Energy metabolism and inflammation -
Fatty acid and non-alcoholic fatty liver disease: meta-analyses of case-control and randomized controlled trials. Clin Nutr. Hesselink MKC, Schrauwen-Hinderling V, Schrauwen P. Skeletal muscle mitochondria as a target to prevent or treat type 2 diabetes mellitus.
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Branched-chain amino acid supplementation restores reduced insulinotropic activity of a low-protein diet through the vagus nerve in rats. Nutr Metab. Ringseis R, Eder K, Mooren FC, Krüger K. Metabolic signals and innate immune activation in obesity and exercise.
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A branched-chain amino acid metabolite drives vascular fatty acid transport and causes insulin resistance. Newgard CB. Interplay between lipids and branched-chain amino acids in development of insulin resistance.
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Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. Glatz JF, Luiken JJ, Bonen A. Membrane fatty acid transporters as regulators of lipid metabolism: implications for metabolic disease Physiol Rev.
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Nisoli E, Clementi E, Paolucci C, Cozzi V, Tonello C, Sciorati C, et al. Mitochondrial biogenesis in mammals: the role of endogenous nitric oxide. Wu Z, Puigserver P, Andersson U, Zhang C, Adelmant G, Mootha V, et al.
Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC Mootha VK, Lindgren CM, Eriksson KF, Subramanian A, Sihag S, Lehar J, et al.
PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat Genet. Cunningham JT, Rodgers JT, Arlow DH, Vazquez F, Mootha VK, Puigserver P. mTOR controls mitochondrial oxidative function through a YY1—PGC-1α transcriptional complex.
Tedesco L, Corsetti G, Ruocco C, Ragni M, Rossi F, Carruba MO, et al. A specific amino acid formula prevents alcoholic liver disease in rodents. Am J Physiol Gastr Liver Physiol. Nisoli E, Falcone S, Tonello C, Cozzi V, Palomba L, Fiorani M, et al.
Mitochondrial biogenesis by NO yields functionally active mitochondria in mammals. Process Natl Acad Sci USA. Liang C, Curry BJ, Brown PL, Zemel MB. Leucine modulates mitochondrial biogenesis and SIRT1-AMPK signaling in C 2 C 12 myotubes.
J Nutr Metab. Kimball SR, Jefferson LS. Signaling pathways and molecular mechanisms through which branched-chain amino acids mediate translational control of protein synthesis. Schnuck JK, Sunderland KL, Gannon NP, Kuennen MR, Vaughan RA. Chen X, Xiang L, Jia G, Liu G, Zhao H, Huang Z.
Anim Sci J. Manio MC, Matsumura S, Inoue K. Low-fat diet, and medium-fat diets containing coconut oil and soybean oil exert different metabolic effects in untrained and treadmill-trained mice. J Int Soc Sport Nutr. Augustin K, Khabbush A, Williams S, Eaton S, Orford M, Cross JH, et al.
Mechanisms of action for the medium-chain triglyceride ketogenic diet in neurological and metabolic disorders. Lancet Neurol. Hughes SD, Kanabus M, Anderson G, Hargreaves IP, Rutherford T, Donnell MO, et al. The ketogenic diet component decanoic acid increases mitochondrial citrate synthase and complex I activity in neuronal cells.
J Neurochem. Kanabus M, Fassone E, Hughes SD, Bilooei SF, Rutherford T, Donnell MO, et al. The pleiotropic effects of decanoic acid treatment on mitochondrial function in fibroblasts from patients with complex I deficient Leigh syndrome. J Inherit Metab Dis.
Hu J, Kyrou I, Tan BK, Dimitriadis GK, Ramanjaneya M, Tripathi G, et al. Short-chain fatty acid acetate stimulates adipogenesis and mitochondrial biogenesis via GPR43 in brown adipocytes. Gao Z, Yin J, Zhang J, Ward RE, Martin RJ, Lefevre M, et al.
Butyrate improves insulin sensitivity and increases energy expenditure in mice. Montgomery MK, Osborne B, Brown SHJ, Small L, Mitchell TW, Cooney GJ, et al.
Contrasting metabolic effects of medium- versus long-chain fatty acids in skeletal muscle. J Lipid Res. Kopecky J, Rossmeisl M, Flachs P, Kuda O, Brauner P, Jilkova Z, et al.
n-3 PUFA: bioavailability and modulation of adipose tissue function Proc Nutr Soc. Weyer C, Funahashi T, Tanaka S, Hotta K, Matsuzawa Y, Pratley RE, et al. Hypoadiponectinemia in obesity and type 2 diabetes: close association with insulin resistance and hyperinsulinemia. J Clin Endocrinol Metab. Gao CL, Zhu C, Zhao YP, Chen XH, Ji CB, Zhang CM, et al.
Mitochondrial dysfunction is induced by high levels of glucose and free fatty acids in 3T3-L1 adipocytes. Mol Cell Endocrinol. Coll T, Jove M, Rodriguez-Calvo R, Eyre E, Palomer X, Sanchez RM, et al. Palmitate-mediated downregulation of peroxisome proliferator-activated receptor- coactivator 1. Palomer X, Álvarez-Guardia D, Rodríguez-Calvo R, Coll T, Laguna JC, Davidson MM, et al.
TNF-α reduces PGC-1α expression through NF-κB and p38 MAPK leading to increased glucose oxidation in a human cardiac cell model.
Cardiovasc Res. Lian K, Du C, Liu Y, Zhu D, Yan W, Zhang H, et al. Impaired adiponectin signaling contributes to disturbed catabolism of branched-chain amino acids in diabetic mice. Turer AT, Scherer PE. Adiponectin: mechanistic insights and clinical implications.
Asterholm IW, Scherer PE. Enhanced metabolic flexibility associated with elevated adiponectin levels. Am J Pathol. Tumminia A, Vinciguerra F, Parisi M, Graziano M, Sciacca L, Baratta R, et al. Adipose tissue, obesity and adiponectin: role in endocrine cancer risk.
Int J Mol Sci. Wu H, Kanatous SB, Thurmond FA, Gallardo T, Isotani E, Bassel-Duby R, et al. Regulation of mitochondrial biogenesis in skeletal muscle by CaM.
Garcia Caraballo SC, Comhair TM, Houten SM, Dejong CHC, Lamers WH, Koehler SE. High-protein diets prevent steatosis and induce hepatic accumulation of monomethyl branched-chain fatty acids.
J Nutr Biochem. Liu R, Li H, Fan W, Jin Q, Chao T, Wu Y, et al. Leucine supplementation differently modulates branched-chain amino acid catabolism, mitochondrial function and metabolic profiles at the different stage of insulin resistance in rats on high-fat diet.
Holeček M. Branched-chain amino acids in health and disease: metabolism, alterations in blood plasma, and as supplements. Grevengoed TJ, Klett EL, Coleman RA.
Acyl-CoA metabolism and partitioning. Annu Rev Nutr. Teodoro BG, Sampaio IH, Bomfim LHM, Queiroz AL, Silveira LR, Souza AO, et al. Long-chain acyl-CoA synthetase 6 regulates lipid synthesis and mitochondrial oxidative capacity in human and rat skeletal muscle.
J Physiol. Ellis JM, Frahm JL, Li LO, Coleman RA. Acyl-coenzyme A synthetases in metabolic control. Curr Opin Lipidol. Li T, Zhang Z, Kolwicz SC, Abell L, Roe ND, Kim M, et al.
Defective branched-chain amino acid catabolism disrupts glucose metabolism and sensitizes the heart to ischemia-reperfusion injury.
Savage DB, Petersen KF, Shulman GI. Disordered lipid metabolism and the pathogenesis of insulin resistance. Physiol Rev. Wang J, Liu Y, Lian K, Shentu X, Fang J, Shao J, et al. BCAA catabolic defect alters glucose metabolism in lean mice.
Front Physiol. Boulangé CL, Claus SP, Chou CJ, Collino S, Montoliu I, Kochhar S, et al. J Proteome Res. Mootha VK, Handschin C, Arlow D, Xie X, St PJ, Sihag S, et al. Vaughan RA, Garcia-Smith R, Gannon NP, Bisoffi M, Trujillo KA, Conn CA.
Leucine treatment enhances oxidative capacity through complete carbohydrate oxidation and increased mitochondrial density in skeletal muscle cells. Abdul-Ghani MA, Muller FL, Liu Y, Chavez AO, Balas B, Zuo P, et al. Deleterious action of FA metabolites on ATP synthesis: possible link between lipotoxicity, mitochondrial dysfunction, and insulin resistance.
Zhenyukh O, González Amor M, Rodrigues Diez RR, Esteban V, Ruiz Ortega M, Salaices M, et al. Branched-chain amino acids promote endothelial dysfunction through increased reactive oxygen species generation and inflammation. J Cell Mol Med. Zhenyukh O, Civantos E, Ruiz-Ortega M, Sanchez MS, Vazquez C, Peiro C, et al.
High concentration of branched-chain amino acids promotes oxidative stress, inflammation and migration of human peripheral blood mononuclear cells via mTORC1 activation.
Free Radic Biol Med. Senn JJ. Toll-like receptor-2 is essential for the development of palmitate-induced insulin resistance in myotubes. J Biol Chem. Lee JY, Ye J, Gao Z, Youn HS, Lee WH, Zhao L, et al. Wen H, Gris D, Lei Y, Jha S, Zhang L, Huang MT, et al. Fatty acid-induced NLRP3-ASC inflammasome activation interferes with insulin signaling.
Nat Immunol. Xu L, Lin X, Guan M, Zeng Y, Liu Y. Although histone methylases and demethylases were only identified recently 60 , 61 , studies have also found that changes in histone methylation play an important role in inflammatory responses as well Also of interest are the recent findings demonstrating the role of hypoxia in epigenetic modification through the significant increase in global DNA methylation Although histone methylases and demethylases have only recently been identified 60 , 61 , the discovery of site-specific histone demethylases demonstrates that histone methylation is a dynamic process, providing a mechanism for alteration of chromatin conformation in response to cellular stresses, such as inflammation.
Of particular interest are the findings that at least two of these histone demethylase enzymes belonging to the Jumonji gene family, JMJD1A and JMJD2B, are induced by hypoxia in an HIFα-dependent manner 64 — These studies provide insight into new mechanisms for regulation of the cellular response to limiting O 2 supply.
Additionally, studies have also demonstrated important links between changes in histone methylation and cellular inflammatory responses as well Cellular methylation reactions include modification of DNA, RNA, proteins, and lipids.
These reactions all require a methyl donor for the modification of the target. The methyl donor for the majority of these reactions is S -adenosylmethionine SAM SAM is distributed throughout the cell to act as donor for the various methylases.
The donation of its methyl group produces S -adenosylhomocysteine SAH from SAM. SAH is a potent inhibitor of methyltransferase enzymes because these enzymes have a higher affinity for SAH 69 , and SAH is rapidly converted to homocysteine and adenosine by SAH hydrolase.
Therefore, inhibition of SAH hydrolase represents a powerful means of inhibiting cellular methylation reactions It has been known for several years that inhibition of methylation had immunosuppressive effects This led to the development of more specific, reversible, and less toxic SAH inhibitors for use in animal models of inflammation.
Utilizing these compounds, it was demonstrated that SAH hydrolase inhibition particularly downregulates T cell activation and adaptive immune responses. One of these SAH hydrolase inhibitors, DZ [methyl 4- adeninyl hydroxybutanoate], has been found to have potent immunosuppressive effects and ameliorates disease in a number of animal models including delayed type hypersensitivity 72 , arthritis 72 , and experimental autoimmune encephalomyelitis Additionally, inhibition of SAH hydrolase has also been shown to influence cells of the innate immune system, particularly macrophages These studies demonstrate that inhibition of cellular methylation reactions may be an important therapeutic intervention for the treatment of Ag-induced immune responses.
A significant metabolic sink during inflammation and within the immune response involves the generation of lipid mediators. The majority of these short-lived signaling molecules are generated by either cyclooxygenases COXs or lipoxygenases.
As their names might imply, these enzymatic responses require large amounts of oxygen and as such can function to change intracellular metabolism in fundamental ways. Polyunsaturated fatty acids PUFAs are essential to tissue homeostasis but cannot be synthesized in mammals, thus they must be obtained from the diet.
PUFAs have received much attention in recent years as the metabolism of ω-6 fatty acids appear to have opposing physiological consequences to ω-3 Dietary ω-6 and ω-3 fatty acids are converted by various desaturases and elongases to arachidonic acid AA and eicosapentaenoic acid or docosahexaenoic acid DHA , respectively, and incorporated into membrane phospholipids.
Unsaturated fatty acids are liberated from membranes by phospholipase A 2 and are further metabolized to generate what are considered proinflammatory mediators e. As a general rule, ω-6 PUFAs give rise to proinflammatory lipids, whereas ω-3 PUFAs are metabolized to anti-inflammatory lipid mediators.
Oxygenases, such as COXs and lipoxygenases, are crucial oxygen-dependent, rate-limiting enzymes in the metabolism of PUFAs. COX catalyzes the conversion of AA to PGG 2 and subsequently converts PGG 2 to PGH 2 PGH 2 serves as the substrate for numerous enzymes, each resulting in a different PG end product.
There are two known isoforms of COX: the COX-1 isoform is constitutively expressed, whereas COX-2 is thought to be inducible As the name suggests, COX requires two molecules of oxygen to catalyze the oxidation of AA to PGG 2 78 , thus it may seem intuitive that in an oxygen-depleted environment, such as an inflammatory lesion, eicosanoid production would be attenuated.
Contradictory reports exist in the literature. Some groups observe that hypoxia increases COX-2 but not PGE 2 79 , 80 or prostacyclin 81 levels. Others reports indicate that hypoxia paradoxically stimulates production of PGs 82 , likely via induction of COX-2 expression Furthermore, hypoxia has been demonstrated to increase cytosolic phospholipase A 2 activity, liberating more unsaturated fatty acids from lipid membranes to act as substrates for COX or lipoxygenases This disparity between hypoxia-induced changes in PGE 2 production may be due to tissue specificity, extenuating metabolic influences, or even time-dependent sampling.
A recent report examined the difference in PGE 2 levels and COX-2 activity in acute and chronic periodontitis. Their findings indicated that PGE 2 and COX-2 activity increases in acute disease but is suppressed in chronic disease states, which was mechanistically attributed to COX-2 promoter hypermethylation Conversely, the contribution of diminished molecular oxygen in inflamed-hypoxic tissue to eicosanoid production has been poorly characterized.
The affinities of various oxygenases for molecular O 2 have been investigated, but the results appear to inconclusive Much recent attention has been paid to understanding lipid metabolism involved in the resolution of inflammation and in productive immune responses at mucosal sites.
Of particular interest are series of COX-derived lipid mediators termed the resolvins and the maresins Resolvins are the best understood of these molecules and are ω-3 PUFA-derived lipid mediators central to activation of the inflammatory resolution program Among them, RvE1 was the first isolated and has been studied in the greatest detail.
RvE1 displays potent stereoselective actions in vivo and in isolated cell systems. At nanomolar levels in vitro, RvE1 potently reduces human PMN transendothelial migration, DC migration, and IL production In several animal models of inflammatory disease, RvE1 and more recently RvE2 89 display potent counter-regulatory actions that protect against leukocyte-mediated tissue injury and excessive proinflammatory gene expression.
The discovery of a novel family of DHA-derived lipid mediators termed maresins macrophage mediator in resolving inflammation [MaR] MaRs were identified from murine peritonitis exudates and human macrophages that biosynthesized a new class of lipoxygenase-derived lipids derived from endogenous DHA.
MaR1s were demonstrated to promote inflammatory resolution with the potency of resolvins, reflected as decreased neutrophil accumulation and increased macrophage phagocytosis during murine peritonitis.
However, brief intermittent exposure to hypoxia ischemic preconditioning [IPC] has been demonstrated to be protective. Adenosine, mentioned earlier, is generated during IPC and capable of eliciting anti-inflammatory effects Sphingosine 1-phosphate S1P is a sphingolipid signaling molecule that mediates cardioprotection during IPC Sphingosine kinases catalyze the conversion of sphingosine to S1P, which binds to S1P G-protein—coupled receptors to mediate cell survival signals.
Both the SK1 94 and SK2 95 isoform of sphingosine kinase are upregulated in hypoxia, resulting in increased S1P. Concomitantly, conversion of sphingosine to S1P prevents its conversion to ceramide, a proapoptotic signaling lipid mediator The dynamic interplay of leukocytes and parenchymal cells during disease defines an elegant lesson in biology.
In particular, studies of model disease systems have allowed for the identification of metabolomic changes now well accepted in the scientific literature.
The discovery of differences and similarities between innate and adaptive immune responses will continue to teach us important lessons about the complexity of biological systems.
Such information will provide previously unappreciated insight into the pathogenesis of disease and, importantly, will provide new targets as templates for the development of novel therapies for human disease.
Abbreviations used in this paper: AA arachidonic acid. Sign In or Create an Account. Search Dropdown Menu. header search search input Search input auto suggest. filter your search All Content The Journal of Immunology. Advanced Search. User Tools Dropdown. Sign In.
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Skip Nav Destination Close navigation menu Article navigation. Volume , Issue 8. Metabolic comparisons between innate and adaptive immunity. Energy metabolism in inflammation and immune responses. Transcriptional control of immune metabolism by HIF.
mTOR and innate immunity. Nucleotide metabolism in inflammation and immunity. Methylation-dependent control of metabolism. Lipid metabolism and innate immunity.
Article Navigation. Review Article April 15 Metabolic Shifts in Immunity and Inflammation Douglas J. Kominsky ; Douglas J. Address correspondence and reprint requests to Dr. Kominsky Mucosal Inflammation Program, East 19th Avenue, Mailstop B, Aurora, CO E-mail address: douglas. kominsky UCDenver.
This Site. Google Scholar. Eric L. Campbell ; Eric L. Sean P. Colgan Sean P. Received: December 02 Accepted: February 14 Published: April 15 Online ISSN: Copyright © by The American Association of Immunologists, Inc.
J Immunol 8 : — Article history Received:. toolbar search Search Dropdown Menu. toolbar search search input Search input auto suggest. Table I. Type of Immunity. Cells involved PMN, eosinophil Macrophage DC T cell, B cell, NK cell Metabolic trigger s Recruitment Differentiation Local proliferation Recruitment Activation stressor s Migration Phagocytosis Respiratory burst Ag-induced differentiation Metabolic adaptor s HIF, mTOR, Akt HIF, mTOR, Akt Mitochondria Few Many Primary energy source Glycolysis Respiration Methylation dependence Unknown Proliferation Ag-induced differentiation.
View Large. FIGURE 1. View large Download slide. Disclosures The authors have no financial conflicts of interest. AR adenosine receptor. Monocytes are white blood cells or immune cells that help to fight off bacteria and infections. Cytokines are proteins that help other cells to turn into effector cells, and annihilate cancerous or infected cells.
Stress — Stress activates the sympathetic nervous system and releases cortisol as it triggers the fight-or-flight response. Cortisol suppresses the immune function. During inflammation, the immune system transmits an army of chemicals, called pro-inflammatory cytokines, to fight off the invaders.
During stress, these cytokines are upregulated in the system. This means that they bolster the cycle of stress.
Stress management is important to lower inflammation. Your immune system is geared into a defensive combat mode when your body recognizes anything that is foreign—such as an invading microbe, plant pollen, or chemicals and even psychological stressors. One of the mechanisms leading to insulin resistance is low-grade inflammation or metaflammation.
Primarily catalysed by obesity, metabolic inflammation can be managed. With a healthier diet with good cholesterol, lower levels of sugar, and a balance of protein and anti-inflammatory foods, one can combat obesity and inflammation. This, in turn, reduces insulin resistance, galvanising a variety of functions — liver effectiveness, blood sugar levels, and cells processing glucose or energy efficiently.
Disclaimer: The contents of this article are for general information and educational purposes only. It neither provides any medical advice nor intends to substitute professional medical opinion on the treatment, diagnosis, prevention or alleviation of any disease, disorder or disability.
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As important metabolic substrates, metabolims amino acids BCAAs and fatty Ehergy FAs participate in many significant ajd processes, such as mitochondrial biogenesis, Potassium and pregnancy metabolism, and inflammation, along with intermediate metabolites generated in their Energy metabolism and inflammation. Inflanmation increased levels of Emergy Energy metabolism and inflammation fatty acids can lead to mitochondrial dysfunction by altering mitochondrial biogenesis and Energy metabolism and inflammation triphosphate ATP production and interfering Energy metabolism and inflammation glycolysis, fatty acid oxidation, the tricarboxylic acid cycle TCA cycle, and oxidative phosphorylation. BCAAs can directly activate the mammalian target of rapamycin mTOR signaling pathway to induce insulin resistance, or function together with fatty acids. In addition, elevated levels of BCAAs and fatty acids can activate the canonical nuclear factor-κB NF-κB signaling pathway and inflammasome and regulate mitochondrial dysfunction and metabolic disorders through upregulated inflammatory signals. This review provides a comprehensive summary of the mechanisms through which BCAAs and fatty acids modulate energy metabolism, insulin sensitivity, and inflammation synergistically. Carbohydrates, lipids, and amino acids are the three major nutrients for humans. They are oxidized, and they supply energy in various ways to maintain activities of the body. The paper by Immune-boosting cold and flu den Boer et al. Energy metabolism and inflammation, ihflammation results appeared to be negative with respect to Energy metabolism and inflammation insulin-mediated glucose lnflammation. However, the authors did report effects on fat metabolism Immune system wellness general, Energg in the liver. Their findings represent an important contribution to understanding the network that links inflammatory processes, energy metabolism, and the behavioral state. Upon microbial invasion or injury, the organism responds with a local protective process of inflammation. This process is fine-tuned at both the local cell-to-cell level and a systemic level that is monitored by the brain. TNF, a proinflammatory cytokine, is produced by activated immunologically competent cells in response to pathogens and injurious stimuli.Energy metabolism and inflammation -
A chronic inflammatory response can eventually start damaging healthy cells, tissues, and organs. Over time, it is conducive to DNA damage, tissue death, and internal scarring.
Oxidative stress is defined as a disturbance in the balance between the production of reactive oxygen species free radicals and antioxidant defences. Free radicals fight pathogens that provoke infections. They are extremely reactive, while antioxidants stabilize the reactive nature of free radicals, creating harmony.
A reactive oxygen species ROS is a molecule containing oxygen that has gained an extra electron. This causes the molecule to become highly chemically reactive.
These free radicals are produced during normal cell metabolism. ROS accumulation leads to dysfunction in the neurons. Oxidative stress can lead to chronic inflammation. Immune cells known as macrophages generate free radicals while combating invading germs.
These free radicals can be detrimental to healthy cells, causing inflammation. It usually goes away after the immune system overthrows the infection or repairs the damaged tissue.
But oxidative stress can also stimulate the inflammatory response, which consequently produces more free radicals leading to additional oxidative stress and perpetuating a cycle.
Chronic inflammation due to oxidative stress may lead to several conditions, including diabetes, cardiovascular disease. There are significant ties between metabolism and inflammation. This is detailed in a review of studies on the subject by Roche.
In turn, this influences our inflammatory response when it occurs. This can either be towards inflammation staying present or towards the process of inflammation fulfilling its resolutory function.
In the former, a cycle of increased glycolysis a series of reactions that help extract energy from glucose and inflammation increases mitochondrial stress principal regulators of cellular function and metabolism through the production of ATP for energy homeostasis. In the latter cycle, fatty acid oxidation reduces inflammation and increases immune surveillance correspondingly causing a drop in oxidative stress or ROS levels, ie, elevated levels or reactive oxygen that can damage DNA, lipids, and proteins.
One of the factors leading to insulin resistance is low-grade inflammation or metabolic inflammation. When the pancreas is no longer able to facilitate appropriate insulin secretion, hyperglycemia high blood sugar is detected.
Research confirms that one of the mechanisms leading to insulin resistance is low-grade inflammation that ropes in a host of protagonists such as inflammatory cytokines small proteins important in cell signalling , lipids and their metabolites, reactive oxygen species ROS , hypoxia a condition in which the body or a region of the body is deprived of adequate oxygen supply at the tissue level and changes in gut microbiota profiles.
Further, there is the case of metabolic inflammation, aka metaflammation. This is found in people with diets consisting of high levels of fat and sugars along with a sedentary lifestyle.
Metabolic inflammation is a state of diluted chronic inflammation induced in the body during obesity. When obese, the body may release hypertrophied adipocytes a tissue with nutrient buffering capacity as a response to nutritional excess and inflammatory cells of pro-inflammatory cytokines small proteins released by cells with particular impact on inter-cell communication and interactions With an increase in fatty acid, these cytokines signal pathways to inhibit insulin receptors.
Further, this pathway can activate NFkB a protein complex that controls transcription of DNA, cytokine production and cell survival - resulting in chronic inflammation from a release of further inflammatory cytokines.
Further, stress in the endoplasmic reticulum can contribute to a spike in insulin resistance, while hydrophilic statins have a positive impact on insulin sensitivity. Metabolic syndrome is a cluster of conditions that simultaneously occur, increasing your risk of heart disease , stroke and type 2 diabetes.
These conditions include increased blood pressure, high blood sugar, excess body fat around the waist, and abnormal cholesterol or triglyceride levels. How can metabolic inflammation impact mThe effects of obesity, a marker of metabolic impairment, on inflammation are an increase in storage of immune cells and a sharp polarity between its types.
It could be a factor in metabolic malfunctions caused by conditional obesity, namely insulin resistance. Metabolic inflammation is associated with several cardiometabolic complications.
accompany obesity. Research upholds a synergistic partnership between cholesterol and fatty acids in stimulating metabolic inflammation. Cardiovascular disorder is classified as both a cholesterol disorder as well as a disease arising from inflammation. etabolic health? Metabolic inflammation can be improved upon.
This can take place nutritionally. An activated AMPK pathway, believed to be a metabolic super-state, along with peroxisome proliferator-activated receptors can regulate cellular homeostasis.
In turn, these influence inflammatory as well as metabolic pathways. HIF-1 and HIF-2 also called endothelial Per-ARNT-Sim protein are members of the Per-ARNT-Sim family of basic helix-loop helix transcription factors. HIF activation is dependent upon stabilization of an O 2 -dependent degradation domain of the α-subunit and subsequent nuclear translocation to form a functional complex with HIF-1β and cofactors, such as CBP and its ortholog p Under conditions of adequate oxygen supply, iron- and oxygen-dependent hydoxylation of two prolines Pro and Pro within the oxygen-dependent degradation domain ODD of HIF-1α or HIF-2α initiates the association with the von Hippel-Lindau tumor suppressor protein and rapid degradation via ubiquitin-E3 ligase proteasomal targeting 14 , A second hypoxic switch operates in the carboxy terminal transactivation domain of HIF-1 or HIF-2α.
HIF-2α was subsequently identified by homology searches and as a binding partner for the heterodimeric partner HIF-1β It was originally thought that the HIF-2α isoform was expressed only in endothelial cells hence the name endothelial Per-ARNT-Sim protein, or EPAS HIF-3α is a more distantly related isoform, and, when spliced appropriately, can encode a protein that antagonizes hypoxia-responsive element-dependent gene induction For a number of years, it remained poorly understood how hypoxia might stabilize the expression of HIF.
In the past several years, the molecular mechanisms of HIF activation have become clarified. These studies have defined two HIF selective iron- and oxygen-dependent hydroxylation enzymes on HIF prolines and within the ODD of the HIF-α subunit 21 — Because other mammalian prolyl hydroxylases e.
Based on conserved structural features 25 , a candidate molecular approach was used to define HIF-modifying enzymes. This approach identified the HIF prolyl hydroxylases as the products of genes related to C. elegans egl-9, a gene that was first described in the context of an egg-laying abnormal phenotype In mammalian cells, three PHD isoforms were identified PHD 1—3 and shown to hydroxylate HIF-α in vitro 22 , The discovery of HIF-selective PHDs as central regulators of HIF expression has now provided the basis for potential development of PHD-based molecular tools and therapies 26 , Pharmacological inactivation of the PHDs by 2-oxoglutarate analogs is sufficient to stabilize HIF-α 26 , but this action is nonspecific with respect to individual PHD isoforms.
In vitro studies do suggest significant differences in substrate specificity. For example, PHD3 does not hydroxylate proline on HIF-α, and comparison of enzyme activity in vitro showed that the ODD sequence is hydroxylated most efficiently by PHD2 25 , These observations have generated an interest in identifying enzyme-modifying therapeutics.
Indeed, a number of PHD inhibitors have been described, including direct inhibitors of the prolyl-hydroxylase 29 , analogs of naturally occurring cyclic hydroxymates 30 , and antagonists of α-keto-glutarate Activated T cells show increased expression of HIF-1α. In particular, HIF-1α has been shown to provide an important survival signal for T cells, preventing them from undergoing activation-induced cell death in hypoxic settings.
T cell survival in hypoxia is, at least in part, mediated by the vasoactive peptide adrenomedullin Other studies using chimeric mice bearing HIF-1α—deficient T and B cells have revealed lineage-specific defects that result in increased autoimmunity, including autoantibodies, increased rheumatoid factor, and kidney damage 4.
HIF function has been studied in some detail in myeloid cells. Cre-LoxP—based elimination of HIF-1α in cells of the myeloid lineage lysozyme M promoter have revealed multiple features that importantly implicate metabolic control of myeloid function In particular, these studies have shown that PMN and macrophage bacterial killing capacities are severely limited in the absence of HIF-1α, as HIF-1α is central to production of antimicrobial peptides and granule proteases.
These findings are explained, at least in part, by the inability of myeloid cells to mount appropriate metabolic responses to diminished O 2 characteristic of infectious sites Finally, compelling evidence has revealed that HIF-1α transcriptionally controls the critical integrin important in all myeloid cell adhesion and transmigration, namely the β2 integrin CD18 33 , A growing body of evidence indicates that HIF-mediated signaling pathways in parenchymal cells e.
For instance, intestinal epithelial cells form a critical barrier to the flux of antigenic material across the gut. During episodes of inflammation, barrier function is compromised and can lead to accelerated inflammatory responses.
In response to multiple metabolic insults initiated within inflammatory lesions e. Studies in mice lacking intestinal epithelial HIF-1α have revealed that HIF-based signaling is central to the protection of barrier function through the induction of multiple genes and is important in the restitution of barrier function following injury These findings may be somewhat model-dependent, as epithelial HIF-based signaling has also been shown to promote inflammation in some models Nonetheless, ongoing studies targeting the induction of HIF through inhibition of PHDs are promising in animal models of intestinal inflammation 37 , Metabolic stress points in inflammation and immunity.
Migration of inflammatory cells to sites of infection changes local tissue metabolism in fundamental ways. A number of metabolic limitations contribute to substantial a shift in tissue metabolism A. Adapted with permission from Fig. The mammalian target of rapamycin mTOR is an evolutionary conserved serine-threonine kinase that is central to cellular sensing of environmental stress As an integral part of overall metabolism, mTOR monitors cellular ATP:AMP ratios, insulin, and amino acid levels mTOR functions as part of two major protein complexes mTORC1 and mTORC2 that coordinate signaling for anabolic and catabolic metabolism.
An important function of the mTORC1 complex is integration of PI3K- and Akt-mediated signaling and in complex and is sensitive to rapamycin inhibition when complexed to FKbinding protein mTORC2, in contrast, phosphorylates Akt Ser but is insensitive to rapamycin inhibition. In lymphocytes, mTOR controls cell cycle progression from G1 to S phase and can therefore control proliferative responses.
It is through these mechanisms that inhibitors of rapamycin sirolimus have been used as a potent immunosuppressive agent mTOR is activated by growth factor, extracellular signaling molecules e. Activation of mTOR through these various stimuli provides increased capacity for aerobic glycolysis and ATP generation during episodes of high T cell proliferation 3.
In myeloid cells, such as macrophages and dendritic cells DCs , mTOR1-based metabolism is particularly important in the integration of PI3K and Akt signaling.
This nexus between mTOR and Akt forms a critical linkage to multiple cytokine signaling cascades In addition to its role in intracellular energy transfer, the nucleotide ATP plays an important role in extracellular signaling reactions in inflammation and immune responses.
Extracellular ATP or ADP can directly bind to cell surface purinergic receptors termed P2-type or can be metabolized to adenosine at the cell surface, where it is made available to bind and activate adenosine receptor s P1-type. Extracellular nucleotides are metabolized primarily by cell-surface enzymes called ectonucleotidases whose enzymatic activity is to hydrolyze phosphate groups from circulating nucleotides with varying degrees of specificity for their substrates.
CD39 is one such ectonucleotidase initially observed as an activation marker in paracortical lymphocytes, macrophages, and DCs resident within lymphoid tissue Cloning of CD39 revealed the presence of apyrase conserved regions and striking sequence homology with yeast guanosine diphosphatase, an enzyme involved in catalyzing the removal of a phosphate from GDP after sugar transfer within the Golgi apparatus Further identification of a number of CDlike NTP diphosphohydrolases NTPDases have since revealed a family of eight related proteins, denoted NTPDase1—8 NTPDase1 representing CD39 under this nomenclature.
NTPDase1, -2, -3, and -8 are transmembrane proteins with five apyrase conserved regions situated on the extracellular region, conferring nucleotidase activity to the enzyme and allowing for hydrolysis of extracellular nucleotides Together, these NTPDases act in a concerted manner to regulate the production of extracellular AMP.
CD73 is the predominant source for accumulation of extracellular adenosine from released adenine nucleotides CD73 metabolizes AMP to adenosine, which is then either free to act on adenosine receptors or is transported into the cell by dipyridamole-sensitive channels and degraded by the purine salvage pathway.
Extracellular adenosine binds to one or more of four adenosine receptors ARs; A1AR, A2AAR, A2BAR, and A3AR A number of studies have addressed the contribution of individual ARs in murine mucosal inflammation.
Although less is known about the role of the A1 or A3AR, both A2A and A2BAR have been shown to attenuate mucosal inflammation and to provide tissue protection From this perspective, A2AAR and A2BAR agonists represent a potential group of therapeutics for the treatment of mucosal inflammation.
One study found a critical role for the A2AAR signaling in T cell-mediated regulation of colitis and treatment with a specific A2AAR agonist attenuated the production of proinflammatory cytokines and attenuation of colitis Activation of adenosine A2AAR seems to limit reperfusion injury by inhibiting inflammatory processes in neutrophils, platelets, macrophages, and T cells The contribution of A2BAR to mucosal inflammation has been somewhat discrepant, where in two separate studies, mice lacking A2BAR have shown either increased and decreased susceptibility to dextran sodium sulfate-induced intestinal inflammation 48 , Additional studies will be necessary to rectify these differences.
Immune responses and cellular differentiation are tightly controlled by epigenetic modifications, which constitute an additional level of control of gene expression. Regulation of gene expression works primarily through modification of chromatin structure, allowing regions of DNA to be more or less accessible to transcription.
Epigenetic modifications include ubiquitylation, acetylation, and methylation of histones, proteins that interact with DNA to form the secondary and tertiary structures of chromatin, and DNA methylation of cytosine residues at CpG dinucleotides.
All cell types possess a unique epigenetic profile determined early in differentiation and carried through to fully differentiated cells and tissue It is becoming increasingly appreciated, however, that this epigenetic profile can be perturbed by environmental stress For example, it has been known for many years that changes in epigenetic modifications contribute to a number of cancer types 52 , and it is now becoming clear that these changes play roles in other disease states as well.
Epigenetic modifications are a crucial part of normal immune system function. The differentiation of T cells from progenitor to the Th1 or Th2 lineage requires silencing of the genes associated with other lineages, which is accomplished via epigenetic mechanisms 53 , Similarly, development of two other important T cell lineages, Th17 and regulatory T cells, is controlled through epigenetic modifications 55 , Recent studies also suggest that epigenetic changes are important for cells of the innate immune system, such as macrophages Several lines of evidence suggest that aberrant epigenetic regulation plays a role in chronic inflammation.
Although no DNA demethylase has been identified, there are types of modifications that occur during chronic inflammation that influence DNA methylation states and render genes more or less accessible to transcription Additionally, methotrexate, a drug commonly used to treat arthritis, actively inhibits DNA methylation by inhibiting DNA methyltransferases 59 and may ameliorate symptoms by upregulation of silenced anti-inflammatory genes.
Although histone methylases and demethylases were only identified recently 60 , 61 , studies have also found that changes in histone methylation play an important role in inflammatory responses as well Also of interest are the recent findings demonstrating the role of hypoxia in epigenetic modification through the significant increase in global DNA methylation Although histone methylases and demethylases have only recently been identified 60 , 61 , the discovery of site-specific histone demethylases demonstrates that histone methylation is a dynamic process, providing a mechanism for alteration of chromatin conformation in response to cellular stresses, such as inflammation.
Of particular interest are the findings that at least two of these histone demethylase enzymes belonging to the Jumonji gene family, JMJD1A and JMJD2B, are induced by hypoxia in an HIFα-dependent manner 64 — These studies provide insight into new mechanisms for regulation of the cellular response to limiting O 2 supply.
Additionally, studies have also demonstrated important links between changes in histone methylation and cellular inflammatory responses as well Cellular methylation reactions include modification of DNA, RNA, proteins, and lipids.
These reactions all require a methyl donor for the modification of the target. The methyl donor for the majority of these reactions is S -adenosylmethionine SAM SAM is distributed throughout the cell to act as donor for the various methylases.
The donation of its methyl group produces S -adenosylhomocysteine SAH from SAM. SAH is a potent inhibitor of methyltransferase enzymes because these enzymes have a higher affinity for SAH 69 , and SAH is rapidly converted to homocysteine and adenosine by SAH hydrolase.
Therefore, inhibition of SAH hydrolase represents a powerful means of inhibiting cellular methylation reactions It has been known for several years that inhibition of methylation had immunosuppressive effects This led to the development of more specific, reversible, and less toxic SAH inhibitors for use in animal models of inflammation.
Utilizing these compounds, it was demonstrated that SAH hydrolase inhibition particularly downregulates T cell activation and adaptive immune responses. One of these SAH hydrolase inhibitors, DZ [methyl 4- adeninyl hydroxybutanoate], has been found to have potent immunosuppressive effects and ameliorates disease in a number of animal models including delayed type hypersensitivity 72 , arthritis 72 , and experimental autoimmune encephalomyelitis Additionally, inhibition of SAH hydrolase has also been shown to influence cells of the innate immune system, particularly macrophages These studies demonstrate that inhibition of cellular methylation reactions may be an important therapeutic intervention for the treatment of Ag-induced immune responses.
A significant metabolic sink during inflammation and within the immune response involves the generation of lipid mediators. The majority of these short-lived signaling molecules are generated by either cyclooxygenases COXs or lipoxygenases.
As their names might imply, these enzymatic responses require large amounts of oxygen and as such can function to change intracellular metabolism in fundamental ways. Polyunsaturated fatty acids PUFAs are essential to tissue homeostasis but cannot be synthesized in mammals, thus they must be obtained from the diet.
PUFAs have received much attention in recent years as the metabolism of ω-6 fatty acids appear to have opposing physiological consequences to ω-3 Dietary ω-6 and ω-3 fatty acids are converted by various desaturases and elongases to arachidonic acid AA and eicosapentaenoic acid or docosahexaenoic acid DHA , respectively, and incorporated into membrane phospholipids.
Unsaturated fatty acids are liberated from membranes by phospholipase A 2 and are further metabolized to generate what are considered proinflammatory mediators e.
As a general rule, ω-6 PUFAs give rise to proinflammatory lipids, whereas ω-3 PUFAs are metabolized to anti-inflammatory lipid mediators. Mikael Rydén's and Niklas Mejhert's group at the Department of Medicine, Huddinge, examines what drives the development of inflammation in adipose tissue in people with obesity.
This stimulates the genes that lead to chronic inflammation in the body with an increased risk of insulin resistance", says Dr. Salwan Maqdasy , one of the study's first authors.
Energy metabolism and inflammation JMetabolsim JN. Regulation of energy metabolism by inflammation: A feedback response Energy metabolism and inflammation obesity and calorie inflmmation. Aging Albany Tailored meal plans. Copyright: © Indlammation Energy metabolism and inflammation al. This is an inflammatiom article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Caloric restriction CRin the absence of malnutrition, delays aging and prevents aging-related diseases through multiple mechanisms. A reduction in chronic inflammation is widely observed in experimental models of caloric restriction.
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