Imbalances in energy intake and expenditure are the leading cause of the dramatic surge in obesity and cardiovascular disease affecting >60% of Americans. Increasing fat content in the average diet alters metabolism and contributes to disease. FGF21, a secreted hepatokine, modulates feeding behavior and energy expenditure (EE) primarily through signaling in brain and adipose tissue. FGF21 analogues are actively in clinical trials for several metabolic diseases, and it is therefore important to understand the various pathways that control FGF21. FGF21 is regulated by well-defined transcriptional programs, but its post-transcriptional regulation is less understood. Post-transcriptional regulation is mediated by RNA binding proteins (RBPs) that control mRNA stability. One family of such RBPs is the ZFP36 family proteins (ZFP36, ZFP36L1, ZFP36L2) that bind to AU-rich regions in the 3’UTR, leading to mRNA degradation. All 3 ZFP36 family proteins are redundant, therefore we knocked out Zfp36 , Zfp36l1 and Zfp36l2 in livers of adult mice. Fgf21 was the most upregulated gene following loss of ZFP36 family proteins in the liver. Consistent with elevated FGF21, these mice rapidly lost weight and fat mass while remaining metabolically healthy. Using metabolic cages, we observed that mice lacking hepatic ZFP36 family proteins had increased food intake and EE and decreased respiratory exchange ratio, indicating preferential fat burning. We then generated mice lacking the ZFP36 family proteins and Fgf21 which partially restored the metabolic phenotypes observed, leading to the hypothesis that ZFP36 family proteins post-transcriptionally regulate Fgf21 in controlling food intake and energy homeostasis. To determine if loss of ZFP36 family proteins protects against diet-induced obesity, we fed mice lacking the ZFP36 family proteins a high fat diet, however, they were entirely protected from diet induced obesity. The protection was partially reversed by additional deletion of Fgf21 . These findings demonstrate that FGF21 is regulated post-transcriptionally by the ZFP36 family proteins and loss of this mode of regulation has significant metabolic implications in diet-induced obesity and could lead to new therapeutic approaches to treat metabolic disease.