-
Cell Reports Oct 2021Glucose tolerance represents a complex phenotype in which many tissues play important roles and interact to regulate metabolic homeostasis. Here, we perform an analysis...
Glucose tolerance represents a complex phenotype in which many tissues play important roles and interact to regulate metabolic homeostasis. Here, we perform an analysis of C-glucose tissue distribution, which maps the metabolome and lipidome across 12 metabolically relevant mouse organs and plasma, with integrated C-glucose-derived carbon tracing during oral glucose tolerance test (OGTT). We measure time profiles of water-soluble metabolites and lipids and integrate the global metabolite response into metabolic pathways. During the OGTT, glucose use is turned on with specific kinetics at the organ level, but fasting substrates like β-hydroxybutyrate are switched off in all organs simultaneously. Timeline profiling of C-labeled fatty acids and triacylglycerols across tissues suggests that brown adipose tissue may contribute to the circulating fatty acid pool at maximal plasma glucose levels. The GTTAtlas interactive web application serves as a unique resource for the exploration of whole-body glucose metabolism and time profiles of tissue and plasma metabolites during the OGTT.
Topics: Animals; Biomarkers; Blood Glucose; Chromatography, Liquid; Energy Metabolism; Glucose Tolerance Test; Lipidomics; Lipids; Male; Metabolome; Metabolomics; Mice, Inbred C57BL; Spectrometry, Mass, Electrospray Ionization; Tandem Mass Spectrometry; Time Factors; Tissue Distribution; Mice
PubMed: 34644567
DOI: 10.1016/j.celrep.2021.109833 -
Trends in Cell Biology Feb 2014Cells are capable of metabolizing a variety of carbon substrates, including glucose, fatty acids, ketone bodies, and amino acids. Cellular fuel choice not only fulfills... (Review)
Review
Cells are capable of metabolizing a variety of carbon substrates, including glucose, fatty acids, ketone bodies, and amino acids. Cellular fuel choice not only fulfills specific biosynthetic needs, but also enables programmatic adaptations to stress conditions beyond compensating for changes in nutrient availability. Emerging evidence indicates that specific switches from utilization of one substrate to another can have protective or permissive roles in disease pathogenesis. Understanding the molecular determinants of cellular fuel preference may provide insights into the homeostatic control of stress responses, and unveil therapeutic targets. Here, we highlight overarching themes encompassing cellular fuel choice; its link to cell fate and function; its advantages in stress protection; and its contribution to metabolic dependencies and maladaptations in pathological conditions.
Topics: Cell Differentiation; Cells; Energy Metabolism; Humans
PubMed: 24018218
DOI: 10.1016/j.tcb.2013.07.010 -
Free Radical Biology & Medicine Nov 2018Selenium (Se) is a redox-active environmental mineral that is converted to only a small number of metabolites and required for a relatively small number of mammalian... (Review)
Review
Selenium (Se) is a redox-active environmental mineral that is converted to only a small number of metabolites and required for a relatively small number of mammalian enzymes. Despite this, dietary and environmental Se has extensive impact on every layer of omics space. This highlights a need for global network response structures to provide reference for targeted, hypothesis-driven Se research. In this review, we survey the Se research literature from the perspective of the responsive physical and chemical barrier between an organism (functional genome) and its environment (exposome), which we have previously termed the redox interface. Recent advances in metabolomics allow molecular phenotyping of the integrated genome-metabolome-exposome structure. Use of metabolomics with transcriptomics to map functional network responses to supplemental Se in mice revealed complex network responses linked to dyslipidemia and weight gain. Central metabolic hubs in the network structure in liver were not directly linked to transcripts for selenoproteins but were, instead, linked to transcripts for glucose transport and fatty acid β-oxidation. The experimental results confirm the survey of research literature in showing that Se interacts with the functional genome through a complex network response structure. The results imply that systematic application of data-driven integrated omics methods to models with controlled Se exposure could disentangle health benefits and risks from Se exposures and also serve more broadly as an experimental paradigm for exposome research.
Topics: Animals; Genome; Humans; Metabolome; Oxidation-Reduction; Selenium
PubMed: 29883789
DOI: 10.1016/j.freeradbiomed.2018.06.002 -
Critical Reviews in Oncology/hematology Jun 2017Pancreatic cancer is a highly deadly disease: almost all patients develop metastases and conventional treatments have little impact on survival. Therapeutically, this... (Review)
Review
Pancreatic cancer is a highly deadly disease: almost all patients develop metastases and conventional treatments have little impact on survival. Therapeutically, this tumor is poorly responsive, largely due to drug resistance. Accumulating evidence suggest that this chemoresistance is intimately linked to specific metabolic aberrations of pancreatic cancer cells, notably an increased use of glucose and the amino acid glutamine fueling anabolic processes. Altered metabolism contributes also to modulation of apoptosis, angiogenesis and drug targets, conferring a resistant phenotype. As a modality to overcome chemoresistance, a variety of experimental compounds inhibiting key metabolic pathways emerged as a promising approach to potentiate the standard treatments for pancreatic cancer in preclinical studies. These results warrant confirmation in clinical trials. Thus, this review summarizes the impact of metabolic aberrations from the perspective of drug resistance and discusses possible novel applications of metabolic inhibition for the development of more effective drugs against pancreatic cancer.
Topics: Antineoplastic Agents; Drug Resistance, Neoplasm; Energy Metabolism; Humans; Pancreatic Neoplasms
PubMed: 28477742
DOI: 10.1016/j.critrevonc.2017.03.026 -
Journal of Hazardous Materials Nov 2020TiO-nanoparticles (TiO-NP) have the potential to impair plant development. Nevertheless, the metabolic processes behind the physiological responses to TiO-NP are still...
TiO-nanoparticles (TiO-NP) have the potential to impair plant development. Nevertheless, the metabolic processes behind the physiological responses to TiO-NP are still far from being fully understood. In this study, Triticum aestivum plants were exposed for 21 days to different concentrations (0; 5; 50; 150 mg L) of TiO-NP (P25). After treatment, the metabolite profiles of roots and leaves were analysed. The content of >70 % of the identified metabolites changed in response to P25 and the impact on metabolic pathways increased with TiO-NP dose, with leaves showing higher alterations. Roots up-regulated monosaccharides, azelaic acid, and γ-aminobutanoic acid and triggered the tyrosine metabolism, whereas leaves up-regulated the metabolisms of reserve sugars and tocopherol, and the phenylalanine and tryptophan pathways. Both organs (mainly leaves) up-regulated the aspartate family pathway together with serine, alanine and valine metabolisms and the glycerolipids' biosynthesis. In addition, the citrate and glyoxylate metabolisms were down-regulated in both organs (highest dose). Sugar biosynthesis breakdown, due to photosynthetic disturbances, shifted the cell metabolism to use amino acids as an alternative energy source, and both ROS and sugars worked as signalling molecules activating organ dependent antioxidant responses. Concluding, these NP-pollutants severely impact multiple crop metabolic pathways and may ultimately compromise plant performance.
Topics: Amino Acids; Metabolic Networks and Pathways; Nanoparticles; Sugars; Titanium; Triticum
PubMed: 32534391
DOI: 10.1016/j.jhazmat.2020.122982 -
Nitric Oxide : Biology and Chemistry Feb 2010Mitochondrial function is integral to maintaining cellular homeostasis through the production of ATP, the generation of reactive oxygen species (ROS) for signaling, and... (Review)
Review
Mitochondrial function is integral to maintaining cellular homeostasis through the production of ATP, the generation of reactive oxygen species (ROS) for signaling, and the regulation of the apoptotic cascade. A number of small molecules, including nitric oxide (NO), are well-characterized regulators of mitochondrial function. Nitrite, an NO metabolite, has recently been described as an endocrine reserve of NO that is reduced to bioavailable NO during hypoxia to mediate physiological responses. Accumulating data suggests that mitochondria may play a role in metabolizing nitrite and that nitrite is a regulator of mitochondrial function. Here, what is known about the interactions of nitrite with the mitochondria is reviewed, with a focus on the role of the mitochondrion as a metabolizer and target of nitrite.
Topics: Animals; Humans; Mitochondria; Nitrites
PubMed: 19788924
DOI: 10.1016/j.niox.2009.09.002 -
Current Opinion in Cell Biology Dec 2012The complex signaling pathways that control cellular fate can be intimately influenced by metabolic status. Although the ability of nutrients to influence intracellular... (Review)
Review
The complex signaling pathways that control cellular fate can be intimately influenced by metabolic status. Although the ability of nutrients to influence intracellular decisions has been appreciated for some time, the complex signaling mechanisms linking metabolic inputs to cell proliferation and death are not fully understood. An emerging theme in the literature is that intracellular metabolite levels can directly influence cell fate decisions through modulation of nutrient-derived protein modifications. It appears that varying the level of intracellular metabolites can alter the abundance of post-translational modifications, both by altering the availability of donor substrates and changing the activity of the nutrient-sensitive enzymes regulating these reactions. We focus here on protein acetylation, a modification that can modulate both cell proliferation and cell death in response to changes in extracellular nutrient supply.
Topics: Acetylation; Acetyltransferases; Animals; Cell Death; Cell Proliferation; Cell Survival; Cells; Humans; Protein Processing, Post-Translational; Signal Transduction
PubMed: 23103123
DOI: 10.1016/j.ceb.2012.10.002 -
Journal of Theoretical Biology Sep 2014In this work, a kinetic-metabolic model previously developed for CHO cells is used to study glycolysis regulation. The model is assessed for its biological relevance by...
In this work, a kinetic-metabolic model previously developed for CHO cells is used to study glycolysis regulation. The model is assessed for its biological relevance by analyzing its ability to simulate metabolic events induced following a hypoxic perturbation. Feedback and feedforward regulatory mechanisms known to occur to either inhibit or activate fluxes of glycolysis, are implemented in various combined scenarios and their effects on the metabolic response were analyzed. This study aims at characterizing the role of intermediates of glycolysis and of the cell energetic state, described as the AMP-to-ATP ratio, as inhibitors and activators of glycolysis pathway. In addition to the glycolysis pathway, we here describe the transient metabolic response of pathways that are connected to glycolysis, such as the pentose phosphate pathway, TCA cycle, cell bioenergetics system, glutamine and amino acids metabolisms. Taken individually, each regulatory mechanism leads to an oscillatory behavior in response to a hypoxic perturbation, while their combination clearly damps oscillations. However, only the addition of the cell energetic state to the regulatory mechanisms results in a non-oscillating response leading to metabolic flux rate rearrangement corresponding to the anaerobic metabolism expected to prevail under hypoxic conditions. We thus demonstrate in this work, from model simulations, that the robustness of a cell energetic metabolism can be described from a combination of feedback and feedforward inhibition and activation regulatory mechanisms of glycolysis fluxes, involving intermediates of glycolysis and the cell energetic state itself.
Topics: Animals; CHO Cells; Citric Acid Cycle; Computer Simulation; Cricetinae; Cricetulus; Glycolysis; Models, Biological; Pentose Phosphate Pathway
PubMed: 24801859
DOI: 10.1016/j.jtbi.2014.04.035 -
European Journal of Clinical Nutrition Mar 2017Obesity is a physiological condition of chronic positive energy balance. While the regulation of energy metabolism varies widely among individuals, identifying those who... (Review)
Review
Obesity is a physiological condition of chronic positive energy balance. While the regulation of energy metabolism varies widely among individuals, identifying those who are metabolically prone to weight gain and intervening accordingly is a key challenge for reversing the course of the obesity epidemic. Indirect calorimetry is the most commonly used method to measure energy expenditure in the research setting. By measuring oxygen consumption and carbon dioxide production, indirect calorimetry provides minute-by-minute energy expenditure data that makes it the most valuable tool to distinguish the various components of energy expenditure, that is, sleeping and resting metabolic rate, thermic effect of food and the energy cost of activity. Importantly, such measures also provide information on energy substrate utilization. Here we summarized some of the research that revealed resting metabolic rate, spontaneous physical activity and respiratory quotient as key metabolic predictors of weight gain and obesity. Recent studies using indirect calorimetry in response to mid-term fasting or overfeeding have identified 'thrifty' and 'spendthrift' phenotypes in people who differ in propensity to weight gain. We propose the use of indirect calorimetry data as a basis for personalized interventions that may be efficacious in slowing down the rise of global obesity.
Topics: Body Composition; Calorimetry, Indirect; Energy Metabolism; Exercise; Humans; Models, Theoretical; Obesity; Sleep; Weight Gain
PubMed: 27848941
DOI: 10.1038/ejcn.2016.220 -
Journal of Experimental Botany Aug 2019The sulfur metabolism pathway in plants produces a variety of compounds that are central to the acclimation response to oxidative stresses such as drought and high... (Review)
Review
The sulfur metabolism pathway in plants produces a variety of compounds that are central to the acclimation response to oxidative stresses such as drought and high light. Primary sulfur assimilation provides the amino acid cysteine, which is utilized in protein synthesis and as a precursor for the cellular redox buffer glutathione. In contrast, the secondary sulfur metabolism pathway produces sulfated compounds such as glucosinolates and sulfated peptides, as well as a corresponding by-product 3'-phosphoadenosine 5'-phosphate (PAP). Emerging evidence over the past decade has shown that secondary sulfur metabolism also has a crucial engagement during oxidative stress. This occurs across various cellular, tissue, and organismal levels including chloroplast-to-nucleus retrograde signalling events mediated by PAP, modulation of hormonal signalling by sulfated compounds and PAP, control of physiological responses such as stomatal closure, and potential regulation of plant growth. In this review, we examine the contribution of the different components of plant secondary metabolism to oxidative stress homeostasis, and how this pathway is metabolically regulated. We further outline the key outstanding questions in the field that are necessary to understand how and why this 'specialized' metabolic pathway plays significant roles in plant oxidative stress tolerance.
Topics: Arabidopsis; Droughts; Gene Expression Regulation, Plant; Oxidative Stress; Secondary Metabolism; Signal Transduction; Sulfur
PubMed: 30868163
DOI: 10.1093/jxb/erz119