Sickness behaviors, including anorexia, are evolutionarily conserved responses to acute infections. 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, β-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.
Hepatic FGF21 preserves thermoregulation and cardiovascular function during bacterial inflammation
Disclosures: H.H. Luan reported "other" from NGM Biopharmaceuticals outside the submitted work. No other disclosures were reported.
H.H. Luan’s present address is NGM Biopharmaceuticals, South San Francisco, CA.
- Award Id(s): AI046688,AI089771,CA157461
- Award Id(s): K08DK110424,R35GM137984
- Award Id(s): T32 AR07107-39,K08AI128745
- Award Id(s): P30-DK079310
- Award Id(s): P30-DK079328
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Sarah C. Huen, Andrew Wang, Kyle Feola, Reina Desrouleaux, Harding H. Luan, Richard Hogg, Cuiling Zhang, Qing-Jun Zhang, Zhi-Ping Liu, Ruslan Medzhitov; Hepatic FGF21 preserves thermoregulation and cardiovascular function during bacterial inflammation. J Exp Med 4 October 2021; 218 (10): e20202151. doi: https://doi.org/10.1084/jem.20202151
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