Orchestrating inter-organ communication and treating metabolic disorders by mRNA decay of hepatokines
Dr. Sakie KATSUMURA
University of Texas Health Science Center at San Antonio
Whole-body metabolic homeostasis is tightly controlled by secretory proteins, called organokines, such as hepatokines from the liver and adiopokines from adipose tissues. Hepatokines are known to mediate inter-organ communication to maintain a metabolic balance, however, molecular mechanisms by which hepatokine levels are rapidly adjusted following stimuli (e.g., exercise and food) are largely unknown. Here, we unravel that CNOT6L deadenylase, a component of the mRNA decay machinery, switches off expression of hepatokines after responding to stimuli to orchestrate energy intake and expenditure. Mechanistically, CNOT6L inhibition stabilizes hepatic Gdf15 and Fgf21 mRNAs, leading to an increase in corresponding serum protein levels. The resulting up-regulation of circulating GDF15 stimulates the hindbrain to suppress appetite, while increased FGF21 affects the liver and adipose tissues to induce energy expenditure and lipid consumption. Although hepatokines showed potentials for treatment of metabolic disorders, their administration therapies have been challenging due to their low stabilities and emerging resistance. Using small-molecule screening, we identified a bioactive CNOT6L inhibitor enhancing expression of hepatokines, which dramatically improved diet-induced metabolic disorders in mice. Our discovery, therefore, lays the foundation for an unprecedented strategy to treat metabolic disorders.
Hepatokines, energy expenditure, food intake, CNOT6L, FGF21, GDF15