Horm Mol Biol Clin Invest 2017; 30(1): 20160016 Review Anjeza Erickson and Régis Moreau* The regulation of FGF21 gene expression by metabolic factors and nutrients DOI 10.1515/hmbci-2016-0016 epiphenomenon; and (iii) whether FGF21 may have some Received March 28, 2016; accepted May 8, 2016; previously published adverse effects alongside beneficial outcomes. online June 10, 2016 Keywords: butyric acid; curcumin; lipoic acid; methio- Abstract: Fibroblast growth factor 21 (FGF21) gene expres- nine; retinoic acid. sion is altered by a wide array of physiological, metabolic, and environmental factors. Among dietary factors, high dextrose, low protein, methionine restriction, short-chain Introduction fatty acids (butyric acid and lipoic acid), and all-trans- retinoic acid were repeatedly shown to induce FGF21 The importance of diet and nutrition in the etiology of a expression and circulating levels. These effects are usually number of diseases affecting morbidity and mortality is more pronounced in liver or isolated hepatocytes than in well recognized. However, the exact nature of how diet adipose tissue or isolated fat cells. Although peroxisome impacts health and disease is complex and not fully under- proliferator-activated receptor α (PPARα) is a key media- stood. Nutrients and dietary molecules alter gene expres- tor of hepatic FGF21 expression and function, including sion, modulate protein and metabolite levels in blood and the regulation of gluconeogenesis, ketogenesis, torpor, tissues, modify cellular and metabolic pathways, affect epi- and growth inhibition, there is increasing evidence of genetic phenomena, and modify response to drugs. These PPARα-independent transactivation of the FGF21 gene by nutrient-gene interactions thus influence an individual’s dietary molecules. FGF21 expression is believed to follow response to the environment – including diet – and to the circadian rhythm and be placed under the control of therapy. Nutrients act directly, indirectly, and cooperatively first order clock-controlled transcription factors, retinoic with hormones to influence the rate and extent of transcrip- acid receptor-related orphan receptors (RORs) and nuclear tion. Among nutrients, glucose, fatty acids, sterols, vitamin receptors subfamily 1 group D (REV-ERBs), with FGF21 A, vitamin D, and their metabolites are prominent regula- rhythm being anti-phase to REV-ERBs. Key metabolic hor- tors of gene expression. Chief among hormones, insulin, mones such as glucagon, insulin, and thyroid hormone glucagon, glucocorticoids, and growth and thyroid hor- have presumed or clearly demonstrated roles in regulating mones, are essential regulators of metabolic homeostasis. FGF21 transcription and secretion. The control of the FGF21 Since fibroblast growth factor 21 (FGF21) was discov- gene by glucagon and insulin appears more complex than ered nearly two decades ago [1], its physiological and phar- first anticipated. Some discrepancies are noted and will macological effects have been extensively studied whereas, need continued studies. The complexity in assessing the comparatively, the regulation of FGF21 gene expression significance of FGF21 gene expression resides in the diffi- by diet, nutrients, and dietary bioactive compounds is culty to ascertain (i) when transcription results in local or not well characterized. FGF21 is expressed across several systemic increase of FGF21 protein; (ii) if FGF21 is among tissues, predominantly in liver and adipocyte tissues, the first or second order genes upregulated by physiologi- and, to a lower extent, in the pancreas, skeletal muscle, cal, metabolic, and environmental stimuli, or merely an heart, kidneys and testes [1–3]. Unlike most members of the FGF family, FGF21 lacks the FGF heparin-binding domain, allowing FGF21 to be secreted in the bloodstream *Corresponding author: Régis Moreau, Department of Nutrition and and act peripherally as well as centrally [4]. Circulating Health Sciences, University of Nebraska-Lincoln, Lincoln, NE 68583, levels of FGF21 are increased in response to fasting [5–7], USA, Phone: 402-472-7291, Fax: 402-472-1587, E-mail: [email protected] macronutrient diet composition [6, 8], and physiological Anjeza Erickson: Department of Nutrition and Health Sciences, or environmental stress [9] in individuals with obesity, University of Nebraska-Lincoln, Lincoln, Nebraska, USA type 2 diabetes, and non-alcoholic fatty liver disease [10]. 2 Erickson and Moreau: Nutritional regulation of FGF21 gene expression The broad range responsiveness of FGF21 expression to catabolism of fatty acids, ketogenesis, and gluconeogenesis. metabolic variations suggests that FGF21 contributes to The FGF21 gene is also upregulated by fasting signals con- metabolic homeostasis in health and disease. Indeed, the veyed by glucagon. The actions of the glucagon receptor on pharmacological administration of recombinant FGF21 glucose and lipid metabolism and on the regulation of body resulted in a plethora of metabolic outcomes including the weight and fat mass are mediated in part by FGF21 [36]. The increase of fat utilization and energy expenditure, the pro- glucagon/FGF21 axis is further discussed below. motion of fat browning in white and brown adipose tissue, Fat cell FGF21 has been shown to be upregulated the improvement of thermogenesis, the stimulation of fatty during adipocyte differentiation [28] and to stimulate acid oxidation, the stimulation of peroxisome proliferator- glucose uptake in adipocytes [11, 13]. ChREBP is upregu- activated receptor α (PPARα) and PPARγ transactivation, lated during adipocyte differentiation and, thus, may glucose tolerance and insulin sensitivity, decreased body be involved in the induction of FGF21 in these cells [37]. weight and lowered cholesterol along with serum and In adipocytes, FGF21 is induced by feeding in a PPARγ- hepatic triglyceride levels [5, 6, 11–21]. This review focuses dependent manner [38]. PPARγ agonists, such as the thia- on the nutritional factors and metabolic hormones that zolidinedione drugs, also induce FGF21 gene expression modulate FGF21 gene expression in rodents and humans, in white adipose tissue and isolated adipocytes [28, 39, and discusses the underlying transcriptional mechanisms. 40]. Supporting the mediating role of FGF21 in the thera- peutic effects of thiazolidinedione is the observation that FGF21-null mice are refractory to both the beneficial and adverse effects of this family of drugs [17]. Body of review There is evidence to indicate that the FGF21 gene is autoregulated by circulating FGF21. The administration of Regulation by starvation and overnutrition recombinant FGF21 to streptozotocin-treated mice dose- dependently repressed FGF21 gene expression in the liver Animal studies have shown that FGF21 expression is to a greater extent than streptozotocin alone [41]. In a upregulated by drastically different nutritional states, separate study, FGF21 transcript levels were substantially such as in starvation and overnutrition. In contrast, the lowered in the liver following FGF21 administration [42]. FGF21 serum levels of healthy subjects remain stable over These results suggest the presence of a negative feedback the course of a day despite wide interindividual varia- by FGF21 directed at its own expression. tions (21–5300 pg/mL; mean, 450 pg/mL) [22]. Moreover, serum FGF21 is largely unchanged in humans who fasted for 2 days [22], suggesting that secreted FGF21 remains Regulation by hormones within the tissue of production and acts locally. It is after 7 days of fasting that serum FGF21 notably increases in Glucagon and insulin human subjects [22, 23]. Plasma FGF21 levels are report- edly higher in the obese, in individuals with type 2 diabe- A physiological link was established between hepatic tes, and in subjects with non-alcoholic liver disease, which glucagon signaling, 5′ adenosine monophosphate-acti- correlate with elevated levels of triacylglycerols in the liver vated protein kinase (AMPK), PPARα, and the expres- [24–29]. Overnutrition and refeeding also upregulate FGF21 sion of FGF21 in mice lacking the glucagon receptor [43]. gene expression. This response may be induced by dietary In these mice, glucagon failed to induce liver AMPK carbohydrates as it was shown that carbohydrates induce phosphorylation, PPARα and FGF21 gene expression. A FGF21 gene expression through the transcription factor lipid infusion composed of PPARα natural ligands also carbohydrate response element binding protein (ChREBP). failed to induce liver AMPK phosphorylation, and PPARα In the liver and isolated hepatocytes, FGF21 expression and FGF21 gene expression in glucagon receptor-null is induced by starvation in PPARα-dependent and independ- mice, suggesting that a functional glucagon signaling ent manners [5–7, 30, 31]. As a transcription factor activated is required for the PPARα-mediated upregulation of the by fatty acids, phosphatidylcholine, oleoylethanolamine, FGF21 gene. The use of a glucagon receptor agonist raised and hypolipidemic fibrate drugs, PPARα binds to PPRE in hepatic expression and blood levels of FGF21 in wild-type the 5′-flanking region of the FGF21 gene and induces tran- mice [36], supporting the notion that chronic glucagon scription [5, 7] (Figure 1). Liver FGF21 is also induced by a action is mediated through FGF21 expression. Cyphert high-fat low-carbohydrate diet [6], a condition that, similar et al. [44] found that glucagon stimulates FGF21 secretion to starvation, stimulates the breakdown of stored fat,