Deadenylase-dependent mRNA decay of GDF15 and FGF21 orchestrates food intake and energy expenditure.
Cell Metab
; 34(4): 564-580.e8, 2022 04 05.
Article
en En
| MEDLINE
| ID: mdl-35385705
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.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Estabilidad del ARN
/
Síndrome Metabólico
Tipo de estudio:
Health_economic_evaluation
/
Prognostic_studies
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Cell Metab
Asunto de la revista:
METABOLISMO
Año:
2022
Tipo del documento:
Article
País de afiliación:
Estados Unidos