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Cell Metabolism Jan 2020Exercise is an effective strategy for diabetes management but is limited by the phenomenon of exercise resistance (i.e., the lack of or the adverse response to exercise... (Randomized Controlled Trial)
Randomized Controlled Trial
Exercise is an effective strategy for diabetes management but is limited by the phenomenon of exercise resistance (i.e., the lack of or the adverse response to exercise on metabolic health). Here, in 39 medication-naive men with prediabetes, we found that exercise-induced alterations in the gut microbiota correlated closely with improvements in glucose homeostasis and insulin sensitivity (clinicaltrials.gov entry NCT03240978). The microbiome of responders exhibited an enhanced capacity for biosynthesis of short-chain fatty acids and catabolism of branched-chain amino acids, whereas those of non-responders were characterized by increased production of metabolically detrimental compounds. Fecal microbial transplantation from responders, but not non-responders, mimicked the effects of exercise on alleviation of insulin resistance in obese mice. Furthermore, a machine-learning algorithm integrating baseline microbial signatures accurately predicted personalized glycemic response to exercise in an additional 30 subjects. These findings raise the possibility of maximizing the benefits of exercise by targeting the gut microbiota.
Topics: Adult; Algorithms; Animals; Bacteria; Diet; Fecal Microbiota Transplantation; Feces; Gastrointestinal Microbiome; Glucose; High-Intensity Interval Training; Humans; Insulin Resistance; Machine Learning; Male; Metabolome; Mice; Mice, Inbred C57BL; Middle Aged; Prediabetic State
PubMed: 31786155
DOI: 10.1016/j.cmet.2019.11.001 -
EBioMedicine Nov 2021Disordered metabolic states, which are characterised by hypoxia and elevated levels of metabolites, particularly lactate, contribute to the immunosuppression in the... (Review)
Review
Disordered metabolic states, which are characterised by hypoxia and elevated levels of metabolites, particularly lactate, contribute to the immunosuppression in the tumour microenvironment (TME). Excessive lactate secreted by metabolism-reprogrammed cancer cells regulates immune responses via causing extracellular acidification, acting as an energy source by shuttling between different cell populations, and inhibiting the mechanistic (previously 'mammalian') target of rapamycin (mTOR) pathway in immune cells. This review focuses on recent advances in the regulation of immune responses by lactate, as well as therapeutic strategies targeting lactate anabolism and transport in the TME, such as those involving glycolytic enzymes and monocarboxylate transporter inhibitors. Considering the multifaceted roles of lactate in cancer metabolism, a comprehensive understanding of how lactate and lactate-targeting therapies regulate immune responses in the TME will provide insights into the complex relationships between metabolism and antitumour immunity.
Topics: Animals; Biological Transport; Biomarkers; Disease Management; Disease Susceptibility; Energy Metabolism; Glycolysis; Humans; Immunomodulation; Immunotherapy; Lactic Acid; Metabolic Networks and Pathways; Neoplasms; Tumor Microenvironment
PubMed: 34656878
DOI: 10.1016/j.ebiom.2021.103627 -
International Journal of Molecular... Jul 2019As a major component of cell membrane lipids, Arachidonic acid (AA), being a major component of the cell membrane lipid content, is mainly metabolized by three kinds of... (Review)
Review
As a major component of cell membrane lipids, Arachidonic acid (AA), being a major component of the cell membrane lipid content, is mainly metabolized by three kinds of enzymes: cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP450) enzymes. Based on these three metabolic pathways, AA could be converted into various metabolites that trigger different inflammatory responses. In the kidney, prostaglandins (PG), thromboxane (Tx), leukotrienes (LTs) and hydroxyeicosatetraenoic acids (HETEs) are the major metabolites generated from AA. An increased level of prostaglandins (PGs), TxA and leukotriene B4 (LTB) results in inflammatory damage to the kidney. Moreover, the LTB-leukotriene B4 receptor 1 (BLT1) axis participates in the acute kidney injury via mediating the recruitment of renal neutrophils. In addition, AA can regulate renal ion transport through 19-hydroxystilbenetetraenoic acid (19-HETE) and 20-HETE, both of which are produced by cytochrome P450 monooxygenase. Epoxyeicosatrienoic acids (EETs) generated by the CYP450 enzyme also plays a paramount role in the kidney damage during the inflammation process. For example, 14 and 15-EET mitigated ischemia/reperfusion-caused renal tubular epithelial cell damage. Many drug candidates that target the AA metabolism pathways are being developed to treat kidney inflammation. These observations support an extraordinary interest in a wide range of studies on drug interventions aiming to control AA metabolism and kidney inflammation.
Topics: Animals; Arachidonic Acid; Biomarkers; Disease Susceptibility; Humans; Lipid Metabolism; Metabolic Networks and Pathways; Molecular Targeted Therapy; Nephritis; Signal Transduction
PubMed: 31357612
DOI: 10.3390/ijms20153683 -
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 -
Immunological Reviews May 2021While the existence of a special relationship between Mycobacterium tuberculosis (Mtb) and host lipids has long been known, it remains a challenging enigma. It was... (Review)
Review
While the existence of a special relationship between Mycobacterium tuberculosis (Mtb) and host lipids has long been known, it remains a challenging enigma. It was clearly established that Mtb requires host fatty acids (FAs) and cholesterol to produce energy, build its distinctive lipid-rich cell wall, and produce lipid virulence factors. It was also observed that in infected hosts, Mtb constantly resides in a FA-rich environment that the pathogen contributes to generate by inducing a lipid-laden "foamy" phenotype in host macrophages. These observations and the proximity between lipid droplets and phagosomes containing bacteria within infected macrophages gave rise to the hypothesis that Mtb reprograms host cell lipid metabolism to ensure a continuous supply of essential nutrients and its long-term persistence in vivo. However, recent studies question this principle by indicating that in Mtb-infected macrophages, lipid droplet formation prevents bacterial acquisition of host FAs while supporting the production of FA-derived protective lipid mediators. Further, in vivo investigations reveal discrete macrophage phenotypes linking the FA metabolisms of host cell and intracellular pathogen. Notably, FA storage within lipid droplets characterizes both macrophages controlling Mtb infection and dormant intracellular Mtb. In this review, we integrate findings from immunological and microbiological studies illustrating the new concept that cytoplasmic accumulation of FAs is a metabolic adaptation of macrophages to Mtb infection, which potentiates their antimycobacterial responses and forces the intracellular pathogen to shift into fat-saving, survival mode.
Topics: Fatty Acids; Host-Pathogen Interactions; Humans; Lipid Metabolism; Macrophages; Mycobacterium tuberculosis; Tuberculosis
PubMed: 33559209
DOI: 10.1111/imr.12952 -
Open Biology Nov 2022Neutrophils are front line cells in immunity that quickly recognize and eliminate pathogens, relying mainly on glycolysis to exert their killing functions. Even though... (Review)
Review
Neutrophils are front line cells in immunity that quickly recognize and eliminate pathogens, relying mainly on glycolysis to exert their killing functions. Even though investigations into the influence of metabolic pathways in neutrophil function started in the 1930s, the knowledge of how neutrophils metabolically adapt during a bacterial infection remains poorly understood. In this review, we discuss the current knowledge about the metabolic regulation underlying neutrophils response to bacterial infection. Glycogen metabolism has been shown to be important for multiple neutrophil functions. The potential contribution of metabolic pathways other than glycolysis, such as mitochondrial metabolism, for neutrophil function has recently been explored, including fatty acid oxidation in neutrophil differentiation. Complex III in the mitochondria might also control glycolysis via glycerol-3-phosphate oxidation. Future studies should yield new insights into the role of metabolic change in the anti-bacterial response in neutrophils.
Topics: Humans; Neutrophils; Glycolysis; Bacterial Infections; Mitochondria; Oxidation-Reduction
PubMed: 36416011
DOI: 10.1098/rsob.220248 -
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 -
Molecular Biology Reports Oct 2022Energy metabolism maintains the activation of intracellular and intercellular signal transduction, and plays a crucial role in immune response. Under environmental... (Review)
Review
Energy metabolism maintains the activation of intracellular and intercellular signal transduction, and plays a crucial role in immune response. Under environmental stimulation, immune cells change from resting to activation and trigger metabolic reprogramming. The immune system cells exhibit different metabolic characteristics when performing functions. The study of immune metabolism provides new insights into the function of immune cells, including how they differentiate, migrate and exert immune responses. Studies of immune cell energy metabolism are beginning to shed light on the metabolic mechanism of disease progression and reveal new ways to target inflammatory diseases such as autoimmune diseases, chronic viral infections, and cancer. Here, we discussed the relationship between immune cells and metabolism, and proposed the possibility of targeted metabolic process for disease treatment.
Topics: Autoimmune Diseases; Energy Metabolism; Humans; Immune System; Neoplasms; Signal Transduction
PubMed: 35696048
DOI: 10.1007/s11033-022-07474-2 -
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 -
Biomolecules Jan 2023Heat shock protein 90 (Hsp90) is a highly conserved molecular chaperone that assists in the maturation of many client proteins involved in cellular signal transduction.... (Review)
Review
Heat shock protein 90 (Hsp90) is a highly conserved molecular chaperone that assists in the maturation of many client proteins involved in cellular signal transduction. As a regulator of cellular signaling processes, it is vital for the maintenance of cellular proteostasis and adaptation to environmental stresses. Emerging research shows that Hsp90 function in an organism goes well beyond intracellular proteostasis. In metazoans, Hsp90, as an environmentally responsive chaperone, is involved in inter-tissue stress signaling responses that coordinate and safeguard cell nonautonomous proteostasis and organismal health. In this way, Hsp90 has the capacity to influence evolution and aging, and effect behavioral responses to facilitate tissue-defense systems that ensure organismal survival. In this review, I summarize the literature on the organismal roles of Hsp90 uncovered in multicellular organisms, from plants to invertebrates and mammals.
Topics: Humans; Animals; HSP90 Heat-Shock Proteins; Molecular Chaperones; Signal Transduction; Proteostasis; Stress, Physiological; Mammals
PubMed: 36830620
DOI: 10.3390/biom13020251