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Molecular Systems Biology Oct 2021Cells metabolize nutrients through a complex metabolic and signaling network that governs redox homeostasis. At the core of this, redox regulatory network is a mutually...
Cells metabolize nutrients through a complex metabolic and signaling network that governs redox homeostasis. At the core of this, redox regulatory network is a mutually inhibitory relationship between reduced glutathione and reactive oxygen species (ROS)-two opposing metabolites that are linked to upstream nutrient metabolic pathways (glucose, cysteine, and glutamine) and downstream feedback loops of signaling pathways (calcium and NADPH oxidase). We developed a nutrient-redox model of human cells to understand system-level properties of this network. Combining in silico modeling and ROS measurements in individual cells, we show that ROS dynamics follow a switch-like, all-or-none response upon glucose deprivation at a threshold that is approximately two orders of magnitude lower than its physiological concentration. We also confirm that this ROS switch can be irreversible and exhibits hysteresis, a hallmark of bistability. Our findings evidence that bistability modulates redox homeostasis in human cells and provide a general framework for quantitative investigations of redox regulation in humans.
Topics: Glutathione; Homeostasis; Humans; Oxidation-Reduction; Reactive Oxygen Species; Signal Transduction
PubMed: 34612597
DOI: 10.15252/msb.202110480 -
Clinical Nutrition (Edinburgh, Scotland) May 2021Owing to the "obesity-pandemic", an increasing number of individuals are in need of treatment for obesity and obesity-related disorders. For patients with severe... (Review)
Review
BACKGROUND & AIMS
Owing to the "obesity-pandemic", an increasing number of individuals are in need of treatment for obesity and obesity-related disorders. For patients with severe disease, results with conventional treatment modalities such as diet regimens, physical activity, and pharmacologic agents most often lack satisfactory efficacy and/or sustainability. In contrast, bariatric surgery has been demonstrated to be associated with marked, long-term weight loss as well as resolution or improvement of co-morbid disease, in particular metabolic aberrations such as insulin resistance and type 2 diabetes. The underlying mechanisms for the effects of surgery-induced weight loss on such morbidity are incompletely understood.
METHODS
This article gives an updated overview of some aspects on the mechanisms involved in the improvement in metabolism in obese individuals submitted to surgery-induced weight loss. Patients undergoing Roux en-Y Gastric Bypass (RYGB) were studied before and at various times after the operation. Weight, body composition with determination of distribution of adipose tissue (DEXA), and insulin sensitivity (hyperinsulinemic clamp) was determined. In vitro; lipolytic activity and adipose morphology (fat cell size) was assessed.
RESULTS
Low calorie intake, rerouting of nutrients as well as loss of fat mass are all associated with improved insulin sensitivity after RYGB. In obese individuals, an increase in lipolytic activity in visceral adipose tissue might contribute to the association with cardiometabolic disease. However, selective reduction (omentectomy) seems not to improve insulin sensitivity or cardiometabolic risk. Adipose hyperplasia (many small cells) might be protective against metabolic abnormalities compared to hypertrophy (large cells). Preoperative fat cell size is related to improvement in insulin sensitivity after RYGB. Two years after weight loss, a change in adipose morphology to a more metabolically benign phenotype (remodeling) is seen, with a reduction of fat cell size which is correlated to the improvement in insulin sensitivity. Patients with weight regain 5 years after RYGB, still display a more benign metabolic profile compared to weight-matched controls.
CONCLUSIONS
Several factors contribute to the improvements in insulin sensitivity and cardiometabolic disease after surgery-induced weight loss, including low calorie intake rerouting of nutrients and loss of adipose tissue mass. Increased lipolytic activity in visceral adipose tissue as well as adipose hypertrophy relates to increased metabolic risk. RYGB-induced weight loss is associated with redistribution of adipose tissue as well as remodeling of fat cells to a more benign profile. Reduction of fat cell size might be a possible target to improve insulin sensitivity in patients with obesity in the future.
Topics: Bariatric Surgery; Energy Intake; Energy Metabolism; Humans; Obesity
PubMed: 33933726
DOI: 10.1016/j.clnu.2021.03.044 -
Journal of Personalized Medicine Jul 2023Due to the chronic relapsing nature of mental disorders and increased life expectancy, the societal burden of these non-communicable diseases will increase even further.... (Review)
Review
Due to the chronic relapsing nature of mental disorders and increased life expectancy, the societal burden of these non-communicable diseases will increase even further. Treatments for mental disorders, such as depression, are available, but their effect is limited due to patients' (genetic) heterogeneity, low treatment compliance and frequent side effects. In general, only one-third of the patients respond to treatment. Today, medication selection in psychiatry relies on a trial-and-error approach based mainly on physicians' experience. Pharmacogenetic (PGx) testing can help in this process by determining the person-specific genetic factors that may predict clinical response and side effects associated with genetic variants that impact drug-metabolizing enzymes, drug transporters or drug targets. PGxis a discipline that investigates genetic factors that affect the absorption, metabolism, and transport of drugs, thereby affecting therapy outcome. These genetic factors can, among other things, lead to differences in the activity of enzymes that metabolize drugs. Studies in depressed patients show that genotyping of drug-metabolizing enzymes can increase the effectiveness of treatment, which could benefit millions of patients worldwide. This review highlights these studies, gives recommendations and provides future perspectives on how to proceed with PGx testing. Finally, it is recommended to consider genotyping for and , when there is an indication (side effects or inefficacy).
PubMed: 37511796
DOI: 10.3390/jpm13071183 -
Annual Review of Physiology Feb 2024The perception of adipose tissue as a metabolically quiescent tissue, primarily responsible for lipid storage and energy balance (with some endocrine, thermogenic, and... (Review)
Review
The perception of adipose tissue as a metabolically quiescent tissue, primarily responsible for lipid storage and energy balance (with some endocrine, thermogenic, and insulation functions), has changed. It is now accepted that adipose tissue is a crucial regulator of metabolic health, maintaining bidirectional communication with other organs including the cardiovascular system. Additionally, adipose tissue depots are functionally and morphologically heterogeneous, acting not only as sources of bioactive molecules that regulate the physiological functioning of the vasculature and myocardium but also as biosensors of the paracrine and endocrine signals arising from these tissues. In this way, adipose tissue undergoes phenotypic switching in response to vascular and/or myocardial signals (proinflammatory, profibrotic, prolipolytic), a process that novel imaging technologies are able to visualize and quantify with implications for clinical prognosis. Furthermore, a range of therapeutic modalities have emerged targeting adipose tissue metabolism and altering its secretome, potentially benefiting those at risk of cardiovascular disease.
Topics: Humans; Cardiovascular Diseases; Adipose Tissue; Myocardium; Energy Metabolism
PubMed: 37931169
DOI: 10.1146/annurev-physiol-042222-021346 -
Appetite 2008Anticipatory physiological regulation is an adaptive strategy that enables animals to respond faster to physiologic and metabolic challenges. The cephalic phase... (Review)
Review
Anticipatory physiological regulation is an adaptive strategy that enables animals to respond faster to physiologic and metabolic challenges. The cephalic phase responses are anticipatory responses that prepare animals to digest, absorb, and metabolize nutrients. They enable the sensory aspects of the food to interact with the metabolic state of the animal to influence feeding behavior. The anticipatory digestive secretions and metabolic adjustments in response to food cues are key adaptations that affect digestive and metabolic efficiency and aid in controlling the resulting elevation of metabolic fuels in the blood. Cephalic phase responses enable digestion, metabolism, and appetite to be regulated in a coordinated fashion. These responses have significant effects on meal size. For example, if the cephalic phase insulin response is blocked the result is poor glucose control and smaller meals. Cephalic phase responses also are linked to motivation to feed, and may play a more direct role in regulating meal size beyond the permissive one of ameliorating negative consequences of feeding. For example, the orexigenic peptide ghrelin appears to display a cephalic phase response, rising before expected meal times. This anticipatory ghrelin response increases appetite; interestingly it also enhances fat absorption, linking appetite with digestion and metabolism.
Topics: Brain; Digestion; Eating; Homeostasis; Humans; Intestinal Absorption; Metabolism; Reflex; Smell; Taste
PubMed: 18045735
DOI: 10.1016/j.appet.2007.10.006 -
Environmental Health Perspectives Apr 1984The lung is a metabolically active organ that is engaged in secretion, clearance and other maintenance functions that require reducing potential, energy and substrates... (Review)
Review
The lung is a metabolically active organ that is engaged in secretion, clearance and other maintenance functions that require reducing potential, energy and substrates for biosynthesis. These metabolic requirements are met in part through uptake and catabolism of glucose which represents the major fuel utilized by lung tissues. Gluconeogenesis does not occur, and glycogen stores are limited so that the lung depends on the circulation for its glucose requirement. Other substrates can be metabolized by lung and contribute to the metabolic pool although their role has been less thoroughly studied. Glucose is catabolized in the lung by cytoplasmic and mitochondrial pathways that are responsive to regulatory mechanisms as in other tissues. Activity of the pentose cycle pathway of glucose catabolism is relatively high and generates the NADPH required for biosynthesis of lipid, detoxification reactions, and protection against oxidant stress. The ATP content of the lung is maintained by oxidative metabolism at levels comparable to other metabolically active organs. Alterations in lung intermediary metabolism may depress amine clearance, alter lung permeability, and influence the lung response to oxidant stress.
Topics: Adenosine Triphosphate; Animals; Biogenic Amines; Biological Transport, Active; Biotransformation; Cytoplasm; Energy Metabolism; Gluconeogenesis; Glucose; Glycolysis; Lung; Mitochondria; NAD; NADP; Oxygen; Oxygen Consumption; Pulmonary Edema; Rats
PubMed: 6376097
DOI: 10.1289/ehp.8455149 -
Drug Metabolism and Personalized Therapy Jun 2015Drug-metabolizing enzymes play a major role in the biotransformation and subsequent elimination of most drugs and xenobiotics from the body. Both phase I and phase II... (Review)
Review
Drug-metabolizing enzymes play a major role in the biotransformation and subsequent elimination of most drugs and xenobiotics from the body. Both phase I and phase II enzymes are highly polymorphic. Inter-individual differences in genes coding for drug-metabolizing enzymes are important for understanding variability in drug response and for individualization of drug prescription. The prevalence of genetic polymorphisms in drug metabolism varies widely with ethnicity, and marked differences in the distribution of allelic variants of genes encoding drug-metabolizing enzymes have been documented in populations of different racial origin. This review aimed to summarize the available studies on genetic polymorphisms associated with drug metabolism conducted in Italian populations and to compare the frequency of the various metabolizer phenotypes and most common variant alleles (and resulting genotypes) with corresponding values from other populations. Notably, published data are not extensive, and most studies were performed on relatively low numbers of individuals. In general, the frequency of polymorphisms in the cytochrome P450 (CYP) genes as well as in the investigated phase II enzymes in the Italian population was similar to values reported for other Caucasian populations. However, the prevalence of CYP2D6 gene duplication among Italians was found to be very high, confirming the higher frequency of CYP2D6 ultrarapid metabolizers in the Mediterranean area compared to Northern Europe. It is worth noting that a geographic gradient in the flavin-containing monooxygenase 3 polymorphism distribution was also seen, the Italian population showing higher similarity to other Mediterranean populations than to North Europeans.
Topics: Adult; Aged; Catechol O-Methyltransferase; Cytochrome P-450 Enzyme System; Genotype; Glucuronosyltransferase; Glutathione Transferase; Humans; Italy; Methyltransferases; Middle Aged; N-Terminal Acetyltransferases; Pharmaceutical Preparations; Polymorphism, Genetic; Sulfotransferases
PubMed: 25527811
DOI: 10.1515/dmdi-2014-0028 -
Journal of Innate Immunity 2022Immunological memory is classically attributed to adaptive immune responses, but recent studies have shown that challenged innate immune cells can display long-term... (Review)
Review
Immunological memory is classically attributed to adaptive immune responses, but recent studies have shown that challenged innate immune cells can display long-term functional changes that increase nonspecific responsiveness to subsequent infections. This phenomenon, coined trained immunity or innate immune memory, is based on the epigenetic reprogramming and the rewiring of intracellular metabolic pathways. Here, we review the different metabolic pathways that are modulated in trained immunity. Glycolysis, oxidative phosphorylation, the tricarboxylic acid cycle, amino acid, and lipid metabolism are interplaying pathways that are crucial for the establishment of innate immune memory. Unraveling this metabolic wiring allows for a better understanding of innate immune contribution to health and disease. These insights may open avenues for the development of future therapies that aim to harness or dampen the power of the innate immune response.
Topics: Epigenesis, Genetic; Glycolysis; Immunity, Innate; Immunologic Memory; Metabolic Networks and Pathways
PubMed: 33378755
DOI: 10.1159/000512280 -
American Journal of Physiology. Heart... Apr 2013Ketone bodies are metabolized through evolutionarily conserved pathways that support bioenergetic homeostasis, particularly in brain, heart, and skeletal muscle when... (Review)
Review
Ketone bodies are metabolized through evolutionarily conserved pathways that support bioenergetic homeostasis, particularly in brain, heart, and skeletal muscle when carbohydrates are in short supply. The metabolism of ketone bodies interfaces with the tricarboxylic acid cycle, β-oxidation of fatty acids, de novo lipogenesis, sterol biosynthesis, glucose metabolism, the mitochondrial electron transport chain, hormonal signaling, intracellular signal transduction pathways, and the microbiome. Here we review the mechanisms through which ketone bodies are metabolized and how their signals are transmitted. We focus on the roles this metabolic pathway may play in cardiovascular disease states, the bioenergetic benefits of myocardial ketone body oxidation, and prospective interactions among ketone body metabolism, obesity, metabolic syndrome, and atherosclerosis. Ketone body metabolism is noninvasively quantifiable in humans and is responsive to nutritional interventions. Therefore, further investigation of this pathway in disease models and in humans may ultimately yield tailored diagnostic strategies and therapies for specific pathological states.
Topics: Animals; Cardiomyopathies; Cardiovascular Diseases; Coenzyme A-Transferases; Fatty Acids; Humans; Hydroxymethylglutaryl-CoA Synthase; Ketone Bodies; Lipogenesis; Liver; Mitochondria, Heart; Mitochondria, Liver; Myocardium; Obesity; Oxidation-Reduction; Signal Transduction
PubMed: 23396451
DOI: 10.1152/ajpheart.00646.2012 -
International Journal of Molecular... Feb 2021RNA modifications are diverse post-transcriptional modifications that regulate RNA metabolism and gene expression. RNA modifications, and the writers, erasers, and... (Review)
Review
RNA modifications are diverse post-transcriptional modifications that regulate RNA metabolism and gene expression. RNA modifications, and the writers, erasers, and readers that catalyze these modifications, serve as important signaling machineries in cellular stress responses and disease pathogenesis. In response to stress, RNA modifications are mobilized to activate or inhibit the signaling pathways that combat stresses, including oxidative stress, hypoxia, therapeutic stress, metabolic stress, heat shock, DNA damage, and ER stress. The role of RNA modifications in response to these cellular stressors is context- and cell-type-dependent. Due to their pervasive roles in cell biology, RNA modifications have been implicated in the pathogenesis of different diseases, including cancer, neurologic and developmental disorders and diseases, and metabolic diseases. In this review, we aim to summarize the roles of RNA modifications in molecular and cellular stress responses and diseases.
Topics: Animals; DNA Damage; Endoplasmic Reticulum Stress; Heat-Shock Response; Humans; Hypoxia; Metabolic Diseases; Neoplasms; Nervous System Diseases; Oxidative Stress; RNA; RNA Processing, Post-Transcriptional; Stress, Physiological
PubMed: 33669361
DOI: 10.3390/ijms22041949