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Trends in Biochemical Sciences Apr 2010The metabolic network has a modular architecture, is robust to perturbations, and responds to biological stimuli and environmental conditions. Through monitoring by... (Review)
Review
The metabolic network has a modular architecture, is robust to perturbations, and responds to biological stimuli and environmental conditions. Through monitoring by metabolite responsive macromolecules, metabolic pathways interact with the transcriptome and proteome. Whereas pathway interconnecting cofactors and substrates report on the overall state of the network, specialised intermediates measure the activity of individual functional units. Transitions in the network affect many of these regulatory metabolites, facilitating the parallel regulation of the timing and control of diverse biological processes. The metabolic network controls its own balance, chromatin structure and the biosynthesis of molecular cofactors; moreover, metabolic shifts are crucial in the response to oxidative stress and play a regulatory role in cancer.
Topics: Carbohydrate Metabolism; Metabolic Networks and Pathways; Transcription, Genetic
PubMed: 20060301
DOI: 10.1016/j.tibs.2009.12.001 -
Biochemical Society Transactions Apr 2012There is an intimate, yet poorly understood, link between cellular metabolic status, cell signalling and transcription. Central metabolic pathways are under the control... (Review)
Review
There is an intimate, yet poorly understood, link between cellular metabolic status, cell signalling and transcription. Central metabolic pathways are under the control of signalling pathways and, vice versa, the cellular metabolic profile influences cell signalling through the incorporation of various metabolic sensors into the signalling networks. Thus information about nutrients availability directly and crucially influences crucial cell decisions. In the present review, I summarize our current knowledge of various metabolic sensors and give some examples of the integration of metabolically derived inputs into the signalling system and the regulation of transcription. I also discuss the Warburg effect where the cross-talk between metabolism and signalling is used to orchestrate rapid cell growth and division. It is becoming clear that future research will concentrate on the collection of small-molecule metabolites, whose concentration fluctuates in response to cellular energy levels, searching for their sensors that connect them to the signalling and transcriptional networks.
Topics: Animals; Cell Proliferation; Cells; Energy Metabolism; Humans; Metabolic Networks and Pathways; Signal Transduction; Transcription, Genetic
PubMed: 22435805
DOI: 10.1042/BST20110767 -
Cancer Letters Mar 2023Immunometabolism, a branch of biology describing the link between immunity and metabolism, is an emerging topic in cancer immunology. It is currently well accepted that... (Review)
Review
Immunometabolism, a branch of biology describing the link between immunity and metabolism, is an emerging topic in cancer immunology. It is currently well accepted that B cells and tertiary lymph structures formed by them are associated with favorable outcomes when patients undergo cancer immunotherapy. Understanding the determinants of B-cell fate and function in cancer patients is necessary for improving cancer immunotherapy. Accumulating evidence points to the tumor microenvironment being a critical metabolic hurdle to an efficient antitumor B-cell response. At the same time, several B-cell-derived metabolites have recently been reported to inhibit anticancer immunity. In this literature review, key B-cell immunometabolism studies and the metabolic life of B cells were summarized. Then, we discussed the intrinsic metabolic pathways of B cells themselves and how the tumor microenvironment and B cells in tumors metabolically influence each other. Finally, we pointed out key questions to provide some inspiration for further study of the role of B-cell immunometabolism in the antitumor immune response.
Topics: Humans; Neoplasms; Immunity; Immunotherapy; Metabolic Networks and Pathways; Tumor Microenvironment
PubMed: 36724837
DOI: 10.1016/j.canlet.2023.216076 -
Reproduction in Domestic Animals =... Oct 2016The placenta is a dynamic, metabolically active organ with significant nutrient and energy requirements for growth, nutrient transfer and protein synthesis. It uses a... (Review)
Review
The placenta is a dynamic, metabolically active organ with significant nutrient and energy requirements for growth, nutrient transfer and protein synthesis. It uses a range of substrates to meet its energy needs and has a higher rate of oxygen (O ) consumption than many other foetal and adult tissues. Placental metabolism varies with species and alters in response to a range of nutritional and endocrine signals of adverse environmental conditions. The placenta integrates these signals and adapts its metabolic phenotype to help maintain pregnancy and to optimize offspring fitness by diversifying the sources of carbon and nitrogen available for energy production, hormone synthesis and foeto-placental growth. The metabolic response of the placenta to adversity depends on the nature, severity and duration of the stressful challenge and on whether the insult is maternal, placental or foetal in origin. This review examines placental metabolism and its response to stresses common in pregnancy with particular emphasis on farm species like the sheep. It also considers the consequences of changes in placental metabolism for the supply of O and nutrients to the foetus.
Topics: Amino Acids; Animals; Animals, Domestic; Energy Metabolism; Fatty Acids; Female; Fetus; Glucose; Maternal-Fetal Exchange; Oxygen Consumption; Phenotype; Placenta; Pregnancy; Sheep; Signal Transduction; Stress, Physiological
PubMed: 27762057
DOI: 10.1111/rda.12797 -
Advances in Experimental Medicine and... 2019The liver plays a capital role in the control of whole body energy homeostasis through the metabolization of dietary carbohydrates and lipids. However, under excess... (Review)
Review
The liver plays a capital role in the control of whole body energy homeostasis through the metabolization of dietary carbohydrates and lipids. However, under excess macronutrient uptake, those pathways overcharge nucleus-to-endoplasmic reticulum (ER) traffic pathways, leading to luminal overload of unfolded proteins which activates a series of adaptive signaling pathways known as unfolded protein response (UPR). The UPR is a central network mechanism for cellular stress adaptation, however far from a global nonspecific all-or-nothing response. Such a complex signaling network is able to display considerable specificity of responses, with activation of specific signaling branches trimmed for distinct types of stimuli. This makes the UPR a fundamental mechanism underlying metabolic processes and diseases, especially those related to lipid and carbohydrate metabolism. Thus, for a better understanding of the role of UPR on the physiopathology of lipid metabolism disorders, the concepts discussed along this chapter will demonstrate how several metabolic derangements activate UPR components and, in turn, how UPR triggers several metabolic adaptations through its component signaling proteins. This dual role of UPR on lipid metabolism will certainly foment the pursuit of an answer for the question: is UPR cause or consequence of lipid and lipoprotein metabolism disturbances?
Topics: Endoplasmic Reticulum; Lipid Metabolism; Lipoproteins; Signal Transduction; Unfolded Protein Response
PubMed: 31140172
DOI: 10.1007/978-3-030-11488-6_5 -
The Journal of Endocrinology Aug 2023The gastrointestinal system is now considered the largest endocrine organ, highlighting the importance of gut-derived peptides and metabolites in metabolic homeostasis.... (Review)
Review
The gastrointestinal system is now considered the largest endocrine organ, highlighting the importance of gut-derived peptides and metabolites in metabolic homeostasis. Gut peptides are secreted from intestinal enteroendocrine cells in response to nutrients, microbial metabolites, and neural and hormonal factors, and they regulate systemic metabolism via multiple mechanisms. While extensive research is focused on the neuroendocrine effects of gut peptides, evidence suggests that several of these hormones act as endocrine signaling molecules with direct effects on the target organ, especially in a therapeutic setting. Additionally, the gut microbiota metabolizes ingested nutrients and fiber to produce compounds that impact host metabolism indirectly, through gut peptide secretion, and directly, acting as endocrine factors. This review will provide an overview of the role of endogenous gut peptides in metabolic homeostasis and disease, as well as the potential endocrine impact of microbial metabolites on host metabolic tissue function.
Topics: Gastrointestinal Microbiome; Energy Metabolism; Endocrine System; Homeostasis; Intestines
PubMed: 37171833
DOI: 10.1530/JOE-23-0019 -
Human Cell Jul 2023Metabolic and inflammatory pathways are highly interdependent, and both systems are dysregulated in Type 2 diabetes (T2D). T2D is associated with pre-activated... (Review)
Review
Metabolic and inflammatory pathways are highly interdependent, and both systems are dysregulated in Type 2 diabetes (T2D). T2D is associated with pre-activated inflammatory signaling networks, aberrant cytokine production and increased acute phase reactants which leads to a pro-inflammatory 'feed forward loop'. Nutrient 'excess' conditions in T2D with hyperglycemia, elevated lipids and branched-chain amino acids significantly alter the functions of immune cells including neutrophils. Neutrophils are metabolically active cells and utilizes energy from glycolysis, stored glycogen and β-oxidation while depending on the pentose phosphate pathway for NADPH for performing effector functions such as chemotaxis, phagocytosis and forming extracellular traps. Metabolic changes in T2D result in constitutive activation and impeded acquisition of effector or regulatory activities of neutrophils and render T2D subjects for recurrent infections. Increased flux through the polyol and hexosamine pathways, elevated production of advanced glycation end products (AGEs), and activation of protein kinase C isoforms lead to (a) an enhancement in superoxide generation; (b) the stimulation of inflammatory pathways and subsequently to (c) abnormal host responses. Neutrophil dysfunction diminishes the effectiveness of wound healing, successful tissue regeneration and immune surveillance against offending pathogens. Hence, Metabolic reprogramming in neutrophils determines frequency, severity and duration of infections in T2D. The present review discusses the influence of the altered immuno-metabolic axis on neutrophil dysfunction along with challenges and therapeutic opportunities for clinical management of T2D-associated infections.
Topics: Humans; Neutrophils; Diabetes Mellitus, Type 2; Glycolysis; Hyperglycemia; Oxidation-Reduction
PubMed: 37115481
DOI: 10.1007/s13577-023-00905-7 -
The Proceedings of the Nutrition Society Aug 2019This review examines the metabolic adaptations that occur in response to negative energy balance and their potential putative or functional impact on appetite and food... (Review)
Review
This review examines the metabolic adaptations that occur in response to negative energy balance and their potential putative or functional impact on appetite and food intake. Sustained negative energy balance will result in weight loss, with body composition changes similar for different dietary interventions if total energy and protein intake are equated. During periods of underfeeding, compensatory metabolic and behavioural responses occur that attenuate the prescribed energy deficit. While losses of metabolically active tissue during energy deficit result in reduced energy expenditure, an additional down-regulation in expenditure has been noted that cannot be explained by changes in body tissue (e.g. adaptive thermogenesis). Sustained negative energy balance is also associated with an increase in orexigenic drive and changes in appetite-related peptides during weight loss that may act as cues for increased hunger and food intake. It has also been suggested that losses of fat-free mass (FFM) could also act as an orexigenic signal during weight loss, but more data are needed to support these findings and the signalling pathways linking FFM and energy intake remain unclear. Taken together, these metabolic and behavioural responses to weight loss point to a highly complex and dynamic energy balance system in which perturbations to individual components can cause co-ordinated and inter-related compensatory responses elsewhere. The strength of these compensatory responses is individually subtle, and early identification of this variability may help identify individuals that respond well or poorly to an intervention.
Topics: Appetite; Body Composition; Body Weight; Energy Intake; Energy Metabolism; Humans; Obesity; Weight Loss
PubMed: 30777142
DOI: 10.1017/S0029665118002811 -
International Journal of Molecular... Feb 2021The metabolic microenvironment, comprising all soluble and insoluble nutrients and co-factors in the extracellular milieu, has a major impact on cancer cell... (Review)
Review
The metabolic microenvironment, comprising all soluble and insoluble nutrients and co-factors in the extracellular milieu, has a major impact on cancer cell proliferation and survival. A large body of evidence from recent studies suggests that tumor cells show a high degree of metabolic flexibility and adapt to variations in nutrient availability. Insufficient vascular networks and an imbalance of supply and demand shape the metabolic tumor microenvironment, which typically contains a lower concentration of glucose compared to normal tissues. The present review sheds light on the recent literature on adaptive responses in cancer cells to nutrient deprivation. It focuses on the utilization of alternative nutrients in anabolic metabolic pathways in cancer cells, including soluble metabolites and macromolecules and outlines the role of central metabolic enzymes conferring metabolic flexibility, like gluconeogenesis enzymes. Moreover, a conceptual framework for potential therapies targeting metabolically flexible cancer cells is presented.
Topics: Gluconeogenesis; Humans; Metabolic Networks and Pathways; Neoplasms; Signal Transduction; Tumor Microenvironment
PubMed: 33540663
DOI: 10.3390/ijms22031476 -
BMC Systems Biology Aug 2016The malarial parasite Plasmodium falciparum undergoes a complex life cycle, including an intraerythrocytic developmental cycle, during which it is metabolically...
BACKGROUND
The malarial parasite Plasmodium falciparum undergoes a complex life cycle, including an intraerythrocytic developmental cycle, during which it is metabolically dependent on the infected human red blood cell (RBC). To describe whole cell metabolic activity within both P. falciparum and RBCs during the asexual reproduction phase of the intraerythrocytic developmental cycle, we developed an integrated host-parasite metabolic modeling framework driven by time-dependent gene expression data.
RESULTS
We validated the model by reproducing the experimentally determined 1) stage-specific production of biomass components and their precursors in the parasite and 2) metabolite concentration changes in the medium of P. falciparum-infected RBC cultures. The model allowed us to explore time- and strain-dependent P. falciparum metabolism and hypothesize how host cell metabolism alters in response to malarial infection. Specifically, the metabolic analysis showed that uninfected RBCs that coexist with infected cells in the same culture decrease their production of 2,3-bisphosphoglycerate, an oxygen-carrying regulator, reducing the ability of hemoglobin in these cells to release oxygen. Furthermore, in response to parasite-induced oxidative stress, infected RBCs downgraded their glycolytic flux by using the pentose phosphate pathway and secreting ribulose-5-phosphate. This mechanism links individually observed experimental phenomena, such as glycolytic inhibition and ribulose-5-phosphate secretion, to the oxidative stress response.
CONCLUSIONS
Although the metabolic model does not incorporate regulatory mechanisms per se, alterations in gene expression levels caused by regulatory mechanisms are manifested in the model as altered metabolic states. This provides the model the capability to capture complex multicellular host-pathogen metabolic interactions of the infected RBC culture. The system-level analysis revealed complex relationships such as how the parasite can reduce oxygen release in uninfected cells in the presence of infected RBCs as well as the role of different metabolic pathways involved in the oxidative stress response of infected RBCs.
Topics: Erythrocytes; Glycolysis; Host-Parasite Interactions; Humans; Life Cycle Stages; Malaria, Falciparum; Oxidative Stress; Plasmodium falciparum; Species Specificity
PubMed: 27502771
DOI: 10.1186/s12918-016-0291-2