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Inflammation-induced anorexia causes dramatic metabolic changes, of which components critical to survival are unique depending on the type of inflammation. Glucose supplementation during the anorectic period induced by bacterial inflammation suppresses adaptive fasting metabolic pathways, including fibroblast growth factor 21 (FGF21), and decreases survival. Consistent with this observation, FGF21-deficient mice are more susceptible to mortality from endotoxemia and polybacterial peritonitis. Here, we report that increased circulating FGF21 during bacterial inflammation is hepatic derived and required for survival through the maintenance of thermogenesis, energy expenditure, and cardiac function. FGF21 signaling downstream of its obligate coreceptor, \u03b2-Klotho (KLB), is required in bacterial sepsis. However, FGF21 modulates thermogenesis and chronotropy independent of the adipose, forebrain, and hypothalamus, which are operative in cold adaptation, suggesting that in bacterial inflammation, either FGF21 signals through a novel, undescribed target tissue or concurrent signaling of multiple KLB-expressing tissues is required.<\/jats:p>","DOI":"10.1084\/jem.20202151","type":"journal-article","created":{"date-parts":[[2021,8,18]],"date-time":"2021-08-18T10:11:36Z","timestamp":1629281496000},"update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":36,"title":["Hepatic FGF21 preserves thermoregulation and cardiovascular function during bacterial inflammation"],"prefix":"10.1084","volume":"218","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6420-2400","authenticated-orcid":true,"given":"Sarah C.","family":"Huen","sequence":"first","affiliation":[{"name":"Department of Internal Medicine (Nephrology) and Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6951-8081","authenticated-orcid":true,"given":"Andrew","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine (Rheumatology), Yale University School of Medicine, New Haven, CT 2"},{"name":"Department of Immunobiology, Yale University School of Medicine, New Haven, CT 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1190-9696","authenticated-orcid":true,"given":"Kyle","family":"Feola","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine (Nephrology) and Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3570-0125","authenticated-orcid":true,"given":"Reina","family":"Desrouleaux","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine (Rheumatology), Yale University School of Medicine, New Haven, CT 2"},{"name":"Department of Immunobiology, Yale University School of Medicine, New Haven, CT 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2044-2159","authenticated-orcid":true,"given":"Harding H.","family":"Luan","sequence":"additional","affiliation":[{"name":"Department of Immunobiology, Yale University School of Medicine, New Haven, CT 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Hogg","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine (Nephrology) and Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6236-7356","authenticated-orcid":true,"given":"Cuiling","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine (Rheumatology), Yale University School of Medicine, New Haven, CT 2"},{"name":"Department of Immunobiology, Yale University School of Medicine, New Haven, CT 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0749-642X","authenticated-orcid":true,"given":"Qing-Jun","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine (Cardiology) and Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 4"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1341-3878","authenticated-orcid":true,"given":"Zhi-Ping","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine (Cardiology) and Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 4"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7021-2012","authenticated-orcid":true,"given":"Ruslan","family":"Medzhitov","sequence":"additional","affiliation":[{"name":"Department of Immunobiology, Yale University School of Medicine, New Haven, CT 3"},{"name":"Howard Hughes Medical Institute, Chevy Chase, MD 5"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2021,8,18]]},"reference":[{"key":"2023072723500374000_bib1","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1002\/arch.20068","article-title":"Parasitic suppression of feeding in the tobacco hornworm, Manduca sexta: parallels with feeding depression after an immune challenge","volume":"60","author":"Adamo","year":"2005","journal-title":"Arch. 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