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Obesity (Silver Spring, Md.) May 2019One of the fundamental challenges in obesity research is to identify subjects prone to weight gain so that obesity and its comorbidities can be promptly prevented or... (Review)
Review
One of the fundamental challenges in obesity research is to identify subjects prone to weight gain so that obesity and its comorbidities can be promptly prevented or treated. The principles of thermodynamics as applied to human body energetics demonstrate that susceptibility to weight gain varies among individuals as a result of interindividual differences in energy expenditure and energy intake, two factors that counterbalance one another and determine daily energy balance and, ultimately, body weight change. This review focuses on the variability among individuals in human metabolism that determines weight change. Conflicting results have been reported about the role of interindividual differences in energy metabolism during energy balance in relation to future weight change. However, recent studies have shown that metabolic responses to acute, short-term dietary interventions that create energy imbalance, such as low-protein overfeeding or fasting for 24 hours, may reveal the underlying metabolic phenotype that determines the degree of resistance to diet-induced weight loss or the propensity to spontaneous weight gain over time. Metabolically "thrifty" individuals, characterized by a predilection for saving energy in settings of undernutrition and dietary protein restriction, display a minimal increase in plasma fibroblast growth factor 21 concentrations in response to a low-protein overfeeding diet and tend to gain more weight over time compared with metabolically "spendthrift" individuals. Similarly, interindividual variability in the causal relationship between energy expenditure and energy intake ("energy sensing") and in the metabolic response to cold exposure (e.g., brown adipose tissue activation) seems, to some extent, to be indicative of individual propensity to weight gain. Thus, an increased understanding and the clinical characterization of phenotypic differences in energy metabolism among individuals (metabolic profile) may lead to new strategies to prevent weight gain or improve weight-loss interventions by targeted therapies on the basis of metabolic phenotype and susceptibility to obesity in individual persons.
Topics: Energy Metabolism; Female; Humans; Male; Obesity; Weight Gain
PubMed: 31012296
DOI: 10.1002/oby.22456 -
Cell Metabolism Sep 2019Reactive microglia are a major pathological feature of Alzheimer's disease (AD). However, the exact role of microglia in AD pathogenesis is still unclear. Here, using...
Reactive microglia are a major pathological feature of Alzheimer's disease (AD). However, the exact role of microglia in AD pathogenesis is still unclear. Here, using metabolic profiling, we found that exposure to amyloid-β triggers acute microglial inflammation accompanied by metabolic reprogramming from oxidative phosphorylation to glycolysis. It was dependent on the mTOR-HIF-1α pathway. However, once activated, microglia reached a chronic tolerant phase as a result of broad defects in energy metabolisms and subsequently diminished immune responses, including cytokine secretion and phagocytosis. Using genome-wide RNA sequencing and multiphoton microscopy techniques, we further identified metabolically defective microglia in 5XFAD mice, an AD mouse model. Finally, we showed that metabolic boosting with recombinant interferon-γ treatment reversed the defective glycolytic metabolism and inflammatory functions of microglia, thereby mitigating the AD pathology of 5XFAD mice. Collectively, metabolic reprogramming is crucial for microglial functions in AD, and modulating metabolism might be a new therapeutic strategy for AD.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Cell Line; Cytokines; Disease Models, Animal; Female; Gene Expression Regulation; Glycolysis; Hypoxia-Inducible Factor 1, alpha Subunit; Inflammation; Interferon-gamma; Male; Mice; Mice, Inbred ICR; Mice, Transgenic; Microglia; Oxidative Phosphorylation; Phagocytosis; Recombinant Proteins; TOR Serine-Threonine Kinases
PubMed: 31257151
DOI: 10.1016/j.cmet.2019.06.005 -
Nature Reviews. Neurology Nov 2019Migraine can be regarded as a conserved, adaptive response that occurs in genetically predisposed individuals with a mismatch between the brain's energy reserve and... (Review)
Review
Migraine can be regarded as a conserved, adaptive response that occurs in genetically predisposed individuals with a mismatch between the brain's energy reserve and workload. Given the high prevalence of migraine, genotypes associated with the condition seem likely to have conferred an evolutionary advantage. Technological advances have enabled the examination of different aspects of cerebral metabolism in patients with migraine, and complementary animal research has highlighted possible metabolic mechanisms in migraine pathophysiology. An increasing amount of evidence - much of it clinical - suggests that migraine is a response to cerebral energy deficiency or oxidative stress levels that exceed antioxidant capacity and that the attack itself helps to restore brain energy homeostasis and reduces harmful oxidative stress levels. Greater understanding of metabolism in migraine offers novel therapeutic opportunities. In this Review, we describe the evidence for abnormalities in energy metabolism and mitochondrial function in migraine, with a focus on clinical data (including neuroimaging, biochemical, genetic and therapeutic studies), and consider the relationship of these abnormalities with the abnormal sensory processing and cerebral hyper-responsivity observed in migraine. We discuss experimental data to consider potential mechanisms by which metabolic abnormalities could generate attacks. Finally, we highlight potential treatments that target cerebral metabolism, such as nutraceuticals, ketone bodies and dietary interventions.
Topics: Animals; Brain; Energy Metabolism; Humans; Migraine Disorders; Mitochondria; Oxidative Stress; Treatment Outcome
PubMed: 31586135
DOI: 10.1038/s41582-019-0255-4 -
Cold Spring Harbor Perspectives in... Oct 2016Stress-signaling pathways are evolutionarily conserved and play an important role in the maintenance of homeostasis. These pathways are also critical for adaptation to... (Review)
Review
Stress-signaling pathways are evolutionarily conserved and play an important role in the maintenance of homeostasis. These pathways are also critical for adaptation to new cellular environments. The endoplasmic reticulum (ER) unfolded protein response (UPR) is activated by biosynthetic stress and leads to a compensatory increase in ER function. The JNK and p38 MAPK signaling pathways control adaptive responses to intracellular and extracellular stresses, including environmental changes such as UV light, heat, and hyperosmotic conditions, and exposure to inflammatory cytokines. Metabolic stress caused by a high-fat diet represents an example of a stimulus that coordinately activates both the UPR and JNK/p38 signaling pathways. Chronic activation of these stress-response pathways ultimately causes metabolic changes associated with obesity and altered insulin sensitivity. Stress-signaling pathways, therefore, represent potential targets for therapeutic intervention in the metabolic stress response and other disease processes.
Topics: Animals; Humans; MAP Kinase Signaling System; Oxidative Stress; Signal Transduction; Unfolded Protein Response; p38 Mitogen-Activated Protein Kinases
PubMed: 27698029
DOI: 10.1101/cshperspect.a006072 -
Annual Review of Immunology Apr 2019ATP, NAD, and nucleic acids are abundant purines that, in addition to having critical intracellular functions, have evolved extracellular roles as danger signals... (Review)
Review
ATP, NAD, and nucleic acids are abundant purines that, in addition to having critical intracellular functions, have evolved extracellular roles as danger signals released in response to cell lysis, apoptosis, degranulation, or membrane pore formation. In general ATP and NAD have excitatory and adenosine has anti-inflammatory effects on immune cells. This review focuses on recent advances in our understanding of purine release mechanisms, ectoenzymes that metabolize purines (CD38, CD39, CD73, ENPP1, and ENPP2/autotaxin), and signaling by key P2 purinergic receptors (P2X7, P2Y2, and P2Y12). In addition to metabolizing ATP or NAD, some purinergic ectoenzymes metabolize other inflammatory modulators, notably lysophosphatidic acid and cyclic GMP-AMP (cGAMP). Also discussed are extracellular signaling effects of NAD mediated by ADP-ribosylation, and epigenetic effects of intracellular adenosine mediated by modification of -adenosylmethionine-dependent DNA methylation.
Topics: ADP-Ribosylation; Adenosine Triphosphate; Animals; DNA Methylation; Humans; Inflammation; Lysophospholipids; Purines; Receptors, Purinergic; Signal Transduction
PubMed: 30676821
DOI: 10.1146/annurev-immunol-051116-052406 -
Molecular Metabolism Aug 2020Organisms can be primed by metabolic exposures to continue expressing response genes even once the metabolite is no longer available, and can affect the speed and... (Review)
Review
BACKGROUND
Organisms can be primed by metabolic exposures to continue expressing response genes even once the metabolite is no longer available, and can affect the speed and magnitude of responsive gene expression during subsequent exposures. This "metabolic transcriptional memory" can have a profound impact on the survivability of organisms in fluctuating environments.
SCOPE OF REVIEW
Here I present several examples of metabolic transcriptional memory in the microbial world and discuss what is known so far regarding the underlying mechanisms, which mainly focus on chromatin modifications, protein inheritance, and broad changes in metabolic network. From these lessons learned in microbes, some insights into the yet understudied human metabolic memory can be gained. I thus discuss the implications of metabolic memory in disease progression in humans - i.e., the memory of high blood sugar exposure and the resulting effects on diabetic complications.
MAJOR CONCLUSIONS
Carbon source shifts from glucose to other less preferred sugars such as lactose, galactose, and maltose for energy metabolism as well as starvation of a signal transduction precursor sugar inositol are well-studied examples of metabolic transcriptional memory in Escherichia coli and Saccharomyces cerevisiae. Although the specific factors guiding metabolic transcriptional memory are not necessarily conserved from microbes to humans, the same basic mechanisms are in play, as is observed in hyperglycemic memory. Exploration of new metabolic transcriptional memory systems as well as further detailed mechanistic analyses of known memory contexts in microbes is therefore central to understanding metabolic memory in humans, and may be of relevance for the successful treatment of the ever-growing epidemic of diabetes.
Topics: Animals; Escherichia coli; Galactose; Gene Expression; Gene Expression Regulation; Glucose; Humans; Metabolic Networks and Pathways; Metabolism; Saccharomyces cerevisiae; Transcriptional Activation
PubMed: 32240621
DOI: 10.1016/j.molmet.2020.01.019 -
Free Radical Biology & Medicine Sep 2018Inflammatory Arthritis is characterized by synovial proliferation, neovascularization and leukocyte extravasation leading to joint destruction and functional disability.... (Review)
Review
Inflammatory Arthritis is characterized by synovial proliferation, neovascularization and leukocyte extravasation leading to joint destruction and functional disability. Efficiency of oxygen supply to the synovium is poor due to the highly dysregulated synovial microvasculature. This along with the increased energy demands of activated infiltrating immune cells and inflamed resident cells leads to an hypoxic microenvironment and mitochondrial dysfunction. This favors an increase of reactive oxygen species, leading to oxidative damage which further promotes inflammation. In this adverse microenvironment synovial cells adapt to generate energy and switch their cell metabolism from a resting regulatory state to a highly metabolically active state which allows them to produce essential building blocks to support their proliferation. This metabolic shift results in the accumulation of metabolic intermediates which act as signaling molecules that further dictate the inflammatory response. Understanding the complex interplay between hypoxia-induced signaling pathways, oxidative stress and mitochondrial function will provide better insight into the underlying mechanisms of disease pathogenesis.
Topics: Animals; Humans; Hypoxia; Inflammation; Oxidation-Reduction; Oxidative Stress; Reactive Oxygen Species; Signal Transduction
PubMed: 29601945
DOI: 10.1016/j.freeradbiomed.2018.03.042 -
Nature Reviews. Rheumatology May 2017Immune cells constantly patrol the body via the bloodstream and migrate into multiple tissues where they face variable and sometimes demanding environmental conditions.... (Review)
Review
Immune cells constantly patrol the body via the bloodstream and migrate into multiple tissues where they face variable and sometimes demanding environmental conditions. Nutrient and oxygen availability can vary during homeostasis, and especially during the course of an immune response, creating a demand for immune cells that are highly metabolically dynamic. As an evolutionary response, immune cells have developed different metabolic programmes to supply them with cellular energy and biomolecules, enabling them to cope with changing and challenging metabolic conditions. In the past 5 years, it has become clear that cellular metabolism affects immune cell function and differentiation, and that disease-specific metabolic configurations might provide an explanation for the dysfunctional immune responses seen in rheumatic diseases. This Review outlines the metabolic challenges faced by immune cells in states of homeostasis and inflammation, as well as the variety of metabolic configurations utilized by immune cells during differentiation and activation. Changes in cellular metabolism that contribute towards the dysfunctional immune responses seen in rheumatic diseases are also briefly discussed.
Topics: Animals; Cell Differentiation; Homeostasis; Humans; Inflammation; Lymphocyte Activation; Metabolic Networks and Pathways
PubMed: 28331208
DOI: 10.1038/nrrheum.2017.37 -
Redox Biology Feb 2023The metabolic associated fatty liver disease (MAFLD) is a public health challenge, leading to a global increase in chronic liver disease. The respiratory exposure of...
The metabolic associated fatty liver disease (MAFLD) is a public health challenge, leading to a global increase in chronic liver disease. The respiratory exposure of silica nanoparticles (SiNPs) has revealed to induce hepatotoxicity. However, its role in the pathogenesis and progression of MAFLD was severely under-studied. In this context, the hepatic impacts of SiNPs were investigated in vivo and in vitro through using ApoE mice and free fatty acid (FFA)-treated L02 hepatocytes. Histopathological examinations and biochemical analysis showed SiNPs exposure via intratracheal instillation aggravated hepatic steatosis, lipid vacuolation, inflammatory infiltration and even collagen deposition in ApoE mice, companied with increased hepatic ALT, AST and LDH levels. The enhanced fatty acid synthesis and inhibited fatty acid β-oxidation and lipid efflux may account for the increased hepatic TC/TG by SiNPs. Consistently, SiNPs induced lipid deposition and elevated TC in FFA-treated L02 cells. Further, the activation of hepatic oxidative stress was detected in vivo and in vitro, as evidenced by ROS accumulation, elevated MDA, declined GSH/GSSG and down-regulated Nrf2 signaling. Endoplasmic reticulum (ER) stress was also triggered in response to SiNPs-induced lipid accumulation, as reflecting by the remarkable ER expansion and increased BIP expression. More importantly, an UPLC-MS-based metabolomics analysis revealed that SiNPs disturbed the hepatic metabolic profile in ApoE mice, prominently on amino acids and lipid metabolisms. In particular, the identified differential metabolites were strongly correlated to the activation of oxidative stress and ensuing hepatic TC/TG accumulation and liver injuries, contributing to the progression of liver diseases. Taken together, our study showed SiNPs promoted hepatic steatosis and liver damage, resulting in the aggravation of MAFLD progression. More importantly, the disturbed amino acids and lipid metabolisms-mediated oxidative stress was a key contributor to this phenomenon from a metabolic perspective.
Topics: Animals; Mice; Lipid Metabolism; Silicon Dioxide; Amino Acids; Chromatography, Liquid; Tandem Mass Spectrometry; Oxidative Stress; Liver; Nanoparticles; Non-alcoholic Fatty Liver Disease; Lipids; Fatty Acids
PubMed: 36512914
DOI: 10.1016/j.redox.2022.102569 -
Nature Biotechnology Oct 2018Phenylketonuria (PKU) is a genetic disease that is characterized by an inability to metabolize phenylalanine (Phe), which can result in neurotoxicity. To provide a...
Phenylketonuria (PKU) is a genetic disease that is characterized by an inability to metabolize phenylalanine (Phe), which can result in neurotoxicity. To provide a potential alternative to a protein-restricted diet, we engineered Escherichia coli Nissle to express genes encoding Phe-metabolizing enzymes in response to anoxic conditions in the mammalian gut. Administration of our synthetic strain, SYNB1618, to the Pah PKU mouse model reduced blood Phe concentration by 38% compared with the control, independent of dietary protein intake. In healthy Cynomolgus monkeys, we found that SYNB1618 inhibited increases in serum Phe after an oral Phe dietary challenge. In mice and primates, Phe was converted to trans-cinnamate by SYNB1618, quantitatively metabolized by the host to hippurate and excreted in the urine, acting as a predictive biomarker for strain activity. SYNB1618 was detectable in murine or primate feces after a single oral dose, permitting the evaluation of pharmacodynamic properties. Our results define a strategy for translation of live bacterial therapeutics to treat metabolic disorders.
Topics: Biomarkers; Escherichia coli; Genetic Therapy; Humans; Phenylketonurias
PubMed: 30102294
DOI: 10.1038/nbt.4222