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<p>Fasting initiates a coordinated metabolic response to preserve energy balance. As glycogen stores are depleted, the body transitions to mobilizing fatty acids from adipose tissue and generating ketone bodies in the liver to sustain the function of vital organs. A network of hormonal signals and transcriptional programs coordinate these adaptations. Among these, the hepatokine fibroblast growth factor 21 (FGF21) is strongly upregulated during fasting and has been proposed as a key mediator of the fasting response. To investigate the physiological functions of FGF21, we study mice with hepatocyte-specific deletion of <i>Fgf21</i>. Although the liver is the primary source of circulating FGF21 during fasting, its absence in hepatocytes does not alter typical fasting-induced gene expression or key metabolic pathways such as hepatic gluconeogenesis, adipose tissue lipolysis, or ketone production. Instead, we uncover a distinct role for FGF21 in promoting protein appetite following a fast. These findings challenge the conventional view of hepatocyte-produced FGF21 as a fasting-acting hormone and reveal a more specialized function in guiding nutrient selection after energy depletion.</p>

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Hepatic FGF21 is not required for fasting metabolism but guides protein appetite post energy depletion

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月27日

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  • Justine Bruse,
  • Clothilde Marbach,
  • Arnaud Polizzi,
  • Tatiana Landre,
  • Juliette Salvi,
  • Valérie Alquier-Bacquie,
  • Shiou-Ping Chen,
  • Marine Huillet,
  • Clémence Rives,
  • Céline M P Martin,
  • Prunelle Perrier,
  • Fadila Benhamed,
  • Marion Régnier,
  • Stefan Weger,
  • Claire Naylies,
  • Yannick Lippi,
  • Caroline Sommer,
  • Mikael Albin,
  • Frédéric Lasserre,
  • Thierry Levade,
  • Michael Schupp,
  • Laurence Gamet-Payrastre,
  • Léon Kautz,
  • Nicolas Loiseau,
  • Walter Wahli,
  • Sandrine Ellero-Simatos,
  • Céline Cruciani-Guglielmacci,
  • Alexandra Montagner,
  • Alexandre Benani,
  • Catherine Postic,
  • Hervé Guillou,
  • Anne Fougerat

摘要

Fasting initiates a coordinated metabolic response to preserve energy balance. As glycogen stores are depleted, the body transitions to mobilizing fatty acids from adipose tissue and generating ketone bodies in the liver to sustain the function of vital organs. A network of hormonal signals and transcriptional programs coordinate these adaptations. Among these, the hepatokine fibroblast growth factor 21 (FGF21) is strongly upregulated during fasting and has been proposed as a key mediator of the fasting response. To investigate the physiological functions of FGF21, we study mice with hepatocyte-specific deletion of Fgf21. Although the liver is the primary source of circulating FGF21 during fasting, its absence in hepatocytes does not alter typical fasting-induced gene expression or key metabolic pathways such as hepatic gluconeogenesis, adipose tissue lipolysis, or ketone production. Instead, we uncover a distinct role for FGF21 in promoting protein appetite following a fast. These findings challenge the conventional view of hepatocyte-produced FGF21 as a fasting-acting hormone and reveal a more specialized function in guiding nutrient selection after energy depletion.