Deadenylase-dependent mRNA decay of GDF15 and FGF21 orchestrates food intake and energy expenditure

Sakie Katsumura, Nadeem Siddiqui, Michael Rock Goldsmith, Jaime H. Cheah, Teppei Fujikawa, Genki Minegishi, Atsushi Yamagata, Yukako Yabuki, Kaoru Kobayashi, Mikako Shirouzu, Takeshi Inagaki, Tim H.M. Huang, Nicolas Musi, Ivan Topisirovic, Ola Larsson, Masahiro Morita

Research output: Contribution to journalArticlepeer-review

Abstract

Hepatokines, secretory proteins from the liver, mediate inter-organ communication to maintain a metabolic balance between food intake and energy expenditure. However, molecular mechanisms by which hepatokine levels are rapidly adjusted following stimuli are largely unknown. Here, we unravel how CNOT6L deadenylase switches off hepatokine expression after responding to stimuli (e.g., exercise and food) to orchestrate energy intake and expenditure. Mechanistically, CNOT6L inhibition stabilizes hepatic Gdf15 and Fgf21 mRNAs, increasing corresponding serum protein levels. The resulting upregulation of GDF15 stimulates the hindbrain to suppress appetite, while increased FGF21 affects the liver and adipose tissues to induce energy expenditure and lipid consumption. Despite the potential of hepatokines to treat metabolic disorders, their administration therapies have been challenging. Using small-molecule screening, we identified a CNOT6L inhibitor enhancing GDF15 and FGF21 hepatokine levels, which dramatically improves diet-induced metabolic syndrome. Our discovery, therefore, lays the foundation for an unprecedented strategy to treat metabolic syndrome.

Original languageEnglish (US)
Pages (from-to)564-580.e8
JournalCell Metabolism
Volume34
Issue number4
DOIs
StatePublished - Apr 5 2022
Externally publishedYes

Keywords

  • CCR4-NOT deadenylase complex
  • energy expenditure
  • FGF21
  • food intake
  • GDF15
  • hepatokine
  • inter-organ communication
  • metabolic syndrome
  • mRNA degradation

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

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