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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.

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