{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T04:17:03Z","timestamp":1791433023995,"version":"4.3.3"},"reference-count":81,"publisher":"Springer Science and Business Media LLC","issue":"8","license":[{"start":{"date-parts":[[2021,6,21]],"date-time":"2021-06-21T00:00:00Z","timestamp":1624233600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2021,6,21]],"date-time":"2021-06-21T00:00:00Z","timestamp":1624233600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ludwig\u2010Maximilians\u2010University (LMU) Munich"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["EMBO Mol Med"],"published-print":{"date-parts":[[2021,8,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Very\u2010low\u2010carbohydrate diet triggers the endogenous production of ketone bodies as alternative energy substrates. There are as yet unproven assumptions that ketone bodies positively affect human immunity. We have investigated this topic in an\n                    <jats:italic>in\u00a0vitro<\/jats:italic>\n                    model using primary human T cells and in an immuno\u2010nutritional intervention study enrolling healthy volunteers. We show that ketone bodies profoundly impact human T\u2010cell responses. CD4\n                    <jats:sup>+<\/jats:sup>\n                    , CD8\n                    <jats:sup>+<\/jats:sup>\n                    , and regulatory T\u2010cell capacity were markedly enhanced, and T memory cell formation was augmented. RNAseq and functional metabolic analyses revealed a fundamental immunometabolic reprogramming in response to ketones favoring mitochondrial oxidative metabolism. This confers superior respiratory reserve, cellular energy supply, and reactive oxygen species signaling. Our data suggest a very\u2010low\u2010carbohydrate diet as a clinical tool to improve human T\u2010cell immunity. Rethinking the value of nutrition and dietary interventions in modern medicine is required.\n                  <\/jats:p>","DOI":"10.15252\/emmm.202114323","type":"journal-article","created":{"date-parts":[[2021,6,21]],"date-time":"2021-06-21T04:24:26Z","timestamp":1624249466000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":100,"title":["Very\u2010low\u2010carbohydrate diet enhances human T\u2010cell immunity through immunometabolic reprogramming"],"prefix":"10.1038","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4221-7377","authenticated-orcid":false,"given":"Simon","family":"Hirschberger","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriele","family":"Strau\u00df","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Effinger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xaver","family":"Marstaller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8349-0978","authenticated-orcid":false,"given":"Alicia","family":"Ferstl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin B","family":"M\u00fcller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tingting","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Max","family":"H\u00fcbner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tim","family":"Rahmel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannah","family":"Mascolo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole","family":"Exner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"He\u00df","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Friedrich W","family":"Kreth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristian","family":"Unger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0073-2098","authenticated-orcid":false,"given":"Simone","family":"Kreth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,6,21]]},"reference":[{"key":"BFEMMM202114323_CR1","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1093\/bioinformatics\/btu638","volume":"31","author":"S Anders","year":"2015","unstructured":"Anders S, Pyl PT, Huber W (2015) HTSeq\u2013a Python framework to work with high\u2010throughput sequencing data. Bioinformatics 31: 166\u2013169","journal-title":"Bioinformatics"},{"key":"BFEMMM202114323_CR2","doi-asserted-by":"crossref","first-page":"105","DOI":"10.3389\/fnut.2018.00105","volume":"5","author":"E Archer","year":"2018","unstructured":"Archer E, Lavie CJ, Hill JO (2018) The Failure to Measure Dietary Intake Engendered a Fictional Discourse on Diet\u2010Disease Relations. Front Nutr 5: 105","journal-title":"Front Nutr"},{"key":"BFEMMM202114323_CR3","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1093\/eurheartj\/ehy736","volume":"40","author":"E Archer","year":"2019","unstructured":"Archer E, Lavie CJ (2019) Is the PURE study pure fiction? Eur Heart J 40: 394","journal-title":"Eur Heart J"},{"key":"BFEMMM202114323_CR4","doi-asserted-by":"crossref","first-page":"962","DOI":"10.3390\/nu11050962","volume":"11","author":"AM Bolla","year":"2019","unstructured":"Bolla AM, Caretto A, Laurenzi A, Scavini M, Piemonti L (2019) Low\u2010carb and ketogenic diets in type 1 and type 2 diabetes. Nutrients 11: 962","journal-title":"Nutrients"},{"key":"BFEMMM202114323_CR5","doi-asserted-by":"crossref","DOI":"10.1038\/s41598-018-20933-w","volume":"8","author":"G Bosco","year":"2018","unstructured":"Bosco G, Rizzato A, Quartesan S, Camporesi E, Mangar D, Paganini M, Cenci L, Malacrida S, Mrakic\u2010Sposta S, Moretti S et\u00a0al (2018) Effects of the ketogenic diet in overweight divers breathing enriched air nitrox. Sci Rep 8: 2655","journal-title":"Sci Rep"},{"key":"BFEMMM202114323_CR6","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.cell.2016.05.035","volume":"166","author":"M Buck","year":"2016","unstructured":"Buck M, O\u2019Sullivan D, Klein\u00a0Geltink R, Curtis J, Chang C\u2010H, Sanin D, Qiu J, Kretz O, Braas D, van der Windt G et\u00a0al (2016) Mitochondrial dynamics controls T cell fate through metabolic programming. Cell 166: 63\u201376","journal-title":"Cell"},{"key":"BFEMMM202114323_CR7","first-page":"149","volume":"114","author":"GF Cahill Jr","year":"2003","unstructured":"Cahill Jr GF, Veech RL (2003) Ketoacids? Good medicine? Trans Am Clin Climatol Assoc 114: 149\u2013161: discussion 162\u20133","journal-title":"Trans Am Clin Climatol Assoc"},{"key":"BFEMMM202114323_CR8","doi-asserted-by":"crossref","first-page":"1239","DOI":"10.1016\/j.cell.2013.05.016","volume":"153","author":"C\u2010H Chang","year":"2013","unstructured":"Chang C\u2010H, Curtis J, Maggi L, Faubert B, Villarino A, O\u2019Sullivan D, Huang S\u2010C, van der Windt G, Blagih J, Qiu J et\u00a0al (2013) Posttranscriptional control of T cell effector function by aerobic glycolysis. Cell 153: 1239\u20131251","journal-title":"Cell"},{"key":"BFEMMM202114323_CR9","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1038\/s41577-020-0402-6","volume":"20","author":"Z Chen","year":"2020","unstructured":"Chen Z, John Wherry E (2020) T cell responses in patients with COVID\u201019. Nat Rev Immunol 20: 529\u2013536","journal-title":"Nat Rev Immunol"},{"key":"BFEMMM202114323_CR10","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1016\/j.cell.2017.12.013","volume":"172","author":"A Christ","year":"2018","unstructured":"Christ A, G\u00fcnther P, Lauterbach MAR, Duewell P, Biswas D, Pelka K, Scholz CJ, Oosting M, Haendler K, Ba\u00dfler K et\u00a0al (2018) Western diet triggers NLRP3\u2010dependent innate immune reprogramming. Cell 172: 162\u2013175","journal-title":"Cell"},{"key":"BFEMMM202114323_CR11","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1038\/s41577-019-0156-1","volume":"19","author":"A Christ","year":"2019","unstructured":"Christ A, Latz E (2019) The western lifestyle has lasting effects on metaflammation. Nat Rev Immunol 19: 267\u2013268","journal-title":"Nat Rev Immunol"},{"key":"BFEMMM202114323_CR12","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1016\/j.nut.2015.02.007","volume":"31","author":"E Cohen","year":"2015","unstructured":"Cohen E, Cragg M, deFonseka J, Hite A, Rosenberg M, Zhou B (2015) Statistical review of US macronutrient consumption data, 1965\u20132011: Americans have been following dietary guidelines, coincident with the rise in obesity. Nutrition 31: 727\u2013732","journal-title":"Nutrition"},{"key":"BFEMMM202114323_CR13","doi-asserted-by":"crossref","first-page":"H1060","DOI":"10.1152\/ajpheart.00646.2012","volume":"304","author":"DG Cotter","year":"2013","unstructured":"Cotter DG, Schugar RC, Crawford PA (2013) Ketone body metabolism and cardiovascular disease. Am J Physiol Heart Circ Physiol 304: H1060\u2013H1076","journal-title":"Am J Physiol Heart Circ Physiol"},{"key":"BFEMMM202114323_CR14","doi-asserted-by":"crossref","first-page":"2288","DOI":"10.1016\/S0140-6736(18)31812-9","volume":"392","author":"M Dehghan","year":"2018","unstructured":"Dehghan M, Mente A, Rangarajan S, Sheridan P, Mohan V, Iqbal R, Gupta R, Lear S, Wentzel\u2010Viljoen E, Avezum A et\u00a0al (2018) Association of dairy intake with cardiovascular disease and mortality in 21 countries from five continents (PURE): a prospective cohort study. Lancet 392: 2288\u20132297","journal-title":"Lancet"},{"key":"BFEMMM202114323_CR15","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.mito.2017.10.006","volume":"41","author":"G Desd\u00edn\u2010Mic\u00f3","year":"2018","unstructured":"Desd\u00edn\u2010Mic\u00f3 G, Soto\u2010Heredero G, Mittelbrunn M (2018) Mitochondrial activity in T cells. Mitochondrion 41: 51\u201357","journal-title":"Mitochondrion"},{"key":"BFEMMM202114323_CR16","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1084\/jem.20010659","volume":"195","author":"S Devadas","year":"2002","unstructured":"Devadas S, Zaritskaya L, Rhee SG, Oberley L, Williams MS (2002) Discrete generation of superoxide and hydrogen peroxide by T cell receptor stimulation: selective regulation of mitogen\u2010activated protein kinase activation and fas ligand expression. J Exp Med 195: 59\u201370","journal-title":"J Exp Med"},{"key":"BFEMMM202114323_CR17","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1093\/bioinformatics\/bts635","volume":"29","author":"A Dobin","year":"2013","unstructured":"Dobin A, Davis CA, Schlesinger F, Drenkow J, Zaleski C, Jha S, Batut P, Chaisson M, Gingeras TR (2013) STAR: ultrafast universal RNA\u2010seq aligner. Bioinformatics 29: 15\u201321","journal-title":"Bioinformatics"},{"key":"BFEMMM202114323_CR18","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1038\/ni.3659","volume":"18","author":"E Dror","year":"2017","unstructured":"Dror E, Dalmas E, Meier DT, Wueest S, Th\u00e9venet J, Thienel C, Timper K, Nordmann TM, Traub S, Schulze F et\u00a0al (2017) Postprandial macrophage\u2010derived IL\u20101\u03b2 stimulates insulin, and both synergistically promote glucose disposal and inflammation. Nat Immunol 18: 283\u2013292","journal-title":"Nat Immunol"},{"key":"BFEMMM202114323_CR19","doi-asserted-by":"crossref","first-page":"e145207","DOI":"10.1172\/jci.insight.145207","volume":"6","author":"G Ferrere","year":"2021","unstructured":"Ferrere G, Tidjani Alou M, Liu P, Goubet A\u2010G, Fidelle M, Kepp O, Durand S, Iebba V, Fluckiger A, Daill\u00e8re R et\u00a0al (2021) Ketogenic diet and ketone bodies enhance the anticancer effects of PD\u20101 blockade. JCI Insight 6: e145207","journal-title":"JCI Insight"},{"key":"BFEMMM202114323_CR20","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1016\/j.it.2018.01.005","volume":"39","author":"DG Franchina","year":"2018","unstructured":"Franchina DG, Dostert C, Brenner D (2018) Reactive oxygen species: involvement in T cell signaling and metabolism. Trends Immunol 39: 489\u2013502","journal-title":"Trends Immunol"},{"key":"BFEMMM202114323_CR21","doi-asserted-by":"crossref","first-page":"2077","DOI":"10.1016\/j.celrep.2017.02.004","volume":"18","author":"EL Goldberg","year":"2017","unstructured":"Goldberg EL, Asher JL, Molony RD, Shaw AC, Zeiss CJ, Wang C, Morozova\u2010Roche LA, Herzog RI, Iwasaki A, Dixit VD (2017) \u03b2\u2010hydroxybutyrate deactivates neutrophil NLRP3 inflammasome to relieve gout flares. Cell Rep 18: 2077\u20132087","journal-title":"Cell Rep"},{"key":"BFEMMM202114323_CR22","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1038\/nm.3893","volume":"21","author":"H Guo","year":"2015","unstructured":"Guo H, Callaway JB, Ting JP\u2010Y (2015) Inflammasomes: mechanism of action, role in disease, and therapeutics. Nat Med 21: 677\u2013687","journal-title":"Nat Med"},{"key":"BFEMMM202114323_CR23","doi-asserted-by":"crossref","first-page":"24384","DOI":"10.1073\/pnas.2015486117","volume":"17","author":"JR Habel","year":"2020","unstructured":"Habel JR, Nguyen THO, van de Sandt CE, Juno JA, Chaurasia P, Wragg K, Koutsakos M, Hensen L, Jia X, Chua B et\u00a0al (2020) Suboptimal SARS\u2010CoV\u20102\u2212specific CD8 T cell response associated with the prominent HLA\u2010A*02:01 phenotype. Proc Natl Acad Sci USA 17: 24384\u201324391","journal-title":"Proc Natl Acad Sci USA"},{"key":"BFEMMM202114323_CR24","doi-asserted-by":"crossref","DOI":"10.1038\/s41598-019-51782-w","volume":"9","author":"S Hirschberger","year":"2019","unstructured":"Hirschberger S, H\u00fcbner M, Strau\u00df G, Effinger D, Bauer M, Weis S, Giamarellos\u2010Bourboulis EJ, Kreth S (2019) Identification of suitable controls for miRNA quantification in T\u2010cells and whole blood cells in sepsis. Sci Rep 9: 15735","journal-title":"Sci Rep"},{"key":"BFEMMM202114323_CR25","doi-asserted-by":"crossref","first-page":"406","DOI":"10.1016\/j.immuni.2017.08.009","volume":"47","author":"GS Hotamisligil","year":"2017","unstructured":"Hotamisligil GS (2017) Foundations of Immunometabolism and Implications for Metabolic Health and Disease. Immunity 47: 406\u2013420","journal-title":"Immunity"},{"key":"BFEMMM202114323_CR26","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1126\/science.7678183","volume":"259","author":"G Hotamisligil","year":"1993","unstructured":"Hotamisligil G, Shargill N, Spiegelman B (1993) Adipose expression of tumor necrosis factor\u2010alpha: direct role in obesity\u2010linked insulin resistance. Science 259: 87\u201391","journal-title":"Science"},{"key":"BFEMMM202114323_CR27","doi-asserted-by":"crossref","first-page":"969","DOI":"10.1001\/jama.2018.11025","volume":"320","author":"JPA Ioannidis","year":"2018","unstructured":"Ioannidis JPA (2018) The challenge of reforming nutritional epidemiologic research. JAMA 320: 969\u2013970","journal-title":"JAMA"},{"key":"BFEMMM202114323_CR28","doi-asserted-by":"crossref","first-page":"818","DOI":"10.1038\/ni1096","volume":"5","author":"SH Jackson","year":"2004","unstructured":"Jackson SH, Devadas S, Kwon J, Pinto LA, Williams MS (2004) T cells express a phagocyte\u2010type NADPH oxidase that is activated after T cell receptor stimulation. Nat Immunol 5: 818\u2013827","journal-title":"Nat Immunol"},{"key":"BFEMMM202114323_CR29","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1016\/j.immuni.2007.05.023","volume":"27","author":"RG Jones","year":"2007","unstructured":"Jones RG, Bui T, White C, Madesh M, Krawczyk CM, Lindsten T, Hawkins BJ, Kubek S, Frauwirth KA, Wang YL et\u00a0al (2007) The proapoptotic factors Bax and Bak regulate T cell proliferation through control of endoplasmic reticulum Ca(2+) homeostasis. Immunity 27: 268\u2013280","journal-title":"Immunity"},{"key":"BFEMMM202114323_CR30","doi-asserted-by":"crossref","first-page":"1300","DOI":"10.1016\/j.celrep.2012.10.009","volume":"2","author":"MM Kamin\u0301ski","year":"2012","unstructured":"Kamin\u0301ski MM, Sauer SW, Kamin\u0301ski M, Opp S, Ruppert T, Grigaravic\u030cius P, Grudnik P, Gr\u00f6ne H\u2010J, Krammer PH, G\u00fclow K (2012) T cell activation is driven by an ADP\u2010dependent glucokinase linking enhanced glycolysis with mitochondrial reactive oxygen species generation. Cell Rep 2: 1300\u20131315","journal-title":"Cell Rep"},{"key":"BFEMMM202114323_CR31","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1016\/0065-2571(66)90027-6","volume":"4","author":"HA Krebs","year":"1966","unstructured":"Krebs HA (1966) The regulation of the release of ketone bodies by the liver. Adv Enzyme Regul 4: 339\u2013354","journal-title":"Adv Enzyme Regul"},{"key":"BFEMMM202114323_CR32","doi-asserted-by":"crossref","first-page":"ra59","DOI":"10.1126\/scisignal.2000976","volume":"3","author":"J Kwon","year":"2010","unstructured":"Kwon J, Shatynski KE, Chen H, Morand S, de Deken X, Miot F, Leto TL, Williams MS (2010) The nonphagocytic NADPH oxidase Duox1 mediates a positive feedback loop during T cell receptor signaling. Sci Signal 3: ra59","journal-title":"Sci Signal"},{"key":"BFEMMM202114323_CR33","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1186\/1756-0500-4-427","volume":"4","author":"C Ledderose","year":"2011","unstructured":"Ledderose C, Heyn J, Limbeck E, Kreth S (2011) Selection of reliable reference genes for quantitative real\u2010time PCR in human T cells and neutrophils. BMC Res Notes 4: 427","journal-title":"BMC Res Notes"},{"key":"BFEMMM202114323_CR34","doi-asserted-by":"crossref","first-page":"1214","DOI":"10.1038\/s41418-019-0410-x","volume":"27","author":"K\u2010P Li","year":"2020","unstructured":"Li K\u2010P, Ladle BH, Kurtulus S, Sholl A, Shanmuganad S, Hildeman DA (2020) T\u2010cell receptor signal strength and epigenetic control of Bim predict memory CD8 T\u2010cell fate. Cell Death Differ 27: 1214\u20131224","journal-title":"Cell Death Differ"},{"key":"BFEMMM202114323_CR35","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1016\/j.neuint.2010.10.017","volume":"59","author":"M Li","year":"2011","unstructured":"Li M, Li C, Allen A, Stanley CA, Smith TJ (2011) The structure and allosteric regulation of glutamate dehydrogenase. Neurochem Int 59: 445\u2013455","journal-title":"Neurochem Int"},{"key":"BFEMMM202114323_CR36","doi-asserted-by":"crossref","first-page":"E8017","DOI":"10.1073\/pnas.1721049115","volume":"115","author":"M Liebmann","year":"2018","unstructured":"Liebmann M, Hucke S, Koch K, Eschborn M, Ghelman J, Chasan AI, Glander S, Sch\u00e4dlich M, Kuhlencord M, Daber NM et\u00a0al (2018) Nur77 serves as a molecular brake of the metabolic switch during T cell activation to restrict autoimmunity. Proc Natl Acad Sci USA 115: E8017\u2013E8026","journal-title":"Proc Natl Acad Sci USA"},{"key":"BFEMMM202114323_CR37","doi-asserted-by":"crossref","first-page":"1209","DOI":"10.1007\/s00204-015-1520-y","volume":"89","author":"DC Liemburg\u2010Apers","year":"2015","unstructured":"Liemburg\u2010Apers DC, Peter HG, Koopman WJH, Grefte S (2015) Interactions between mitochondrial reactive oxygen species and cellular glucose metabolism. Arch Toxicol 89: 1209\u20131226","journal-title":"Arch Toxicol"},{"key":"BFEMMM202114323_CR38","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1186\/s13059-014-0550-8","volume":"15","author":"MI Love","year":"2014","unstructured":"Love MI, Huber W, Anders S (2014) Moderated estimation of fold change and dispersion for RNA\u2010seq data with DESeq2. Genome Biol 15: 550","journal-title":"Genome Biol"},{"key":"BFEMMM202114323_CR39","doi-asserted-by":"crossref","first-page":"2269","DOI":"10.1001\/jama.2016.3829","volume":"315","author":"DS Ludwig","year":"2016","unstructured":"Ludwig DS (2016) Lifespan weighed down by diet. JAMA 315: 2269","journal-title":"JAMA"},{"key":"BFEMMM202114323_CR40","doi-asserted-by":"crossref","DOI":"10.1001\/jamanetworkopen.2019.15360","volume":"2","author":"DS Ludwig","year":"2019","unstructured":"Ludwig DS, Ebbeling CB, Heymsfield SB (2019) Discrepancies in the registries of diet vs drug trials. JAMA Netw Open 2: e1915360","journal-title":"JAMA Netw Open"},{"key":"BFEMMM202114323_CR41","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.cmet.2014.05.004","volume":"20","author":"AN Macintyre","year":"2014","unstructured":"Macintyre AN, Gerriets VA, Nichols AG, Michalek RD, Rudolph MC, Deoliveira D, Anderson SM, Abel ED, Chen BJ, Hale LP et\u00a0al (2014) The glucose transporter Glut1 is selectively essential for CD4 T cell activation and effector function. Cell Metab 20: 61\u201372","journal-title":"Cell Metab"},{"key":"BFEMMM202114323_CR42","doi-asserted-by":"crossref","first-page":"851","DOI":"10.1016\/j.cmet.2013.05.008","volume":"17","author":"D Mathis","year":"2013","unstructured":"Mathis D (2013) Immunological goings\u2010on in visceral adipose tissue. Cell Metab 17: 851\u2013859","journal-title":"Cell Metab"},{"key":"BFEMMM202114323_CR43","doi-asserted-by":"crossref","first-page":"16647","DOI":"10.1073\/pnas.1413965111","volume":"111","author":"MP Mattson","year":"2014","unstructured":"Mattson MP, Allison DB, Fontana L, Harvie M, Longo VD, Malaisse WJ, Mosley M, Notterpek L, Ravussin E, Scheer FAJL et\u00a0al (2014) Meal frequency and timing in health and disease. Proc Natl Acad Sci USA 111: 16647\u201316653","journal-title":"Proc Natl Acad Sci USA"},{"key":"BFEMMM202114323_CR44","doi-asserted-by":"crossref","first-page":"3299","DOI":"10.4049\/jimmunol.1003613","volume":"186","author":"RD Michalek","year":"2011","unstructured":"Michalek RD, Gerriets VA, Jacobs SR, Macintyre AN, MacIver NJ, Mason EF, Sullivan SA, Nichols AG, Rathmell JC (2011) Cutting edge: distinct glycolytic and lipid oxidative metabolic programs are essential for effector and regulatory CD4+ T cell subsets. J Immunol 186: 3299\u20133303","journal-title":"J Immunol"},{"key":"BFEMMM202114323_CR45","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1016\/j.eplepsyres.2011.09.021","volume":"100","author":"J Milder","year":"2012","unstructured":"Milder J, Patel M (2012) Modulation of oxidative stress and mitochondrial function by the ketogenic diet. Epilepsy Res 100: 295\u2013303","journal-title":"Epilepsy Res"},{"key":"BFEMMM202114323_CR46","doi-asserted-by":"crossref","first-page":"783","DOI":"10.3389\/fendo.2018.00783","volume":"9","author":"Z Min","year":"2018","unstructured":"Min Z, Gao J, Yu Y (2018) The roles of mitochondrial SIRT4 in cellular metabolism. Front Endocrinol 9: 783","journal-title":"Front Endocrinol"},{"key":"BFEMMM202114323_CR47","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1186\/s10020-018-0056-z","volume":"24","author":"P M\u00f6hnle","year":"2018","unstructured":"M\u00f6hnle P, Hirschberger S, Hinske LC, Briegel J, H\u00fcbner M, Weis S, Dimopoulos G, Bauer M, Giamarellos\u2010Bourboulis EJ, Kreth S (2018) MicroRNAs 143 and 150 in whole blood enable detection of T\u2010cell immunoparalysis in sepsis. Mol Med 24: 54","journal-title":"Mol Med"},{"key":"BFEMMM202114323_CR48","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1016\/j.immuni.2013.02.005","volume":"38","author":"MP Murphy","year":"2013","unstructured":"Murphy MP, Siegel RM (2013) Mitochondrial ROS fire up T cell activation. Immunity 38: 201\u2013202","journal-title":"Immunity"},{"key":"BFEMMM202114323_CR49","doi-asserted-by":"crossref","first-page":"R1210","DOI":"10.1152\/ajpregu.00240.2018","volume":"315","author":"\u00c9 Myette\u2010C\u00f4t\u00e9","year":"2018","unstructured":"Myette\u2010C\u00f4t\u00e9 \u00c9, Durrer C, Neudorf H, Bammert TD, Botezelli JD, Johnson JD, DeSouza CA, Little JP (2018) The effect of a short\u2010term low\u2010carbohydrate, high\u2010fat diet with or without postmeal walks on glycemic control and inflammation in type 2 diabetes: a randomized trial. Am J Physiol Regul Integr Comp Physiol 315: R1210\u2013R1219","journal-title":"Am J Physiol Regul Integr Comp Physiol"},{"key":"BFEMMM202114323_CR50","doi-asserted-by":"crossref","first-page":"3688","DOI":"10.1073\/pnas.1814273116","volume":"116","author":"BA Napier","year":"2019","unstructured":"Napier BA, Andres\u2010Terre M, Massis LM, Hryckowian AJ, Higginbottom SK, Cumnock K, Casey KM, Haileselassie B, Lugo KA, Schneider DS et\u00a0al (2019) Western diet regulates immune status and the response to LPS\u2010driven sepsis independent of diet\u2010associated microbiome. Proc Natl Acad Sci USA 116: 3688\u20133694","journal-title":"Proc Natl Acad Sci USA"},{"key":"BFEMMM202114323_CR51","doi-asserted-by":"crossref","first-page":"1324","DOI":"10.1038\/ijo.2017.131","volume":"41","author":"SD Neidich","year":"2017","unstructured":"Neidich SD, Green WD, Rebeles J, Karlsson EA, Schultz\u2010Cherry S, Noah TL, Chakladar S, Hudgens MG, Weir SS, Beck MA (2017) Increased risk of influenza among vaccinated adults who are obese. Int J Obesity 41: 1324\u20131330","journal-title":"Int J Obesity"},{"key":"BFEMMM202114323_CR52","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1016\/j.cmet.2017.08.004","volume":"26","author":"JC Newman","year":"2017","unstructured":"Newman JC, Covarrubias AJ, Zhao M, Yu X, Gut P, Ng C\u2010P, Huang Y, Haldar S, Verdin E (2017) Ketogenic diet reduces midlife mortality and improves memory in aging mice. Cell Metab 26: 547\u2013557.e8","journal-title":"Cell Metab"},{"key":"BFEMMM202114323_CR53","doi-asserted-by":"crossref","first-page":"1138","DOI":"10.1056\/NEJMsr043743","volume":"352","author":"SJ Olshansky","year":"2005","unstructured":"Olshansky SJ, Passaro DJ, Hershow RC, Layden J, Carnes BA, Brody J, Hayflick L, Butler RN, Allison DB, Ludwig DS (2005) A potential decline in life expectancy in the United States in the 21st century. N Engl J Med 352: 1138\u20131145","journal-title":"N Engl J Med"},{"key":"BFEMMM202114323_CR54","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.immuni.2014.06.005","volume":"41","author":"D O'Sullivan","year":"2014","unstructured":"O'Sullivan D, van der Windt G, Huang S\u2010C, Curtis J, Chang C\u2010H, Buck M, Qiu J, Smith A, Lam W, DiPlato L et\u00a0al (2014) Memory CD8 T cells use cell\u2010intrinsic lipolysis to support the metabolic programming necessary for development. Immunity 41: 75\u201388","journal-title":"Immunity"},{"key":"BFEMMM202114323_CR55","doi-asserted-by":"crossref","first-page":"996","DOI":"10.3390\/md13020996","volume":"13","author":"A Paoli","year":"2015","unstructured":"Paoli A, Moro T, Bosco G, Bianco A, Grimaldi KA, Camporesi E, Mangar D (2015) Effects of n\u20103 polyunsaturated fatty acids (\u03c9\u20103) supplementation on some cardiovascular risk factors with a ketogenic Mediterranean diet. Mar Drugs 13: 996\u20131009","journal-title":"Mar Drugs"},{"key":"BFEMMM202114323_CR56","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1038\/ejcn.2013.116","volume":"67","author":"A Paoli","year":"2013","unstructured":"Paoli A, Rubini A, Volek JS, Grimaldi KA (2013) Beyond weight loss: a review of the therapeutic uses of very\u2010low\u2010carbohydrate (ketogenic) diets. Eur J Clin Nutr 67: 789\u2013796","journal-title":"Eur J Clin Nutr"},{"key":"BFEMMM202114323_CR57","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1016\/j.cmet.2016.12.022","volume":"25","author":"P Puchalska","year":"2017","unstructured":"Puchalska P, Crawford PA (2017) Multi\u2010dimensional roles of ketone bodies in fuel metabolism, signaling, and therapeutics. Cell Metab 25: 262\u2013284","journal-title":"Cell Metab"},{"key":"BFEMMM202114323_CR58","doi-asserted-by":"crossref","first-page":"eaay4014","DOI":"10.1126\/science.aay4014","volume":"369","author":"B Pulendran","year":"2020","unstructured":"Pulendran B, Davis MM (2020) The science and medicine of human immunology. Science 369: eaay4014","journal-title":"Science"},{"key":"BFEMMM202114323_CR59","doi-asserted-by":"crossref","DOI":"10.1136\/bmjopen-2020-038532","volume":"10","author":"T Rahmel","year":"2020","unstructured":"Rahmel T, H\u00fcbner M, Koos B, Wolf A, Willemsen K\u2010M, Strau\u00df G, Effinger D, Adamzik M, Kreth S (2020) Impact of carbohydrate\u2010reduced nutrition in septic patients on ICU: study protocol for a prospective randomised controlled trial. BMJ Open 10: e038532","journal-title":"BMJ Open"},{"key":"BFEMMM202114323_CR60","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1038\/s41416-019-0651-y","volume":"122","author":"V Raimondi","year":"2020","unstructured":"Raimondi V, Ciccarese F, Ciminale V (2020) Oncogenic pathways and the electron transport chain: a dangeROS liaison. Br J Cancer 122: 168\u2013181","journal-title":"Br J Cancer"},{"key":"BFEMMM202114323_CR61","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1038\/nm.3624","volume":"20","author":"M Ristow","year":"2014","unstructured":"Ristow M (2014) Unraveling the truth about antioxidants: mitohormesis explains ROS\u2010induced health benefits. Nat Med 20: 709\u2013711","journal-title":"Nat Med"},{"key":"BFEMMM202114323_CR62","doi-asserted-by":"crossref","first-page":"5793","DOI":"10.3390\/ijms21165793","volume":"21","author":"A Ritter","year":"2020","unstructured":"Ritter A, Kreis N\u2010N, Louwen F, Yuan J (2020) Obesity and COVID\u201019: molecular mechanisms linking both pandemics. Int J Mol Sci 21: 5793","journal-title":"Int J Mol Sci"},{"key":"BFEMMM202114323_CR63","doi-asserted-by":"crossref","DOI":"10.3390\/nu12020306","volume":"12","author":"J Ruiz Herrero","year":"2020","unstructured":"Ruiz Herrero J, Ca\u00f1edo Villarroya E, Garc\u00eda Pe\u00f1as JJ, Garc\u00eda Alcolea B, G\u00f3mez Fern\u00e1ndez B, Puerta Macfarland LA, Pedr\u00f3n Giner C (2020) Safety and effectiveness of the prolonged treatment of children with a ketogenic diet. Nutrients 12: 306","journal-title":"Nutrients"},{"key":"BFEMMM202114323_CR64","doi-asserted-by":"crossref","first-page":"e419","DOI":"10.1016\/S2468-2667(18)30135-X","volume":"3","author":"SB Seidelmann","year":"2018","unstructured":"Seidelmann SB, Claggett B, Cheng S, Henglin M, Shah A, Steffen LM, Folsom AR, Rimm EB, Willett WC, Solomon SD (2018) Dietary carbohydrate intake and mortality: a prospective cohort study and meta\u2010analysis. Lancet Public Health 3: e419\u2013e428","journal-title":"Lancet Public Health"},{"key":"BFEMMM202114323_CR65","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1016\/j.immuni.2012.10.020","volume":"38","author":"L Sena","year":"2013","unstructured":"Sena L, Li S, Jairaman A, Prakriya M, Ezponda T, Hildeman D, Wang C\u2010R, Schumacker P, Licht J, Perlman H et\u00a0al (2013) Mitochondria are required for antigen\u2010specific T cell activation through reactive oxygen species signaling. Immunity 38: 225\u2013236","journal-title":"Immunity"},{"key":"BFEMMM202114323_CR66","doi-asserted-by":"crossref","DOI":"10.1016\/j.isci.2020.101761","volume":"23","author":"TN Seyfried","year":"2020","unstructured":"Seyfried TN, Arismendi\u2010Morillo G, Mukherjee P, Chinopoulos C (2020) On the origin of ATP synthesis in cancer. iScience 23: 101761","journal-title":"iScience"},{"key":"BFEMMM202114323_CR67","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1186\/s12986-017-0178-2","volume":"14","author":"TN Seyfried","year":"2017","unstructured":"Seyfried TN, Yu G, Maroon JC, D\u2019Agostino DP (2017) Press\u2010pulse: a novel therapeutic strategy for the metabolic management of cancer. Nutr Metab 14: 19","journal-title":"Nutr Metab"},{"key":"BFEMMM202114323_CR68","doi-asserted-by":"crossref","first-page":"1898","DOI":"10.1016\/j.celrep.2020.01.022","volume":"30","author":"B Shin","year":"2020","unstructured":"Shin B, Benavides GA, Geng J, Koralov SB, Hu H, Darley\u2010Usmar VM, Harrington LE (2020) Mitochondrial oxidative phosphorylation regulates the fate decision between pathogenic Th17 and regulatory T cells. Cell Rep 30: 1898\u20131909.e4","journal-title":"Cell Rep"},{"key":"BFEMMM202114323_CR69","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.semcancer.2017.06.007","volume":"47","author":"L Simula","year":"2017","unstructured":"Simula L, Nazio F, Campello S (2017) The mitochondrial dynamics in cancer and immune\u2010surveillance. Semin Cancer Biol 47: 29\u201342","journal-title":"Semin Cancer Biol"},{"key":"BFEMMM202114323_CR70","first-page":"43","volume":"1","author":"BJ Stubbs","year":"2020","unstructured":"Stubbs BJ, Koutnik AP, Goldberg EL, Upadhyay V, Turnbaugh PJ, Verdin E, Newman JC (2020) Investigating ketone bodies as immunometabolic countermeasures against respiratory viral infections. Med (N Y) 1: 43\u201365","journal-title":"Med (N Y)"},{"key":"BFEMMM202114323_CR71","doi-asserted-by":"crossref","first-page":"15545","DOI":"10.1073\/pnas.0506580102","volume":"102","author":"A Subramanian","year":"2005","unstructured":"Subramanian A, Tamayo P, Mootha Vk, Mukherjee S, Ebert Bl, Gillette Ma, Paulovich A, Pomeroy Sl, Golub Tr, Lander Es et\u00a0al (2005) Gene set enrichment analysis: a knowledge\u2010based approach for interpreting genome\u2010wide expression profiles. Proc Natl Acad Sci USA 102: 15545\u201315550","journal-title":"Proc Natl Acad Sci USA"},{"key":"BFEMMM202114323_CR72","doi-asserted-by":"crossref","first-page":"43","DOI":"10.3389\/fimmu.2017.00043","volume":"8","author":"C de Torre\u2010Minguela","year":"2017","unstructured":"de Torre\u2010Minguela C, Mesa Del Castillo P, Pelegr\u00edn P (2017) The NLRP3 and pyrin inflammasomes: implications in the pathophysiology of autoinflammatory diseases. Front Immunol 8: 43","journal-title":"Front Immunol"},{"key":"BFEMMM202114323_CR73","doi-asserted-by":"crossref","first-page":"14336","DOI":"10.1073\/pnas.1221740110","volume":"110","author":"G van der Windt","year":"2013","unstructured":"van der Windt G, O'Sullivan D, Everts B, Huang S c\u2010c, Buck Md, Curtis Jd, Chang C\u2010h, Smith Am, Ai T, Faubert B et\u00a0al (2013) CD8 memory T cells have a bioenergetic advantage that underlies their rapid recall ability. Proc Natl Acad Sci USA 110: 14336\u201314341","journal-title":"Proc Natl Acad Sci USA"},{"key":"BFEMMM202114323_CR74","doi-asserted-by":"crossref","first-page":"2131","DOI":"10.1001\/jama.282.22.2131","volume":"282","author":"M Visser","year":"1999","unstructured":"Visser M, Bouter LM, McQuillan GM, Wener MH, Harris TB (1999) Elevated C\u2010reactive protein levels in overweight and obese adults. JAMA 282: 2131\u20132135","journal-title":"JAMA"},{"key":"BFEMMM202114323_CR75","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1016\/j.immuni.2011.09.021","volume":"35","author":"R Wang","year":"2011","unstructured":"Wang R, Dillon C, Shi L, Milasta S, Carter R, Finkelstein D, McCormick L, Fitzgerald P, Chi H, Munger J et\u00a0al (2011) The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation. Immunity 35: 871\u2013882","journal-title":"Immunity"},{"key":"BFEMMM202114323_CR76","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1111\/j.1600-065X.2012.01155.x","volume":"249","author":"R Wang","year":"2012","unstructured":"Wang R, Green DR (2012) Metabolic reprogramming and metabolic dependency in T cells. Immunol Rev 249: 14\u201326","journal-title":"Immunol Rev"},{"key":"BFEMMM202114323_CR77","doi-asserted-by":"crossref","first-page":"1796","DOI":"10.1172\/JCI200319246","volume":"112","author":"SP Weisberg","year":"2003","unstructured":"Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante Jr AW (2003) Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 112: 1796\u20131808","journal-title":"J Clin Invest"},{"key":"BFEMMM202114323_CR78","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1016\/j.immuni.2011.12.007","volume":"36","author":"GJW van der Windt","year":"2012","unstructured":"van der Windt GJW, Everts B, Chang C\u2010H, Curtis JD, Freitas TC, Amiel E, Pearce EJ, Pearce EL (2012) Mitochondrial respiratory capacity is a critical regulator of CD8+ T cell memory development. Immunity 36: 68\u201378","journal-title":"Immunity"},{"key":"BFEMMM202114323_CR79","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1038\/nm.3804","volume":"21","author":"Y\u2010H Youm","year":"2015","unstructured":"Youm Y\u2010H, Nguyen KY, Grant RW, Goldberg EL, Bodogai M, Kim D, D'Agostino D, Planavsky N, Lupfer C, Kanneganti TD et\u00a0al (2015) The ketone metabolite \u03b2\u2010hydroxybutyrate blocks NLRP3 inflammasome\u2010mediated inflammatory disease. Nat Med 21: 263\u2013269","journal-title":"Nat Med"},{"key":"BFEMMM202114323_CR80","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1038\/s41556-019-0440-0","volume":"22","author":"H Zhang","year":"2020","unstructured":"Zhang H, Tang Ke, Ma J, Zhou Li, Liu J, Zeng L, Zhu L, Xu P, Chen J, Wei K et\u00a0al (2020) Ketogenesis\u2010generated \u03b2\u2010hydroxybutyrate is an epigenetic regulator of CD8 T\u2010cell memory development. Nat Cell Biol 22: 18\u201325","journal-title":"Nat Cell Biol"},{"key":"BFEMMM202114323_CR81","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1152\/physrev.00026.2013","volume":"94","author":"DB Zorov","year":"2014","unstructured":"Zorov DB, Juhaszova M, Sollott SJ (2014) Mitochondrial reactive oxygen species (ROS) and ROS\u2010induced ROS release. Physiol Rev 94: 909\u2013950","journal-title":"Physiol Rev"}],"container-title":["EMBO Molecular Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.15252\/emmm.202114323.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.15252\/emmm.202114323","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.15252\/emmm.202114323\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.embopress.org\/doi\/pdf\/10.15252\/emmm.202114323","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.15252\/emmm.202114323.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T06:43:33Z","timestamp":1779086613000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.15252\/emmm.202114323"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,21]]},"references-count":81,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2021,8,9]]}},"alternative-id":["BFEMMM202114323"],"URL":"https:\/\/doi.org\/10.15252\/emmm.202114323","relation":{},"ISSN":["1757-4676","1757-4684"],"issn-type":[{"value":"1757-4676","type":"print"},{"value":"1757-4684","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,6,21]]},"assertion":[{"value":"24 March 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 June 2021","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 June 2021","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 June 2021","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare that they have no conflict of interest.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}],"article-number":"EMMM202114323"}}