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

Cell Metab. 2022 Apr 5;34(4):564-580.e8. doi: 10.1016/j.cmet.2022.03.005.


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.

Keywords: CCR4-NOT deadenylase complex; FGF21; GDF15; energy expenditure; food intake; hepatokine; inter-organ communication; mRNA degradation; metabolic syndrome.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Eating
  • Energy Metabolism / genetics
  • Fibroblast Growth Factors / metabolism
  • Growth Differentiation Factor 15 / genetics
  • Growth Differentiation Factor 15 / metabolism
  • Humans
  • Liver / metabolism
  • Metabolic Syndrome* / metabolism
  • Mice
  • RNA Stability* / genetics
  • RNA Stability* / physiology
  • Ribonucleases / metabolism


  • GDF15 protein, human
  • Growth Differentiation Factor 15
  • fibroblast growth factor 21
  • Fibroblast Growth Factors
  • CNOT6L protein, human
  • Cnot6l protein, mouse
  • Ribonucleases