Hepatic posttranscriptional network comprised of CCR4–NOT deadenylase and FGF21 maintains systemic metabolic homeostasis

Significance The mRNA poly(A) tail controls gene expression at posttranscriptional levels, including mRNA degradation and translation. Here, we show that a hitherto unknown hepatic posttranscriptional network centered on the CCR4–NOT deadenylase plays a seminal role in regulating FGF21 expression and its effects on systemic metabolism. A genome-wide search for CNOT6L-associated mRNAs unveiled the mechanism whereby CNOT6L selectively degrades a subset of mRNAs encoding metabolic factors, including FGF21. Disruption of CCR4–NOT deadenylase activity, by targeting its catalytic subunit CNOT6L, leads to an increase in FGF21 levels, which is paralleled by a dramatic improvement of metabolic syndrome. Overall, our findings describe a new paradigm in regulation of whole-body metabolism, whereby a hepatic posttranscriptional network governs systemic metabolic regulation via FGF21.