Abstract Body: Systemic adaptation to nutrient availability requires communication between metabolic organs, with the liver playing a central role via hepatokine secretion. To identify novel regulators of nutrient sensing we performed RNA-Seq on livers of fed or fasted mice. Among the top upregulated pathways was regulation of mRNA stability, notably ZFP36 proteins (ZFP36, ZFP36L1, ZFP36L2). ZFP36 proteins are RNA binding proteins that interact with AU-rich regions in the 3’UTR of target genes, leading to mRNA decay. Combined liver-specific loss of all three ZFP36 proteins (L-TKO) resulted in rapid weight loss driven by increases in energy expenditure and fat utilization. To identify ZFP36 protein target genes that contribute to the metabolic changes we performed RNA-Seq on livers of control or L-TKO mice. Fgf21, a secreted hepatokine that modulates feeding behavior and energy expenditure, was the most upregulated gene. To understand the physiologic relevance of this regulatory mechanism, we fasted control and L-TKO mice overnight. Upon fasting, L-TKO mice had dramatically more FGF21 compared to control fasted mice, suggesting ZFP36 proteins establish a critical upper limit for FGF21 expression in fasting. To evaluate the contribution of elevated FGF21 to the metabolic phenotype, we generated a mouse model lacking the three ZFP36 proteins and FGF21. The additional deletion of FGF21 partially reversed the metabolic phenotype observed in mice lacking ZFP36 proteins alone, suggesting ZFP36 protein mediated regulation of FGF21 contributed to the control of systemic metabolism. However, additional ZFP36 protein gene targets are likely involved. To identify additional secreted hepatic factors, we performed a plasma cytokine array in which the metabolic cytokine GDF15 was induced in L-TKO mice. To determine whether the combined regulation of FGF21 and GDF15 by the ZFP36 proteins controlled systemic energy balance, we co-deleted the ZFP36 proteins, FGF21, and GDF15. With combined deletion of FGF21 and GDF15, the weight loss phenotype was almost fully reversed. To determine whether the post-transcriptional regulatory mechanism is relevant in humans, we identified rare 3’UTR variants in FGF21 and GDF15 that functionally impacted the stability of the 3’UTR. Together, our findings identified a novel mechanism of post-transcriptional regulation that co-regulates FGF21 and GDF15 mRNA stability to serve as a critical and tunable regulatory checkpoint in metabolic homeostasis.