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Molecular Metabolism Aug 2021
Topics: Animals; Disease Models, Animal; Humans; Liver; Metabolic Diseases; Non-alcoholic Fatty Liver Disease
PubMed: 34229990
DOI: 10.1016/j.molmet.2021.101274 -
Cell Metabolism Jul 2021The bioactive sphingolipid metabolites ceramide and sphingosine-1-phosphate (S1P) are a recent addition to the lipids accumulated in obesity and have emerged as... (Review)
Review
The bioactive sphingolipid metabolites ceramide and sphingosine-1-phosphate (S1P) are a recent addition to the lipids accumulated in obesity and have emerged as important molecular players in metabolic diseases. Here we summarize evidence that dysregulation of sphingolipid metabolism correlates with pathogenesis of metabolic diseases in humans. This review discusses the current understanding of how ceramide regulates signaling and metabolic pathways to exacerbate metabolic diseases and the Janus faces for its further metabolite S1P, the kinases that produce it, and the multifaceted and at times opposing actions of S1P receptors in various tissues. Gaps and limitations in current knowledge are highlighted together with the need to further decipher the full array of their actions in tissue dysfunction underlying metabolic pathologies, pointing out prospects to move this young field of research toward the development of effective therapeutics.
Topics: Animals; Humans; Lipid Metabolism; Metabolic Diseases; Metabolic Networks and Pathways; Obesity; Sphingolipids
PubMed: 34233172
DOI: 10.1016/j.cmet.2021.06.006 -
Genes & Development Mar 2021Obesity is the most common cause of insulin resistance, and the current obesity epidemic is driving a parallel rise in the incidence of T2DM. It is now widely recognized... (Review)
Review
Obesity is the most common cause of insulin resistance, and the current obesity epidemic is driving a parallel rise in the incidence of T2DM. It is now widely recognized that chronic, subacute tissue inflammation is a major etiologic component of the pathogenesis of insulin resistance and metabolic dysfunction in obesity. Here, we summarize recent advances in our understanding of immunometabolism. We discuss the characteristics of chronic inflammation in the major metabolic tissues and how obesity triggers these events, including a focus on the role of adipose tissue hypoxia and macrophage-derived exosomes. Last, we also review current and potential new therapeutic strategies based on immunomodulation.
Topics: Adipose Tissue; Cell Hypoxia; Chronic Disease; Exosomes; Humans; Immunomodulation; Inflammation; Metabolic Diseases
PubMed: 33649162
DOI: 10.1101/gad.346312.120 -
Cell Metabolism Dec 2014Accumulation of DNA damage has been linked to the process of aging and to the onset of age-related diseases including diabetes. Studies on progeroid syndromes have... (Review)
Review
Accumulation of DNA damage has been linked to the process of aging and to the onset of age-related diseases including diabetes. Studies on progeroid syndromes have suggested that the DNA damage response is involved in regulation of metabolic homeostasis. DNA damage could impair metabolic organ functions by causing cell death or senescence. DNA damage also could induce tissue inflammation that disturbs the homeostasis of systemic metabolism. Various roles of molecules related to DNA repair in cellular metabolism are being uncovered, and such molecules could also have an impact on systemic metabolism. This review explores mechanisms by which the DNA damage response could contribute to metabolic dysfunction.
Topics: Animals; DNA Damage; DNA Repair; Humans; Metabolic Diseases
PubMed: 25456739
DOI: 10.1016/j.cmet.2014.10.008 -
Nature Reviews. Endocrinology Aug 2021Insulin signalling in the central nervous system regulates energy homeostasis by controlling metabolism in several organs and by coordinating organ crosstalk. Studies... (Review)
Review
Insulin signalling in the central nervous system regulates energy homeostasis by controlling metabolism in several organs and by coordinating organ crosstalk. Studies performed in rodents, non-human primates and humans over more than five decades using intracerebroventricular, direct hypothalamic or intranasal application of insulin provide evidence that brain insulin action might reduce food intake and, more importantly, regulates energy homeostasis by orchestrating nutrient partitioning. This Review discusses the metabolic pathways that are under the control of brain insulin action and explains how brain insulin resistance contributes to metabolic disease in obesity, the metabolic syndrome and type 2 diabetes mellitus.
Topics: Animals; Brain; Diabetes Mellitus, Type 2; Energy Metabolism; Homeostasis; Humans; Insulin; Insulin Resistance; Metabolic Diseases; Metabolic Syndrome; Signal Transduction
PubMed: 34108679
DOI: 10.1038/s41574-021-00498-x -
Nature Metabolism Mar 2023While epigenetic modifications of DNA and histones play main roles in gene transcription regulation, recently discovered post-transcriptional RNA modifications, known as... (Review)
Review
While epigenetic modifications of DNA and histones play main roles in gene transcription regulation, recently discovered post-transcriptional RNA modifications, known as epitranscriptomic modifications, have been found to have a profound impact on gene expression by regulating RNA stability, localization and decoding efficiency. Importantly, genetic variations or environmental perturbations of epitranscriptome modifiers (that is, writers, erasers and readers) are associated with obesity and metabolic diseases, such as type 2 diabetes. The epitranscriptome is closely coupled to epigenetic signalling, adding complexity to our understanding of gene expression in both health and disease. Moreover, the epitranscriptome in the parental generation can affect organismal phenotypes in the next generation. In this Review, we discuss the relationship between epitranscriptomic modifications and metabolic diseases, their relationship with the epigenome and possible therapeutic strategies.
Topics: Humans; Diabetes Mellitus, Type 2; Metabolic Diseases; Epigenesis, Genetic; Gene Expression Regulation; RNA Processing, Post-Transcriptional
PubMed: 36959512
DOI: 10.1038/s42255-023-00764-4 -
Nature Reviews. Endocrinology Apr 2019Perturbed diurnal rhythms are becoming increasingly evident as deleterious events in the pathology of metabolic diseases. Exercise is well characterized as a crucial... (Review)
Review
Perturbed diurnal rhythms are becoming increasingly evident as deleterious events in the pathology of metabolic diseases. Exercise is well characterized as a crucial intervention in the prevention and treatment of individuals with metabolic diseases. Little is known, however, regarding optimizing the timing of exercise bouts in order to maximize their health benefits. Furthermore, exercise is a potent modulator of skeletal muscle metabolism, and it is clear that skeletal muscle has a strong circadian profile. In humans, mitochondrial function peaks in the late afternoon, and the circadian clock might be inherently impaired in myotubes from patients with metabolic disease. Timing exercise bouts to coordinate with an individual's circadian rhythms might be an efficacious strategy to optimize the health benefits of exercise. The role of exercise as a Zeitgeber can also be used as a tool in combating metabolic disease. Shift work is known to induce acute insulin resistance, and appropriately timed exercise might improve health markers in shift workers who are at risk of metabolic disease. In this Review, we discuss the literature regarding diurnal skeletal muscle metabolism and the interaction with exercise bouts at different times of the day to combat metabolic disease.
Topics: Circadian Clocks; Circadian Rhythm; Exercise; Exercise Tolerance; Female; Healthy Lifestyle; Humans; Male; Metabolic Diseases; Muscle, Skeletal; Resistance Training
PubMed: 30655625
DOI: 10.1038/s41574-018-0150-x -
Gastroenterology Nov 2016The gut microbiota is associated with metabolic diseases including obesity, insulin resistance, and nonalcoholic fatty liver disease, as shown by correlative studies and... (Review)
Review
The gut microbiota is associated with metabolic diseases including obesity, insulin resistance, and nonalcoholic fatty liver disease, as shown by correlative studies and by transplant of microbiota from obese humans and mice into germ-free mice. Modification of the microbiota by treatment of high-fat diet (HFD)-fed mice with tempol or antibiotics resulted in decreased adverse metabolic phenotypes. This was owing to lower levels of the genera Lactobacillus and decreased bile salt hydrolase (BSH) activity. The decreased BSH resulted in increased levels of tauro-β-muricholic acid (MCA), a substrate of BSH and a potent farnesoid X receptor (FXR) antagonist. Mice lacking expression of FXR in the intestine were resistant to HFD-induced obesity, insulin resistance, and nonalcoholic fatty liver disease, thus confirming that intestinal FXR is involved in the potentiation of metabolic disease. A potent intestinal FXR antagonist, glycine-β-MCA (Gly-MCA), which is resistant to BSH, was developed, which, when administered to HFD-treated mice, mimics the effect of the altered microbiota on HFD-induced metabolic disease. Gly-MCA had similar effects on genetically obese leptin-deficient mice. The decrease in adverse metabolic phenotype by tempol, antibiotics, and Gly-MCA was caused by decreased serum ceramides. Mice lacking FXR in the intestine also have lower serum ceramide levels, and are resistant to HFD-induced metabolic disease, and this was reversed by injection of C16:0 ceramide. In mouse ileum, because of the presence of endogenous FXR agonists produced in the liver, FXR target genes involved in ceramide synthesis are activated and when Gly-MCA is administered they are repressed, which likely accounts for the decrease in serum ceramides. These studies show that ceramides produced in the ileum under control of FXR influence metabolic diseases.
Topics: Animals; Bile Acids and Salts; Biomarkers; Ceramides; Gastrointestinal Microbiome; Homeostasis; Ileum; Insulin Resistance; Metabolic Diseases; Mice; Non-alcoholic Fatty Liver Disease; Obesity; Receptors, Cytoplasmic and Nuclear
PubMed: 27639801
DOI: 10.1053/j.gastro.2016.08.057 -
Nutrients Mar 2018The dietary pattern that characterizes the Western diet is strongly associated with obesity and related metabolic diseases, but biological mechanisms supporting these... (Review)
Review
The dietary pattern that characterizes the Western diet is strongly associated with obesity and related metabolic diseases, but biological mechanisms supporting these associations remain largely unknown. We argue that the Western diet promotes inflammation that arises from both structural and behavioral changes in the resident microbiome. The environment created in the gut by ultra-processed foods, a hallmark of the Western diet, is an evolutionarily unique selection ground for microbes that can promote diverse forms of inflammatory disease. Recognizing the importance of the microbiome in the development of diet-related disease has implications for future research, public dietary advice as well as food production practices. Research into food patterns suggests that whole foods are a common denominator of diets associated with a low level of diet-related disease. Hence, by studying how ultra-processing changes the properties of whole foods and how these foods affect the gut microbiome, more useful dietary guidelines can be made. Innovations in food production should be focusing on enabling health in the super-organism of man and microbe, and stronger regulation of potentially hazardous components of food products is warranted.
Topics: Animals; Diet, Western; Fast Foods; Food Additives; Food Handling; Gastrointestinal Microbiome; Gastrointestinal Tract; Host-Pathogen Interactions; Humans; Inflammation; Metabolic Diseases; Nutritional Status; Nutritive Value; Risk Factors
PubMed: 29562591
DOI: 10.3390/nu10030365 -
Genome Medicine Apr 2016The human gut harbors more than 100 trillion microbial cells, which have an essential role in human metabolic regulation via their symbiotic interactions with the host.... (Review)
Review
The human gut harbors more than 100 trillion microbial cells, which have an essential role in human metabolic regulation via their symbiotic interactions with the host. Altered gut microbial ecosystems have been associated with increased metabolic and immune disorders in animals and humans. Molecular interactions linking the gut microbiota with host energy metabolism, lipid accumulation, and immunity have also been identified. However, the exact mechanisms that link specific variations in the composition of the gut microbiota with the development of obesity and metabolic diseases in humans remain obscure owing to the complex etiology of these pathologies. In this review, we discuss current knowledge about the mechanistic interactions between the gut microbiota, host energy metabolism, and the host immune system in the context of obesity and metabolic disease, with a focus on the importance of the axis that links gut microbes and host metabolic inflammation. Finally, we discuss therapeutic approaches aimed at reshaping the gut microbial ecosystem to regulate obesity and related pathologies, as well as the challenges that remain in this area.
Topics: Animals; Energy Metabolism; Gastrointestinal Microbiome; Homeostasis; Host-Pathogen Interactions; Humans; Inflammation; Metabolic Diseases; Metabolic Syndrome; Obesity
PubMed: 27098727
DOI: 10.1186/s13073-016-0303-2