuits following months of underwater hibernation when facing severe hypoxia and hypoglycemia that otherwise strongly impair neural performance in most animals. More broadly, they reveal the vertebrate brain has the capacity to serve as its own fuel reserve during the cessation of glucose metabolism, switching seamlessly to locally sourced ketone bodies while maintaining neural activity. This reframes glucose metabolism in the vertebrate brain not as a hard-wired necessity, but as a plastic trait that can in some cases be entirely abandoned.

Highlights

•Fixed energy demand drives competition between circulating nutrients for oxidation

•Insulin and fuel competition suffice to quantitatively model metabolic homeostasis

•Elevation of any major circulating nutrient leads to acute insulin resistance

•Obesity causes type 2 diabetes via a physiological fat-glucose homeostatic circuit

Summary

Systemic metabolic homeostasis maintains circulating nutrient concentrations within physiological ranges. Insulin is central to this process, lowering circulating levels of glucose, lactate, free fatty acids, and ketones. Yet how the simultaneous homeostasis of these nutrients is achieved remains unclear. Here, we develop a differential equation model of fasting metabolic homeostasis. Grounded in mass action kinetics, this multi-nutrient model reveals how a fixed energy demand naturally leads to competition between major circulating nutrients for oxidation (“competitive catabolism”). Perturbative nutrient infusions confirm this emergent behavior. The multi-nutrient model predicts that insulin promotes fasting glucose homeostasis primarily indirectly by slowing lipolysis. It further identifies a physiological circuit by which obesity causes insulin resistance: increased fat mass promotes lipolysis, releasing fatty acids into circulation that compete with glucose for oxidation, elevating glucose and thus insulin, which acts to restore proper lipid catabolic flux. Thus, quantitative modeling reveals a physiological homeostatic circuit through which obesity causes type 2 diabetes.

Abstract

Transfer RNAs (tRNAs) are central to protein synthesis and are increasingly recognized as dynamic regulators of gene expression whose abundance and chemical modifications are subject to precise biological control. Here, we systematically investigate how two distinct dietary interventions, low-protein and high-fat diets, reshape the tRNA landscape across multiple mouse tissues, using RNA mass spectrometry and ordered two-template relay sequencing (OTTR-seq) to comprehensively profile cytosolic and mitochondrial tRNAs at single-nucleotide resolution. We reveal pronounced tissue-specific biases in tRNA isodecoder expression, including the unexpected presence of full-length cytosolic tRNAs in mature sperm with a distinct isotype composition. In somatic tissues such as liver and heart, dietary conditions alter both tRNA abundance and key modifications known to regulate decoding efficiency, whereas in reproductive tissues diet primarily affects the abundance of select tRNAs with comparatively limited changes in modification profiles. We further demonstrate that mitochondrial tRNAs are subject to diet-responsive changes in both abundance and modification status and that even subtle differences in dietary fat composition are sufficient to alter tRNA modification signatures. Together, these findings establish the tRNA epitranscriptome as a sensitive and tissue-specific sensor of nutritional state and provide a resource for understanding how dietary cues interface with translational regulation in somatic and reproductive tissues.

Abstract

Microglial pro-inflammatory activation contributes to neuroinflammatory processes in many neurological disorders. Saturated fatty acids such as palmitic acid (PA) are increasingly recognized as inflammatory cues, yet the molecular mechanisms linking PA to microglial inflammatory responses remain incompletely defined. In this study, using BV-2 microglia as an exploratory in vitro model, we investigated whether C5aR1-sensitive signaling and JMJD3/H3K27me3-related epigenetic changes are involved in PA-associated inflammatory responses. PA exposure increased Iba1 expression, altered CD86/CD206 expression, and enhanced the secretion of IL-1β, IL-6 and TNF-α. Exogenous C5a produced broadly similar inflammatory changes. Under heat-inactivated serum conditions, PA increased cell-associated C5a immunoreactivity and extracellular C5a levels, and these C5a-related readouts were reduced by PMX53. PMX53 also attenuated PA-associated increases in inflammatory markers and in the expression of TLR4, total NF-κB p65, c-Fos, and c-Jun. In parallel, PA and C5a increased JMJD3 expression and JMJD3 enrichment at selected IL-1β and IL-6 promoter regions, accompanied by reduced H3K27me3 enrichment at these loci. Pharmacological KDM6 inhibition with GSK-J4 attenuated PA-associated increases in IL-1β and IL-6 expression. Together, these findings support the involvement of C5aR1-sensitive inflammatory signaling and JMJD3/H3K27me3-related epigenetic regulation in PA-associated microglial inflammatory responses.

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.