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FGF21 acting on the noradrenergic nervous system protects against influenza virus infection

Wei Fan1, Yuan Zhang1, Laurent Gautron2

  • 1Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390.

Proceedings of the National Academy of Sciences of the United States of America
|September 25, 2025
PubMed

Insights

Fibroblast growth factor 21 (FGF21) protects against influenza infection by regulating energy expenditure and body temperature. FGF21 administration improves outcomes in mice, highlighting its therapeutic potential.

Area of Science:

  • Immunology
  • Endocrinology
  • Neuroscience

Background:

  • Fibroblast growth factor 21 (FGF21) is a hormone known to be induced by infection.
  • Its role in viral infections, specifically influenza, is not fully understood.

Purpose of the Study:

  • To investigate the role of FGF21 in influenza virus infection in mice and humans.
  • To explore the underlying neuronal mechanisms of FGF21's protective effects.

Main Methods:

  • Studied FGF21 induction in response to influenza in humans and mice.
  • Utilized FGF21 knockout mice and mice lacking βKlotho in noradrenergic neurons.
  • Administered FGF21 pharmacologically post-infection.
  • Conducted pair feeding studies to assess the impact of food intake.
  • Examined gene expression in brown adipose tissue and neuronal activity.

Main Results:

  • FGF21 is induced by influenza virus infection in both humans and mice.
  • FGF21 knockout mice exhibited reduced tolerance to influenza, showing decreased food intake, body weight, and temperature.
  • Pharmacologic FGF21 administration protected mice against influenza-induced pathology.
  • Mice lacking FGF21's coreceptor βKlotho in noradrenergic neurons were more susceptible to infection.
  • FGF21 stimulates energy expenditure and thermogenic gene expression in brown adipose tissue via noradrenergic neurons.

Conclusions:

  • FGF21 plays a critical protective role during influenza virus infection.
  • An FGF21-regulated neuronal pathway involving noradrenergic neurons enhances host defense.
  • FGF21 represents a potential therapeutic agent for improving outcomes in influenza infections.
Keywords:
FGF21energy expenditureinfluenzanoradrenergic nervous systemβKlotho

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