title: FGF21 is increased by inflammatory stimuli and protects leptin-deficient ob/ob mice from the toxicity of sepsis.
abstract: The acute phase response (APR) produces marked alterations in lipid and carbohydrate metabolism including decreasing plasma ketone levels. Fibroblast growth factor 21 (FGF21) is a recently discovered hormone that regulates lipid and glucose metabolism and stimulates ketogenesis. Here we demonstrate that lipopolysaccharide (LPS), zymosan, and turpentine, which induce the APR, increase serum FGF21 levels 2-fold. Although LPS, zymosan, and turpentine decrease the hepatic expression of FGF21, they increase FGF21 expression in adipose tissue and muscle, suggesting that extrahepatic tissues account for the increase in serum FGF21. After LPS administration, the characteristic decrease in plasma ketone levels is accentuated in FGF21-/- mice, but this is not due to differences in expression of carnitine palmitoyltransferase 1α or hydroxymethyglutaryl-CoA synthase 2 in liver, because LPS induces similar decreases in the expression of these genes in FGF21-/- and control mice. However, in FGF21-/- mice, the ability of LPS to increase plasma free fatty acid levels is blunted. This failure to increase plasma free fatty acid could contribute to the accentuated decrease in plasma ketone levels because the transport of fatty acids from adipose tissue to liver provides the substrate for ketogenesis. Treatment with exogenous FGF21 reduced the number of animals that die and the rapidity of death after LPS administration in leptin-deficient ob/ob mice and to a lesser extent in control mice. FGF21 also protected from the toxic effects of cecal ligation and puncture-induced sepsis. Thus, FGF21 is a positive APR protein that protects animals from the toxic effects of LPS and sepsis.
authors.affiliation: Metabolism Section, Department of Veterans Affairs Medical Center, University of California San Francisco, San Francisco, California 94121, USA. kenneth.feingold@ucsf.edu
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Feingold
authors.forename: Carl
authors.initials: C
authors.lastname: Grunfeld
authors.forename: Josef G
authors.initials: JG
authors.lastname: Heuer
authors.forename: Akanksha
authors.initials: A
authors.lastname: Gupta
authors.forename: Martin
authors.initials: M
authors.lastname: Cramer
authors.forename: Tonghai
authors.initials: T
authors.lastname: Zhang
authors.forename: Judy K
authors.initials: JK
authors.lastname: Shigenaga
authors.forename: Sophie M
authors.initials: SM
authors.lastname: Patzek
authors.forename: Zoe W
authors.initials: ZW
authors.lastname: Chan
authors.forename: Arthur
authors.initials: A
authors.lastname: Moser
authors.forename: Holly
authors.initials: H
authors.lastname: Bina
authors.forename: Alexei
authors.initials: A
authors.lastname: Kharitonenkov
mesh_terms: D041721:3T3-L1 Cells; D000210:Acute-Phase Reaction / Q000097:blood / Q000209:etiology / Q000378:metabolism*; D000818:Animals; D004591:Electrophoresis, Polyacrylamide Gel; D004797:Enzyme-Linked Immunosorbent Assay; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005260:Female; D005346:Fibroblast Growth Factors / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D053208:Kaplan-Meier Estimate; D007659:Ketones / Q000097:blood; D020738:Leptin / Q000172:deficiency* / Q000235:genetics; D008070:Lipopolysaccharides / Q000633:toxicity; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D047493:PPAR alpha / Q000172:deficiency / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018805:Sepsis / Q000097:blood / Q000378:metabolism* / Q000503:physiopathology
chemical_list: D005230:Fatty Acids, Nonesterified; D007659:Ketones; D020738:Leptin; D008070:Lipopolysaccharides; D047493:PPAR alpha; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors