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Accounts of Chemical Research Nov 2022Signaling lipids, such as the endocannabinoids, play an important role in the brain. They regulate synaptic transmission and control various neurophysiological... (Review)
Review
Signaling lipids, such as the endocannabinoids, play an important role in the brain. They regulate synaptic transmission and control various neurophysiological processes, including pain sensation, appetite, memory formation, stress, and anxiety. Unlike classical neurotransmitters, lipid messengers are produced on demand and degraded by metabolic enzymes to control their lifespan and signaling actions. Chemical biology approaches have become one of the main driving forces to study and unravel the physiological role of lipid messengers in the brain. Here, we review how the development and use of chemical probes has allowed one to study endocannabinoid signaling by (i) inhibiting the biosynthetic and metabolic enzymes; (ii) visualizing the activity of these enzymes; and (iii) controlling the release and transport of the endocannabinoids. Activity-based probes were instrumental to guide the discovery of highly selective and in vivo active inhibitors of the biosynthetic (DAGL, NAPE-PLD) and metabolic (MAGL, FAAH) enzymes of endocannabinoids. These inhibitors allowed one to study the role of these enzymes in animal models of disease. For instance, the DAGL-MAGL axis was shown to control neuroinflammation and the NAPE-PLD-FAAH axis to regulate emotional behavior. Activity-based protein profiling and chemical proteomics were essential to guide the drug discovery and development of compounds targeting MAGL and FAAH, such as ABX-1431 (Lu AG06466) and PF-04457845, respectively. These experimental drugs are now in clinical trials for multiple indications, including multiple sclerosis and post-traumatic stress disorders. Activity-based probes have also been used to visualize the activity of these lipid metabolizing enzymes with high spatial resolution in brain slices, thereby showing the cell type-specific activity of these lipid metabolizing enzymes. The transport, release, and uptake of signaling lipids themselves cannot, however, be captured by activity-based probes in a spatiotemporal controlled manner. Therefore, bio-orthogonal lipids equipped with photoreactive, photoswitchable groups or photocages have been developed. These chemical probes were employed to investigate the protein interaction partners of the endocannabinoids, such as putative membrane transporters, as well as to study the functional cellular responses within milliseconds upon irradiation. Finally, genetically encoded sensors have recently been developed to monitor the real-time release of endocannabinoids with high spatiotemporal resolution in cultured neurons, acute brain slices, and in vivo mouse models. It is anticipated that the combination of chemical probes, highly selective inhibitors, and sensors with advanced (super resolution) imaging modalities, such as PharmacoSTORM and correlative light-electron microscopy, will uncover the fundamental basis of lipid signaling at nanoscale resolution in the brain. Furthermore, chemical biology approaches enable the translation of these fundamental discoveries into clinical solutions for brain diseases with aberrant lipid signaling.
Topics: Animals; Mice; Endocannabinoids; Lipid Metabolism; Brain; Neurons; Synaptic Transmission
PubMed: 36283077
DOI: 10.1021/acs.accounts.2c00521 -
Physical Review Letters Jul 2023Predicting cellular metabolic states is a central problem in biophysics. Conventional approaches, however, sensitively depend on the microscopic details of individual...
Predicting cellular metabolic states is a central problem in biophysics. Conventional approaches, however, sensitively depend on the microscopic details of individual metabolic systems. In this Letter, we derived a universal linear relationship between the metabolic responses against nutrient conditions and metabolic inhibition, with the aid of a microeconomic theory. The relationship holds in arbitrary metabolic systems as long as the law of mass conservation stands, as supported by extensive numerical calculations. It offers quantitative predictions without prior knowledge of systems.
Topics: Models, Biological; Metabolism
PubMed: 37505963
DOI: 10.1103/PhysRevLett.131.028401 -
Obesity Reviews : An Official Journal... Sep 2020This systematic review has examined more than 300 original papers dealing with the biology of overfeeding. Studies have varied from 1 day to 6 months. Overfeeding... (Review)
Review
This systematic review has examined more than 300 original papers dealing with the biology of overfeeding. Studies have varied from 1 day to 6 months. Overfeeding produced weight gain in adolescents, adult men and women and in older men. In longer term studies, there was a clear and highly significant relationship between energy ingested and weight gain and fat storage with limited individual differences. There is some evidence for a contribution of a genetic component to this response variability. The response to overfeeding was affected by the baseline state of the groups being compared: those with insulin resistance versus insulin sensitivity; those prone to obesity versus those resistant to obesity; and those with metabolically abnormal obesity versus those with metabolically normal obesity. Dietary components, such as total fat, polyunsaturated fat and carbohydrate influenced the patterns of adipose tissue distribution as did the history of low or normal birth weight. Overfeeding affected the endocrine system with increased circulating concentrations of insulin and triiodothyronine frequently present. Growth hormone, in contrast, was rapidly suppressed. Changes in plasma lipids were influenced by diet, exercise and the magnitude of weight gain. Adipose tissue and skeletal muscle morphology and metabolism are substantially altered by chronic overfeeding.
Topics: Adipose Tissue; Adolescent; Adult; Aged; Biology; Energy Metabolism; Female; Humans; Hyperphagia; Insulin Resistance; Male; Obesity; Weight Gain
PubMed: 32515127
DOI: 10.1111/obr.13040 -
The Journal of Endocrinology Oct 2020Endogenous circadian clocks adapt an organism's physiology and behavior to predictable changes in the environment as a consequence of the Earth's rotation around its... (Review)
Review
Endogenous circadian clocks adapt an organism's physiology and behavior to predictable changes in the environment as a consequence of the Earth's rotation around its axis. In mammals, circadian rhythms are the output of a ubiquitous network of cellular timers coordinated by a hypothalamic master pacemaker. Circadian clock function is closely connected to the stress response system which has evolved to ensure survival under less predictable situations of danger. Disruptions in both of these functions are highly prevalent in modern society and have been linked to pathologic alterations in metabolic setpoints, promoting overeating, obesity, and type-2 diabetes. This paper describes the different levels of interaction between the circadian clock and acute and chronic stress responses. It summarizes studies assessing clock-stress crosstalk in the context of metabolic homeostasis and outlines options to use this interaction for diagnostic and therapeutic measures targeting metabolic health and well-being in the highly chronodisruptive environment of modern 24-h globalized societies.
Topics: Animals; Circadian Clocks; Circadian Rhythm; Energy Metabolism; Homeostasis; Humans; Mammals; Metabolism; Stress, Physiological; Stress, Psychological
PubMed: 32738123
DOI: 10.1530/JOE-20-0124 -
Nature Communications Mar 2023Metabolic phenotypes are pivotal for many areas, but disentangling how evolutionary history and environmental adaptation shape these phenotypes is an open problem....
Metabolic phenotypes are pivotal for many areas, but disentangling how evolutionary history and environmental adaptation shape these phenotypes is an open problem. Especially for microbes, which are metabolically diverse and often interact in complex communities, few phenotypes can be determined directly. Instead, potential phenotypes are commonly inferred from genomic information, and rarely were model-predicted phenotypes employed beyond the species level. Here, we propose sensitivity correlations to quantify similarity of predicted metabolic network responses to perturbations, and thereby link genotype and environment to phenotype. We show that these correlations provide a consistent functional complement to genomic information by capturing how network context shapes gene function. This enables, for example, phylogenetic inference across all domains of life at the organism level. For 245 bacterial species, we identify conserved and variable metabolic functions, elucidate the quantitative impact of evolutionary history and ecological niche on these functions, and generate hypotheses on associated metabolic phenotypes. We expect our framework for the joint interpretation of metabolic phenotypes, evolution, and environment to help guide future empirical studies.
Topics: Phylogeny; Phenotype; Genotype; Metabolic Networks and Pathways; Genomics; Gene Regulatory Networks
PubMed: 36973280
DOI: 10.1038/s41467-023-37429-5 -
Free Radical Biology & Medicine Apr 2021Mitochondria are essential signaling organelles that regulate a broad range of cellular processes and thereby heart function. Multiple mechanisms participate in the... (Review)
Review
Mitochondria are essential signaling organelles that regulate a broad range of cellular processes and thereby heart function. Multiple mechanisms participate in the communication between mitochondria and the nucleus that maintain cardiomyocyte homeostasis, including mitochondrial reactive oxygen species (ROS) and metabolic shifts in TCA cycle metabolite availability. An increased rate of ROS generation can cause irreversible damage to the cell and proposed to be a leading cause of many pathologies, including accelerated aging and heart disease. Myocardial impairments are also characterised by specific coordinated metabolic changes and dysregulated inflammatory responses. Hence, the mitochondrial respiratory chain is an important mediator between health and disease in the heart. This review will first outline the sources of ROS in the heart, mitochondrial metabolite dynamics, and provide an overview of their implications for heart disease. In addition, we will concentrate our discussion around current cardioprotective strategies relevant to mitochondrial ROS. Thorough understanding of mitochondrial signaling and the complex interplay with vital signaling pathways in the heart might allow us to develop novel therapeutic approaches to cardiovascular disease.
Topics: Citric Acid Cycle; Mitochondria; Oxidation-Reduction; Oxidative Stress; Reactive Oxygen Species
PubMed: 33675958
DOI: 10.1016/j.freeradbiomed.2021.02.041 -
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 -
Cells Mar 2021Mast cells are essential first responder granulocytes in the innate immune system that are well known for their role in type 1 immune hypersensitivity reactions.... (Review)
Review
Mast cells are essential first responder granulocytes in the innate immune system that are well known for their role in type 1 immune hypersensitivity reactions. Although mostly recognized for their role in allergies, mast cells have a range of influences on other systems throughout the body and can respond to a wide range of agonists to properly prime an appropriate immune response. Mast cells have a dynamic energy metabolism to allow rapid responsiveness to their energetic demands. However, our understanding of mast cell metabolism and its impact on mast cell activation and development is still in its infancy. Mast cell metabolism during stimulation and development shifts between both arms of metabolism: catabolic metabolism-such as glycolysis and oxidative phosphorylation-and anabolic metabolism-such as the pentose phosphate pathway. The potential for metabolic pathway shifts to precede and perhaps even control activation and differentiation provides an exciting opportunity to explore energy metabolism for clues in deciphering mast cell function. In this review, we discuss literature pertaining to metabolic environments and fluctuations during different sources of activation, especially IgE mediated vs. non-IgE mediated, and mast cell development, including progenitor cell types leading to the well-known resident mast cell.
Topics: Cell Differentiation; Energy Metabolism; Humans; Mast Cells
PubMed: 33801300
DOI: 10.3390/cells10030524 -
International Journal of Molecular... May 2020The metabolic abnormality observed in tumors is characterized by the dependence of cancer cells on glycolysis for their energy requirements. Cancer cells also exhibit a... (Review)
Review
The metabolic abnormality observed in tumors is characterized by the dependence of cancer cells on glycolysis for their energy requirements. Cancer cells also exhibit a high level of reactive oxygen species (ROS), largely due to the alteration of cellular bioenergetics. A highly coordinated interplay between tumor energetics and ROS generates a powerful phenotype that provides the tumor cells with proliferative, antiapoptotic, and overall aggressive characteristics. In this review article, we summarize the literature on how ROS impacts energy metabolism by regulating key metabolic enzymes and how metabolic pathways e.g., glycolysis, PPP, and the TCA cycle reciprocally affect the generation and maintenance of ROS homeostasis. Lastly, we discuss how metabolic adaptation in cancer influences the tumor's response to chemotherapeutic drugs. Though attempts of targeting tumor energetics have shown promising preclinical outcomes, the clinical benefits are yet to be fully achieved. A better understanding of the interaction between metabolic abnormalities and involvement of ROS under the chemo-induced stress will help develop new strategies and personalized approaches to improve the therapeutic efficiency in cancer patients.
Topics: Adaptation, Physiological; Animals; Drug Resistance, Neoplasm; Energy Metabolism; Glycolysis; Homeostasis; Humans; Metabolic Networks and Pathways; Neoplasms; Reactive Oxygen Species
PubMed: 32408513
DOI: 10.3390/ijms21103412 -
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