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Previous studies have shown that fibroblast growth factor 21 (FGF21) is partially regulated by the activation of the peroxisome proliferator-activated receptor-α (PPARα) following starvation or the consumption of a high fat, low carbohydrate (HF-LC) ketogenic diet. To understand the nutritional regulation of FGF21, I employed the use of primary rat hepatocytes and screened for factors that could potentially mediate the nutritional regulation of FGF21 mRNA and protein secretion. In preliminary experiments, I discovered that bile acids enhance FGF21 mRNA expression and protein secretion. Bile acids are known ligands for the farnesoid X receptor, a nuclear receptor. Activation of FXR by a synthetic compound (GW4064) also enhanced FGF21 mRNA and protein secretion. To further analyze the role of the bile/acid FXR signaling cascade, I performed transient transfection experiments with reporter constructs of the FGF21 promoter. These experiments identified a cis-acting region that conferred FXR regulation and the electromobility shift assay showed that FXR directly binds to this region. Using FXR knockout animals, I showed that the effects of HF-LC ketogenic consumption, not starvation, on FGF21 are mediated partially through FXR activation. In addition to FXR activation, I have also shown that FGF19, an FXR target gene, enhances FGF19 protein secretion but has no effect on FGF21 mRNA expression. This data suggests that FGF21 is regulated at a post-transcriptional level. In regards to the mechanism by which starvation regulates FGF21, I screened for additional factors that mediate this regulation. Glucagon inhibits FGF21 mRNA expression at 2 and 6 h but enhances FGF21 protein secretion at 6 and 12 h suggesting that glucagon regulates FGF21 at a post-transcriptional mechanism. Other signaling factors in the glucagon-signaling cascade (i.e. cAMP, protein kinase A, and exchange protein activated by cAMP (EPAC)) also enhanced FGF21 secretion. The effects of glucagon on FGF21 mRNA and secretion were reversed by inhibitors of AMPK and p38/MAPK suggesting that these kinases are involved in the regulation of FGF21. Collectively, these results show three distinct pathways (PPARα, FXR, and glucagon) that regulate FGF21 mRNA expression and secretion during the consumption of a HF-LC ketogenic diet and starvation. In addition, these results suggest that the regulation of FGF21 is not limited to a transcriptional mechanism but a post-transcriptional mechanism(s). It is tempting to speculate what step (protein synthesis, protein stability, and/or a secretory process) is involved in the regulation of FGF21 by FGF19 and glucagon. In total, these data offer new options to regulate endogenous production of FGF21. By understanding the regulation of FGF21, we can develop therapeutic targets to attenuate diabetes and obesity through the production of FGF21.