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Rationale: Natural variations in the abundance of the stable isotopes of nitrogen (δ 15 N) and carbon (δ 13 C) offer valuable insights into metabolic fluxes. In the wake of strong interest in cancer metabolism, recent research has revealed δ 15 N and δ 13 C variations in cancerous compared to non-cancerous tissues and cell lines. However, our understanding of natural isotopic variations in cultured mammalian cells, particularly in relation to metabolism, remains limited. This study aims to start addressing this gap using metabolic modulations in cells cultured under controlled conditions., Methods: Prostate cancer cells (PC3) were cultured in different conditions and their δ 15 N and δ 13 C were measured using isotope ratio mass spectrometry. Isotopic variations during successive cell culture passages were assessed and two widely used cell culture media (RPMI and DMEM) were compared. Metabolism was modulated through glutamine deprivation and hypoxia., Results: Successive cell culture passages generally resulted in reproducible δ 15 N and δ 13 C values. The impact of culture medium composition on δ 15 N and δ 13 C of the cells highlights the importance of maintaining a consistent medium composition across conditions whenever possible. Glutamine deprivation and hypoxia induced a lower δ 13 C in bulk cell samples, with only the former affecting δ 15 N. Gaps between theory and experiments were bridged and the lessons learned throughout the process are provided., Conclusions: Exposing cultured cancer cells to hypoxia allowed us to further investigate the relation between metabolic modulations and natural isotopic variations, while mitigating the confounding impact of changing culture medium composition. This study highlights the potential of natural δ 13 C variations for studying substrate fluxes and nutrient allocation in reproducible culture conditions. Considering cell yield and culture medium composition is pivotal to the success of this approach., (© 2024 The Author(s). Rapid Communications in Mass Spectrometry published by John Wiley & Sons Ltd.)

In 2019, the French National Authority for Health (Haute Autorité de Santé, HAS) published guidelines on the diagnosis of undernutrition. The present article focuses on the impact of switching from the 2012 guidelines of the Nutrition Committee of the French Paediatric Society (CNSFP) to the HAS guidelines on the frequency of hospital undernutrition in children. We selected for the period 2010-2019 from the ePINUT database: (1) all children aged more than 2 years with (2) clinically confirmed nutritional status in (3) French sites. The frequency of undernutrition was 15.4% vs. 28.8% using the CNSFP and HAS criteria, respectively (p < 0.01; n = 6304). When compared to non-malnourished children regardless of the criteria used, malnourished children: (1) stayed longer in hospital (CNSFP: 9.0 ± 11.8 vs. 6.5 ± 8.7 days, p < 0.01; HAS: 7.8 ± 10.1 vs. 6.4 ± 8.4 days, p < 0.01), (2) gained more weight during hospitalization (% of weight at admission) (CNSFP: +1.4 ± 4.1 vs. -0.3 ± 3.5%, p < 0.01; HAS: +2.3 ± 4.7 vs. -0.1 ± 3.4%, p < 0.01), and (3) received nutritional support more frequently during hospitalization (CNSFP: 20% vs. 5%, p < 0.01; HAS: 13% vs. 4%, p < 0.01). Switching to the HAS guidelines resulted in an almost twofold higher frequency of undernutrition in hospitalized children. Initiation of nutritional care remained low considering the nutritional status. The present study warrants interventional studies to determine which children may benefit more from nutritional therapy to improve their outcome., (Copyright © 2022 French Society of Pediatrics. Published by Elsevier Masson SAS. All rights reserved.)

While clinical evidence remains limited, an extensive amount of research suggests a beneficial role of n-3 polyunsaturated fatty acid supplementation in cancer treatment. One potential benefit is an improvement of protein homeostasis, but how protein metabolism depends on proinflammatory cytokines in this context remains unclear. Here, using the natural abundance of the stable isotopes of nitrogen as a marker of changes in protein metabolism during a randomized, double-blind, controlled clinical trial, we show that protein homeostasis is affected way faster than proinflammatory cytokines in metastatic breast cancer patients supplemented with n-3 polyunsaturated fatty acids. We provide some evidence that this response is unrelated to major changes in whole-body substrate oxidation. In addition, we demonstrate that more fatty acids were impacted by metabolic regulations than by differences in their intake levels during the supplementation. This study documents that the percentage of patients that complied with the supplementation decreased with time, making compliance assessment crucial for the kinetic analysis of the metabolic and inflammatory responses. Our results highlight the time-dependent nature of metabolic and inflammatory changes during long-chain n-3 fatty acid supplementation.

During starvation, mammalian brains can adapt their metabolism, switching from glucose to alternative peripheral fuel sources. In the Drosophila starved brain, memory formation is subject to adaptative plasticity, but whether this adaptive plasticity relies on metabolic adaptation remains unclear. Here we show that during starvation, neurons of the fly olfactory memory centre import and use ketone bodies (KBs) as an energy substrate to sustain aversive memory formation. We identify local providers within the brain, the cortex glia, that use their own lipid store to synthesize KBs before exporting them to neurons via monocarboxylate transporters. Finally, we show that the master energy sensor AMP-activated protein kinase regulates both lipid mobilization and KB export in cortex glia. Our data provide a general schema of the metabolic interactions within the brain to support memory when glucose is scarce., (© 2022. The Author(s).)

Objective: To capture the early effects of the coronavirus disease 2019 (COVID-19) pandemic on pediatric clinical research., Study Design: Pediatric clinical research networks from 20 countries and 50 of their affiliated research sites completed two surveys over one month from early May to early June 2020. Networks liaised with their affiliated sites and contributed to the interpretation of results through pan-European group discussions. Based on first detection dates of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), countries formed 1 early detecting and 1 late detecting cluster. We tested the hypothesis that this clustering influenced clinical research., Results: Research sites were first impacted by the pandemic in mid-March 2020 (March 16 ± 10 days, the same date as lockdown initiation; P = .99). From first impact up until early June, site initiation and feasibility analysis processes were affected for >50% of the sites. Staff were redirected to COVID-19 research for 44% of the sites, and 75.5% of sites were involved in pediatric COVID-19 research (only 6.3% reported COVID-19 cases in their other pediatric trials). Mitigation strategies were used differently between the early and late detecting country clusters and between countries with and without a pediatric COVID-19 research taskforce. Positive effects include the development of teleworking capacities., Conclusions: Through this collaborative effort from pediatric research networks, we found that pediatric trials were affected and conducted with a range of unequally applied mitigations across countries during the pandemic. The global impact might be greater than captured. In a context where clinical research is increasingly multinational, this report reveals the importance of collaboration between national networks., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Food choices affect the isotopic composition of the body with each food item leaving its distinct isotopic imprint. The common view is that the natural abundance of the stable isotopes of nitrogen (expressed as δ 15 N) is higher in animals than in plants that constitute our contemporary diets. Higher δ 15 N is thus increasingly viewed as a biomarker for meat and fish intake. Here we show that organic compared to conventional farming increases plant δ 15 N to an extent that can appreciably impact the performance of δ 15 N as a biomarker. The error that can arise when organic plants are consumed was modelled for the entire range of proportions of plant versus animal protein intake, and accounting for various intakes of organic and conventionally grown crops. This mass balance model allows the interpretation of differences in δ 15 N in light of organic food consumption. Our approach shows that the relationship between δ 15 N and meat and fish intake is highly contextual and susceptible to variation at the population, community or group level. We recommend that fertilization practices and organic plant consumption must not be overlooked when using δ 15 N as a biomarker for meat and fish intake or to assess compliance to nutritional interventions.

A growing body of evidence supports a role for tissue-to-diet 15 N and 13 C discrimination factors (Δ 15 N and Δ 13 C), as biomarkers of metabolic adaptations to nutritional stress, but the underlying mechanisms remain poorly understood. In obese rats fed ad libitum or subjected to gradual caloric restriction (CR), under a maintained protein intake, we measured Δ 15 N and Δ 13 C levels in tissue proteins and their constitutive amino acids (AA) and the expression of enzymes involved in the AA metabolism. CR was found to lower protein mass in the intestine, liver, heart and, to a lesser extent, some skeletal muscles. This was accompanied by Δ 15 N increases in urine and the protein of the liver and plasma, but Δ 15 N decreases in the proteins of the heart and the skeletal muscles, alongside Δ 13 C decreases in all tissue proteins. In Lys, Δ 15 N levels rose in the plasma, intestine, and some muscles, but fell in the heart, while in Ala, and to a lesser extent Glx and Asx, Δ 13 C levels fell in all these tissues. In the liver, CR was associated with an increase in the expression of genes involved in AA oxidation. During CR, the parallel rises of Δ 15 N in urine, liver, and plasma proteins reflected an increased AA catabolism occurring at the level of the liver metabolic branch point, while Δ 15 N decreases in cardiac and skeletal muscle proteins indicated increased protein and AA catabolism in these tissues. Thus, an increased protein and AA catabolism results in opposite Δ 15 N effects in splanchnic and muscular tissues. In addition, the Δ 13 C decrease in all tissue proteins, reflects a reduction in carbohydrate (CHO) oxidation and routing towards non-indispensable AA, to achieve fuel economy.

Little is known about how diet-induced obesity and insulin resistance affect protein and amino acid (AA) metabolism in tissues. The natural relative abundances of the heavy stable isotopes of C (δ 13C) and N (δ 15N) in tissue proteins offer novel and promising biomarkers of AA metabolism. They, respectively, reflect the use of dietary macronutrients for tissue AA synthesis and the relative metabolic use of tissue AA for oxidation v. protein synthesis. In this study, δ 13C and δ 15N were measured in the proteins of various tissues in young adult rats exposed perinatally and/or fed after weaning with a normal- or a high-fat (HF) diet, the aim being to characterise HF-induced tissue-specific changes in AA metabolism. HF feeding was shown to increase the routing of dietary fat to all tissue proteins via non-indispensable AA synthesis, but did not affect AA allocation between catabolic and anabolic processes in most tissues. However, the proportion of AA directed towards oxidation rather than protein synthesis was increased in the small intestine and decreased in the tibialis anterior muscle and adipose tissue. In adipose tissue, the AA reallocation was observed in the case of perinatal or post-weaning exposure to HF, whereas in the small intestine and tibialis anterior muscle the AA reallocation was only observed after HF exposure that covered both the perinatal and post-weaning periods. In conclusion, HF exposure induced an early reorganisation of AA metabolism involving tissue-specific effects, and in particular a decrease in the relative allocation of AA to oxidation in several peripheral tissues.

Because the majority of cold exposure studies are constrained to short-term durations of several hours, the long-term metabolic demands of cold exposure, such as during survival situations, remain largely unknown. The present study provides the first estimates of thermogenic rate, oxidative fuel selection, and muscle recruitment during a 24-h cold-survival simulation. Using combined indirect calorimetry and electrophysiological and isotopic methods, changes in muscle glycogen, total carbohydrate, lipid, protein oxidation, muscle recruitment, and whole body thermogenic rate were determined in underfed and noncold-acclimatized men during a simulated accidental exposure to 7.5 °C for 12 to 24 h. In noncold-acclimatized healthy men, cold exposure induced a decrease of ∼0.8 °C in core temperature and a decrease of ∼6.1 °C in mean skin temperature (range, 5.4-6.9 °C). Results showed that total heat production increased by approximately 1.3- to 1.5-fold in the cold and remained constant throughout cold exposure. Interestingly, this constant rise in Ḣprod and shivering intensity was accompanied by a large modification in fuel selection that occurred between 6 and 12 h; total carbohydrate oxidation decreased by 2.4-fold, and lipid oxidation doubled progressively from baseline to 24 h. Clearly, such changes in fuel selection dramatically reduces the utilization of limited muscle glycogen reserves, thus extending the predicted time to muscle glycogen depletion to as much as 15 days rather than the previous estimates of approximately 30-40 h. Further research is needed to determine whether this would also be the case under different nutritional and/or colder conditions., (Copyright © 2016 the American Physiological Society.)

In cold exposed humans, increasing thermogenic rate is essential to prevent decreases in core temperature. This review describes the metabolic requirements of thermogenic pathways, mainly shivering thermogenesis, the largest contributor of heat. Research has shown that thermogenesis is sustained from a combination of carbohydrates, lipids, and proteins. The mixture of fuels is influenced by shivering intensity and pattern as well as by modifications in energy reserves and nutritional status. To date, there are no indications that differences in the types of fuel being used can alter shivering and overall heat production. We also bring forth the potential contribution of nonshivering thermogenesis in adult humans via the activation of brown adipose tissue (BAT) and explore some means to stimulate the activity of this highly thermogenic tissue. Clearly, the potential role of BAT, especially in young lean adults, can no longer be ignored. However, much work remains to clearly identify the quantitative nature of this tissue's contribution to total thermogenic rate and influence on shivering thermogenesis. Identifying ways to potentiate the effects of BAT via cold acclimation and/or the ingestion of compounds that stimulate the thermogenic process may have important implications in cold endurance and survival.