Abstract Body: Fasting-feeding transitions require coordinated control of gene expression that regulate these different nutritional states in the liver. To identify novel proteins involved in regulating the fasting-fed response, we performed RNA-Sequencing on livers from fed or fasted mice. Among the top differentially upregulated pathways was regulation of mRNA stability, notably ZFP36 proteins (ZFP36, ZFP36L1, ZFP36L2). ZFP36 proteins bind AU-rich regions in the 3’UTR of target genes, promoting mRNA degradation. All ZFP36 proteins bind the same response element, suggesting redundancy. Thus, we deleted all three ZFP36 proteins in livers of adult mice. Liver-specific loss of ZFP36 proteins resulted in rapid weight loss while metabolic cage data showed increased food intake and energy expenditure, suggesting they remained metabolically healthy. When fed a Western diet (WD) mice lacking hepatic ZFP36 proteins were entirely protected from diet-induced obesity. In addition, when pre-fed WD to induce obesity before gene deletion, loss of hepatic ZFP36 proteins resulted in loss of all the weight gained prior to gene deletion. To mechanistically identify the cause of the metabolic changes we profiled global gene expression by RNA-Sequencing and found Fgf21 was the most upregulated gene with loss of hepatic ZFP36 proteins. FGF21, a secreted hepatokine, modulates feeding behavior and energy expenditure through signaling in brain and adipose. To assess the role of FGF21 in mediating the metabolic effects, we generated mice lacking hepatic ZFP36 proteins and Fgf21, which partially restored the metabolic phenotype. This partial recovery suggested other ZFP36 targets may play a role. We identified GDF15, another metabolic hepatokine, as a ZFP36 target. Mice lacking hepatic ZFP36 proteins, Fgf21, and Gdf15 fully reversed the weight phenotype observed in mice lacking only ZFP36 proteins, indicating ZFP36 proteins regulate FGF21 and GDF15 to control metabolic homeostasis. We hypothesized this regulation is important in the context of fasting, so mice lacking hepatic ZFP36 proteins were fasted overnight. While fasting induces FGF21 expression, in the absence of hepatic ZFP36 proteins fasting FGF21 levels increased markedly further. We propose ZFP36 proteins set an expression threshold for FGF21 to prevent over-production. This adds post-transcriptional control as a key regulatory mechanism of these proteins and improves understanding of metabolic secreted factors in health and disease.