INTRODUCTION

Fibroblast growth factor 21 (FGF21) was identified and cloned as the 21st member of the FGF family [1]. The biological function of FGF21 as a novel metabolic regulator was first reported by researchers from the Lilly Research Laboratories [2]. These researchers discovered that FGF21 is a secretory protein that enhances glucose uptake in adipocytes and has beneficial metabolic effects on insulin resistance and diabetes [2]. Specifically, transgenic mice overexpressing FGF21 exhibit resistance to diet-induced obesity, which indicates the potential of FGF21 as an antiobesity molecule [2]. In line with this report, subsequent studies have suggested that FGF21 and FGF21 mimetics can improve the metabolic parameters of obese diabetic rodents [3,4,5], rhesus monkeys [6,7] and human subjects [8]. Such therapeutic effects of FGF21 have been attributed to the pleiotropic metabolic actions of FGF21 in multiple target organs such as the adipose tissue [9,10,11], liver [4,12], pancreas [13], and hypothalamus [14,15]. Intriguingly, emerging studies have suggested the potential role of FGF21 as a regulator that mediates the therapeutic effects of several antidiabetic drugs or compounds, such as thiazolidinedione [16], glucagon analogue [17], glucagon-like peptide-1 analogue [18], and metformin [19]. In addition to the beneficial pharmacological effects of exogenous FGF21, endogenous FGF21 also plays an important role in the maintenance of energy homeostasis in several stressful conditions, such as nutrient starvation [20,21] and cold exposure [22,23]. Furthermore, a growing body of research suggests that FGF21 is also able to exert protective functions in pathological conditions that occurring after the administration of chemicals, such as acetaminophen-induced liver toxicity [24], dioxin-induced toxicity [25], cerulein-induced pancreatitis [26], and phenylephrine-induced cardiac hypertrophic damage [27]. These findings suggest that FGF21 acts as a key regulator in the adaptation to stress and can limit the progression of stress in diverse disease conditions. Among the numerous actions of FGF21, we highlight our recent understanding of FGF21 as a stress hormone in the present review and focus on the functional significance and molecular mechanisms of the induction of FGF21 in response to diverse stressors such as nutrient deprivation or overload, autophagy deficiency, mitochondrial stress, exercise, and cold exposure (Fig. 1).

FUNCTIONAL IMPORTANCE OF THE INDUCTION OF FGF21 BY VARIOUS METABOLIC STRESSORS

FGF21 and nutrient stress

Several previous studies have suggested that FGF21 expression is regulated by various nutrient stresses such as starvation [20,21,28], a ketogenic diet [29], amino acid deprivation [30,31], undernutrition (or malnutrition) [32], and a high-fat diet or obesity [33,34]. Consequently, increased FGF21 levels might play a role in the adaptation to nutritional stress.

The physiological function of FGF21 in the maintenance of nutritional homeostasis was suggested in papers that showed that FGF21 is a molecule regulating lipid metabolism in response to fasting [20,21]. In starvation, FGF21 expression has been reported to be induced in the liver via the peroxisome proliferator-activated receptor α (PPARα). Additionally, recent studies have suggested that the cAMP-responsive element binding protein H and sirtuin 1 also participate in fasting-induced FGF21 expression [28,35]. Subsequently, increased FGF21 expression promotes lipolysis in adipose tissue, and the fatty acids released from adipose tissue are transported to the liver where they are directly oxidized for energy production or utilized as a source for ketone body formation. Furthermore, hepatic FGF21 induction contributes to the alleviation of fasting-induced hepatosteatosis by enhancing the expression of the genes involved in fatty acid oxidation [28]. In addition to fasting-induced changes in lipid metabolism, PPARα-mediated FGF21 induction is also involved in the increases in fatty acid oxidation and ketogenesis that result from ketogenic diets [29]. These results indicate that FGF21 acts as a critical regulator in the metabolic adaptation to fasting or ketotic states.

In addition to fasting, FGF21 has been reported to be important in the regulation of lipid metabolism in response to amino acid deficiency [30,31]. In mice fed leucine-deficient diets, FGF21 expression increases in the liver likely through the activation of a transcription factor 4 (ATF4)-dependent mechanism, but no differences in the expression of FGF21 in leucine deficient mice and control mice occur in other metabolic organs, including adipose tissue and skeletal muscle [30,36]. Importantly, mice that are fed a leucine-deficient diet exhibit reduced body weight and fat mass compared to mice that are fed a control diet [30,36]. Importantly, such changes in body weight and fat mass due to a leucine-deficient diet are significantly attenuated in FGF21-knockout mice. These results have been attributed to the absence of the action of FGF21, which leads to the suppression of lipolysis and the enhancement of lipogenesis in adipose tissue in the leucine-deficient condition. Taken together, these findings suggest that hepatic FGF21 induction by amino acid deprivation influences lipid metabolism in adipose tissues.

FGF21 has also been reported to affect the changes in skeletal metabolism that are caused by undernutrition (or malnutrition) [32]. It is well known that an insufficient supply of nutrients impedes bone growth. In nutrient-deficient conditions, FGF21-knockout mice exhibit less inhibition of skeletal growth than do control mice [32], which indicates that FGF21 has a causal role in the undernutrition-related reduction in bone growth. FGF21-induced bone loss is probably due to the direct suppression of osteoblastogenesis and chondrogenesis [32,37,38]. Thus, these results demonstrate the functional significance of FGF21 as a key regulator of skeletal homeostasis as well as liver and adipose tissue homeostasis in nutritionally stressful states. In contrast to malnutrition, caloric restriction alone does not cause the induction of FGF21 in mice [30,39]. Furthermore, we did not observe differences in the metabolic parameters between FGF21-knockout and control mice after feeding them calorie-restricted diets [30], which indicates that the beneficial metabolic effects of caloric restriction are unrelated to the induction of FGF21. Thus, we speculate that FGF21 might play an important role in the metabolic response to undernutrition but not in the response to caloric restriction.

Nutrient overload is also capable of influencing FGF21 expression. Specifically, serum FGF21 levels increase in obese human subjects or mice following the consumption of a high-fat diet [33,34]. However, FGF21 signaling is impaired in the liver and white adipose tissue (WAT) of obese insulin-resistant mice [34] and in the pancreas islets of obese diabetic mice [40], which suggests that obesity might be a state of FGF21 resistance. However, the administration of exogenous FGF21 overcomes this resistance and leads to improvements in obesity-related metabolic deterioration. Additionally, the functional importance of endogenous FGF21 induction in the development and progression of obesity-related insulin resistance was recently evaluated using FGF21-knockout mice that were generated independently by three groups. In one study, the FGF21-knockout mice exhibited exacerbated glucose intolerance without changes in body weight compared to the control mice on high-fat diets [16]. In contrast, FGF21-knockout mice on high-fat diets were found to have body weights and glucose intolerance levels that were similar to those of control mice in another study [34]. Intriguingly, the same knockout strain that was employed in the second study exhibited increased body weight compared to control mice despite exhibiting similar glucose intolerance levels after consuming a high-fat diet when the mice were maintained in another facility [41]. However, in our experiments that employed a different FGF21-knockout strain [42], no significant differences in both body weight or glucose intolerance were observed between the FGF21-knockout mice and controls that were fed a high-fat diet. These discrepancies in the metabolic phenotypes of the three FGF21-knockout lines are probably attributable to differences in several factors such as diet composition, animal core facility, age, breeding strategy, and genetic background. Therefore, the fundamental role of the endogenous FGF21 that is induced by obesity remains controversial and to be determined, but the metabolically beneficial effects of exogenous FGF21 are irrefutable.

FGF21, autophagy deficiency, and mitochondrial stress

Autophagy is a lysosomal catabolic process of degradation of subcellular materials that are surrounded by double-membrane structures called autophagosomes. Autophagy plays an important role in the maintenance of energy balance by degrading or recycling cellular constituents and also plays an important role in cellular quality control via the turnover of damaged organelles and in the removal of aggregated proteins [43]. Thus, the impairment of autophagy causes the accumulation of dysfunctional mitochondria and an increase in the lipid contents of the affected organs; these effects might lead to the development of insulin resistance. Contrary to this expectation, it has been reported that mice with autophagy deficiencies in the liver or skeletal muscle are resistant to obesity-induced insulin resistance; this effect has been attributed to the induction of FGF21 in the autophagy-deficient insulin target tissues and the consequent leanness [30]. Mitochondrial dysfunction due to autophagy deficiency appears to be the cause of these metabolic changes and FGF21 induction, which is dependent on the eukaryotic translation factor 2α (eIF2α)-ATF4 axis [30]. The effects of mitochondrial stress on FGF21 induction have also been observed in other reports that observed increased FGF21 levels in patients with mutations of mitochondrial DNA and in mice with mitochondrial myopathy [44,45]. Thus, FGF21 could be a biomarker of human mitochondrial disorders. The induction of FGF21 by metformin might also be due to mitochondrial stress [19] because mitochondrial complex I activity is inhibited by metformin [46]. Thus, we speculate that FGF21 plays a role as an adaptive regulator that counteracts the metabolic stress imposed by autophagy deficiency or by mitochondrial dysfunction. Furthermore, given the evidence of the direct effects of FGF21 on the enhancement of mitochondrial function or capacity [47], we hypothesize that FGF21 induction by mitochondrial stress can serve as a compensatory mechanism that alleviates mitochondrial dysfunction. Further studies are necessary to validate this hypothesis and to evaluate the role of endogenous FGF21 in the pathogenesis of diseases that are related to mitochondrial dysfunction.

FGF21 and exercise

Exercise can ameliorate the severity of obesity and its metabolic complications by increasing energy expenditure [48]. Specifically, exercise increases the levels of circulating proteins called myokines that are released from skeletal muscle and mediate the metabolically beneficial effects of exercise [49]. The expressions of FGF21 in skeletal muscle and in the liver have been reported, which indicates that FGF21 might act as a myokine [50]. Given that FGF21 exerts its beneficial effects by reducing fat mass and enhancing energy expenditure [3], its beneficial metabolic effect are similar to those of exercise. Thus, it has been speculated that exercise might influence circulating FGF21 levels and that exercise-induced metabolic improvements might involve the induction of FGF21. Accordingly, it has recently been shown that acute exercise increases circulating FGF21 levels in humans and mice [51]. However, the induction of FGF21 following exercise has been observed in the livers of mice but not in the skeletal muscle, which suggests that the FGF21 released from the liver contributes to the increased serum FGF21 levels [51]. In addition to the effect of acute exercise on FGF21 induction, chronic exercise has been reported to induce FGF21 expression in human individuals [52]. Although conflicting effects of exercise on FGF21 induction have also been reported [23,53], these results suggest that FGF21 induction might contribute to the beneficial metabolic effects of exercise. Further studies are warranted to determine the functional relevance of FGF21 as a potent regulator that mediates the beneficial effects of exercise on obesity-related metabolic complications.

FGF21 and cold exposure

Cold exposure promotes heat production for the maintenance of body temperature. In addition an increase in thermogenesis in brown adipose tissue (BAT), cold exposure has been reported to stimulate the conversion of WAT to BAT-like tissue in a process called 'browning' [22,54]. BAT-like adipocytes known as 'brite' or 'beige' cells are capable of expressing high levels of uncoupling protein 1 in response to cold exposure, which contributes to heat production and the maintenance of body temperature at the expense of ATP generation [55]. Importantly, emerging studies have suggested that FGF21 expression is increased by cold stimuli in BAT and WAT with thermogenic potential, such as subcutaneous fat, but not in visceral fat [22,56]. FGF21-knockout mice exhibit reduced core body temperatures during cold exposure compared to control mice, which is probably due to an impairment in thermogenesis via the 'browning' effect [22]. Furthermore, humans with relatively abundant BAT exhibit increased FGF21 levels following exposure to cold environments compared to individuals with relative BAT paucities [23]. Together, these results suggest that FGF21 plays a key role in the regulation of adaptive thermogenesis by brown fat or beige fat in response to cold exposure.

CONCLUSIONS

Numerous studies have suggested that FGF21 is promising therapeutic target for the treatment of insulin resistance and obesity. These beneficial effects of FGF21 are mediated by its multiple actions, including enhancing lipolysis and β-oxidation, browning of WAT, increasing glucose uptake and promoting insulin release. Additionally, an emerging body of research suggests that FGF21 is a key mediator in the adaptations to changes in energy homeostasis that are caused by several nutritional or environmental stressors (Fig. 1). Thus, further studies on the fundamental role of FGF21 in adaptive metabolic changes that occur in response to diverse environmental stressors are needed to evaluate the potential of FGF21 as a therapeutic target for the treatment of human diseases that are characterized by chronic stress, such as insulin resistance and obesity.

Acknowledgements

ACKNOWLEDGMENTS

Related work in the authors' laboratory is funded by the Basic Science Research Program through the National Research Foundation of Korea (2013R1A6A3A04065825 to KHK) and the Global Research Laboratory Grant of the National Research Foundation of Korea (K21004000003-10A0500-00310 to MSL).

NOTES

No potential conflict of interest relevant to this article was reported.

REFERENCES

• 1. Nishimura T, Nakatake Y, Konishi M, Itoh N. Identification of a novel FGF, FGF-21, preferentially expressed in the liver. Biochim Biophys Acta 2000;1492:203-206. ArticlePubMed
• 2. Kharitonenkov A, Shiyanova TL, Koester A, Ford AM, Micanovic R, Galbreath EJ, Sandusky GE, Hammond LJ, Moyers JS, Owens RA, Gromada J, Brozinick JT, Hawkins ED, Wroblewski VJ, Li DS, Mehrbod F, Jaskunas SR, Shanafelt AB. FGF-21 as a novel metabolic regulator. J Clin Invest 2005;115:1627-1635. ArticlePubMedPMC
• 3. Coskun T, Bina HA, Schneider MA, Dunbar JD, Hu CC, Chen Y, Moller DE, Kharitonenkov A. Fibroblast growth factor 21 corrects obesity in mice. Endocrinology 2008;149:6018-6027. ArticlePubMedPDF
• 4. Xu J, Lloyd DJ, Hale C, Stanislaus S, Chen M, Sivits G, Vonderfecht S, Hecht R, Li YS, Lindberg RA, Chen JL, Jung DY, Zhang Z, Ko HJ, Kim JK, Veniant MM. Fibroblast growth factor 21 reverses hepatic steatosis, increases energy expenditure, and improves insulin sensitivity in diet-induced obese mice. Diabetes 2009;58:250-259. ArticlePubMedPMCPDF
• 5. Wu AL, Kolumam G, Stawicki S, Chen Y, Li J, Zavala-Solorio J, Phamluong K, Feng B, Li L, Marsters S, Kates L, van Bruggen N, Leabman M, Wong A, West D, Stern H, Luis E, Kim HS, Yansura D, Peterson AS, Filvaroff E, Wu Y, Sonoda J. Amelioration of type 2 diabetes by antibody-mediated activation of fibroblast growth factor receptor 1. Sci Transl Med 2011;3:113ra126.ArticlePubMed
• 6. Kharitonenkov A, Wroblewski VJ, Koester A, Chen YF, Clutinger CK, Tigno XT, Hansen BC, Shanafelt AB, Etgen GJ. The metabolic state of diabetic monkeys is regulated by fibroblast growth factor-21. Endocrinology 2007;148:774-781. ArticlePubMed
• 7. Foltz IN, Hu S, King C, Wu X, Yang C, Wang W, Weiszmann J, Stevens J, Chen JS, Nuanmanee N, Gupte J, Komorowski R, Sekirov L, Hager T, Arora T, Ge H, Baribault H, Wang F, Sheng J, Karow M, Wang M, Luo Y, McKeehan W, Wang Z, Veniant MM, Li Y. Treating diabetes and obesity with an FGF21-mimetic antibody activating the betaKlotho/FGFR1c receptor complex. Sci Transl Med 2012;4:162ra153.PubMed
• 8. Gaich G, Chien JY, Fu H, Glass LC, Deeg MA, Holland WL, Kharitonenkov A, Bumol T, Schilske HK, Moller DE. The effects of LY2405319, an FGF21 analog, in obese human subjects with type 2 diabetes. Cell Metab 2013;18:333-340. ArticlePubMed
• 9. Ding X, Boney-Montoya J, Owen BM, Bookout AL, Coate KC, Mangelsdorf DJ, Kliewer SA. βKlotho is required for fibroblast growth factor 21 effects on growth and metabolism. Cell Metab 2012;16:387-393. ArticlePubMedPMC
• 10. Lin Z, Tian H, Lam KS, Lin S, Hoo RC, Konishi M, Itoh N, Wang Y, Bornstein SR, Xu A, Li X. Adiponectin mediates the metabolic effects of FGF21 on glucose homeostasis and insulin sensitivity in mice. Cell Metab 2013;17:779-789. ArticlePubMed
• 11. Holland WL, Adams AC, Brozinick JT, Bui HH, Miyauchi Y, Kusminski CM, Bauer SM, Wade M, Singhal E, Cheng CC, Volk K, Kuo MS, Gordillo R, Kharitonenkov A, Scherer PE. An FGF21-adiponectin-ceramide axis controls energy expenditure and insulin action in mice. Cell Metab 2013;17:790-797. ArticlePubMedPMC
• 12. Xu J, Stanislaus S, Chinookoswong N, Lau YY, Hager T, Patel J, Ge H, Weiszmann J, Lu SC, Graham M, Busby J, Hecht R, Li YS, Li Y, Lindberg R, Veniant MM. Acute glucose-lowering and insulin-sensitizing action of FGF21 in insulin-resistant mouse models: association with liver and adipose tissue effects. Am J Physiol Endocrinol Metab 2009;297:E1105-E1114. ArticlePubMed
• 13. Wente W, Efanov AM, Brenner M, Kharitonenkov A, Koster A, Sandusky GE, Sewing S, Treinies I, Zitzer H, Gromada J. Fibroblast growth factor-21 improves pancreatic beta-cell function and survival by activation of extracellular signal-regulated kinase 1/2 and Akt signaling pathways. Diabetes 2006;55:2470-2478. PubMed
• 14. Sarruf DA, Thaler JP, Morton GJ, German J, Fischer JD, Ogimoto K, Schwartz MW. Fibroblast growth factor 21 action in the brain increases energy expenditure and insulin sensitivity in obese rats. Diabetes 2010;59:1817-1824. ArticlePubMedPMCPDF
• 15. Bookout AL, de Groot MH, Owen BM, Lee S, Gautron L, Lawrence HL, Ding X, Elmquist JK, Takahashi JS, Mangelsdorf DJ, Kliewer SA. FGF21 regulates metabolism and circadian behavior by acting on the nervous system. Nat Med 2013;19:1147-1152. ArticlePubMedPMCPDF
• 16. Dutchak PA, Katafuchi T, Bookout AL, Choi JH, Yu RT, Mangelsdorf DJ, Kliewer SA. Fibroblast growth factor-21 regulates PPARgamma activity and the antidiabetic actions of thiazolidinediones. Cell 2012;148:556-567. ArticlePubMedPMC
• 17. Habegger KM, Stemmer K, Cheng C, Muller TD, Heppner KM, Ottaway N, Holland J, Hembree JL, Smiley D, Gelfanov V, Krishna R, Arafat AM, Konkar A, Belli S, Kapps M, Woods SC, Hofmann SM, D'Alessio D, Pfluger PT, Perez-Tilve D, Seeley RJ, Konishi M, Itoh N, Kharitonenkov A, Spranger J, DiMarchi RD, Tschop MH. Fibroblast growth factor 21 mediates specific glucagon actions. Diabetes 2013;62:1453-1463. ArticlePubMedPMCPDF
• 18. Yang M, Zhang L, Wang C, Liu H, Boden G, Yang G, Li L. Liraglutide increases FGF-21 activity and insulin sensitivity in high fat diet and adiponectin knockdown induced insulin resistance. PLoS One 2012;7:e48392ArticlePubMedPMC
• 19. Kim KH, Jeong YT, Kim SH, Jung HS, Park KS, Lee HY, Lee MS. Metformin-induced inhibition of the mitochondrial respiratory chain increases FGF21 expression via ATF4 activation. Biochem Biophys Res Commun 2013;440:76-81. ArticlePubMed
• 20. Inagaki T, Dutchak P, Zhao G, Ding X, Gautron L, Parameswara V, Li Y, Goetz R, Mohammadi M, Esser V, Elmquist JK, Gerard RD, Burgess SC, Hammer RE, Mangelsdorf DJ, Kliewer SA. Endocrine regulation of the fasting response by PPARalpha-mediated induction of fibroblast growth factor 21. Cell Metab 2007;5:415-425. PubMed
• 21. Galman C, Lundasen T, Kharitonenkov A, Bina HA, Eriksson M, Hafstrom I, Dahlin M, Amark P, Angelin B, Rudling M. The circulating metabolic regulator FGF21 is induced by prolonged fasting and PPARalpha activation in man. Cell Metab 2008;8:169-174. PubMed
• 22. Fisher FM, Kleiner S, Douris N, Fox EC, Mepani RJ, Verdeguer F, Wu J, Kharitonenkov A, Flier JS, Maratos-Flier E, Spiegelman BM. FGF21 regulates PGC-1alpha and browning of white adipose tissues in adaptive thermogenesis. Genes Dev 2012;26:271-281. ArticlePubMedPMC
• 23. Lee P, Linderman JD, Smith S, Brychta RJ, Wang J, Idelson C, Perron RM, Werner CD, Phan GQ, Kammula US, Kebebew E, Pacak K, Chen KY, Celi FS. Irisin and FGF21 are cold-induced endocrine activators of brown fat function in humans. Cell Metab 2014;19:302-309. ArticlePubMedPMC
• 24. Ye D, Wang Y, Li H, Jia W, Man K, Lo CM, Wang Y, Lam KS, Xu A. FGF21 protects against acetaminophen-induced hepatotoxicity by potentiating PGC-1alpha-mediated antioxidant capacity in mice. Hepatology 2014 2 06 DOI: http://dx.doi.org/10.1002/hep.27060.
• 25. Cheng X, Vispute SG, Liu J, Cheng C, Kharitonenkov A, Klaassen CD. Fibroblast growth factor (Fgf) 21 is a novel target gene of the aryl hydrocarbon receptor (AhR). Toxicol Appl Pharmacol 2014;278:65-71. ArticlePubMedPMC
• 26. Johnson CL, Weston JY, Chadi SA, Fazio EN, Huff MW, Kharitonenkov A, Koester A, Pin CL. Fibroblast growth factor 21 reduces the severity of cerulein-induced pancreatitis in mice. Gastroenterology 2009;137:1795-1804. ArticlePubMed
• 27. Planavila A, Redondo I, Hondares E, Vinciguerra M, Munts C, Iglesias R, Gabrielli LA, Sitges M, Giralt M, van Bilsen M, Villarroya F. Fibroblast growth factor 21 protects against cardiac hypertrophy in mice. Nat Commun 2013;4:2019ArticlePubMedPDF
• 28. Li Y, Wong K, Giles A, Jiang J, Lee JW, Adams AC, Kharitonenkov A, Yang Q, Gao B, Guarente L, Zang M. Hepatic SIRT1 attenuates hepatic steatosis and controls energy balance in mice by inducing fibroblast growth factor 21. Gastroenterology 2014;146:539-549.e7. ArticlePubMed
• 29. Badman MK, Pissios P, Kennedy AR, Koukos G, Flier JS, Maratos-Flier E. Hepatic fibroblast growth factor 21 is regulated by PPARalpha and is a key mediator of hepatic lipid metabolism in ketotic states. Cell Metab 2007;5:426-437. PubMed
• 30. Kim KH, Jeong YT, Oh H, Kim SH, Cho JM, Kim YN, Kim SS, Kim do H, Hur KY, Kim HK, Ko T, Han J, Kim HL, Kim J, Back SH, Komatsu M, Chen H, Chan DC, Konishi M, Itoh N, Choi CS, Lee MS. Autophagy deficiency leads to protection from obesity and insulin resistance by inducing Fgf21 as a mitokine. Nat Med 2013;19:83-92. ArticlePubMedPDF
• 31. De Sousa-Coelho AL, Marrero PF, Haro D. Activating transcription factor 4-dependent induction of FGF21 during amino acid deprivation. Biochem J 2012;443:165-171. ArticlePubMedPDF
• 32. Kubicky RA, Wu S, Kharitonenkov A, De Luca F. Role of fibroblast growth factor 21 (FGF21) in undernutrition-related attenuation of growth in mice. Endocrinology 2012;153:2287-2295. ArticlePubMed
• 33. Zhang X, Yeung DC, Karpisek M, Stejskal D, Zhou ZG, Liu F, Wong RL, Chow WS, Tso AW, Lam KS, Xu A. Serum FGF21 levels are increased in obesity and are independently associated with the metabolic syndrome in humans. Diabetes 2008;57:1246-1253. ArticlePubMedPDF
• 34. Fisher FM, Chui PC, Antonellis PJ, Bina HA, Kharitonenkov A, Flier JS, Maratos-Flier E. Obesity is a fibroblast growth factor 21 (FGF21)-resistant state. Diabetes 2010;59:2781-2789. ArticlePubMedPMCPDF
• 35. Kim H, Mendez R, Zheng Z, Chang L, Cai J, Zhang R, Zhang K. Liver-enriched transcription factor CREBH interacts with peroxisome proliferator-activated receptor alpha to regulate metabolic hormone FGF21. Endocrinology 2014;155:769-782. ArticlePubMedPMC
• 36. De Sousa-Coelho AL, Relat J, Hondares E, Perez-Marti A, Ribas F, Villarroya F, Marrero PF, Haro D. FGF21 mediates the lipid metabolism response to amino acid starvation. J Lipid Res 2013;54:1786-1797. ArticlePubMedPMC
• 37. Wei W, Dutchak PA, Wang X, Ding X, Wang X, Bookout AL, Goetz R, Mohammadi M, Gerard RD, Dechow PC, Mangelsdorf DJ, Kliewer SA, Wan Y. Fibroblast growth factor 21 promotes bone loss by potentiating the effects of peroxisome proliferator-activated receptor gamma. Proc Natl Acad Sci U S A 2012;109:3143-3148. PubMedPMC
• 38. Wu S, Levenson A, Kharitonenkov A, De Luca F. Fibroblast growth factor 21 (FGF21) inhibits chondrocyte function and growth hormone action directly at the growth plate. J Biol Chem 2012;287:26060-26067. ArticlePubMedPMC
• 39. Zhang Y, Xie Y, Berglund ED, Coate KC, He TT, Katafuchi T, Xiao G, Potthoff MJ, Wei W, Wan Y, Yu RT, Evans RM, Kliewer SA, Mangelsdorf DJ. The starvation hormone, fibroblast growth factor-21, extends lifespan in mice. Elife 2012;1:e00065ArticlePubMedPMCPDF
• 40. So WY, Cheng Q, Chen L, Evans-Molina C, Xu A, Lam KS, Leung PS. High glucose represses beta-klotho expression and impairs fibroblast growth factor 21 action in mouse pancreatic islets: involvement of peroxisome proliferator-activated receptor gamma signaling. Diabetes 2013;62:3751-3759. PubMedPMC
• 41. Adams AC, Coskun T, Cheng CC, LS OF, Dubois SL, Kharitonenkov A. Fibroblast growth factor 21 is not required for the antidiabetic actions of the thiazoladinediones. Mol Metab 2013;2:205-214. ArticlePubMedPMC
• 42. Hotta Y, Nakamura H, Konishi M, Murata Y, Takagi H, Matsumura S, Inoue K, Fushiki T, Itoh N. Fibroblast growth factor 21 regulates lipolysis in white adipose tissue but is not required for ketogenesis and triglyceride clearance in liver. Endocrinology 2009;150:4625-4633. ArticlePubMedPDF
• 43. Mizushima N, Komatsu M. Autophagy: renovation of cells and tissues. Cell 2011;147:728-741. ArticlePubMed
• 44. Tyynismaa H, Carroll CJ, Raimundo N, Ahola-Erkkila S, Wenz T, Ruhanen H, Guse K, Hemminki A, Peltola-Mjosund KE, Tulkki V, Oresic M, Moraes CT, Pietilainen K, Hovatta I, Suomalainen A. Mitochondrial myopathy induces a starvation-like response. Hum Mol Genet 2010;19:3948-3958. ArticlePubMed
• 45. Suomalainen A, Elo JM, Pietilainen KH, Hakonen AH, Sevastianova K, Korpela M, Isohanni P, Marjavaara SK, Tyni T, Kiuru-Enari S, Pihko H, Darin N, Ounap K, Kluijtmans LA, Paetau A, Buzkova J, Bindoff LA, Annunen-Rasila J, Uusimaa J, Rissanen A, Yki-Jarvinen H, Hirano M, Tulinius M, Smeitink J, Tyynismaa H. FGF-21 as a biomarker for muscle-manifesting mitochondrial respiratory chain deficiencies: a diagnostic study. Lancet Neurol 2011;10:806-818. ArticlePubMedPMC
• 46. Owen MR, Doran E, Halestrap AP. Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem J 2000;348(Pt 3):607-614. ArticlePubMedPMCPDF
• 47. Chau MD, Gao J, Yang Q, Wu Z, Gromada J. Fibroblast growth factor 21 regulates energy metabolism by activating the AMPK-SIRT1-PGC-1alpha pathway. Proc Natl Acad Sci U S A 2010;107:12553-12558. PubMedPMC
• 48. Strasser B. Physical activity in obesity and metabolic syndrome. Ann N Y Acad Sci 2013;1281:141-159. ArticlePubMedPDF
• 49. Pedersen BK, Febbraio MA. Muscles, exercise and obesity: skeletal muscle as a secretory organ. Nat Rev Endocrinol 2012;8:457-465. ArticlePubMedPDF
• 50. Izumiya Y, Bina HA, Ouchi N, Akasaki Y, Kharitonenkov A, Walsh K. FGF21 is an Akt-regulated myokine. FEBS Lett 2008;582:3805-3810. ArticlePubMedPMC
• 51. Kim KH, Kim SH, Min YK, Yang HM, Lee JB, Lee MS. Acute exercise induces FGF21 expression in mice and in healthy humans. PLoS One 2013;8:e63517ArticlePubMedPMC
• 52. Cuevas-Ramos D, Almeda-Valdes P, Meza-Arana CE, Brito-Cordova G, Gomez-Perez FJ, Mehta R, Oseguera-Moguel J, Aguilar-Salinas CA. Exercise increases serum fibroblast growth factor 21 (FGF21) levels. PLoS One 2012;7:e38022ArticlePubMedPMC
• 53. Fletcher JA, Meers GM, Laughlin MH, Ibdah JA, Thyfault JP, Rector RS. Modulating fibroblast growth factor 21 in hyperphagic OLETF rats with daily exercise and caloric restriction. Appl Physiol Nutr Metab 2012;37:1054-1062. ArticlePubMedPMC
• 54. Cousin B, Cinti S, Morroni M, Raimbault S, Ricquier D, Penicaud L, Casteilla L. Occurrence of brown adipocytes in rat white adipose tissue: molecular and morphological characterization. J Cell Sci 1992;103(Pt 4):931-942. ArticlePubMedPDF
• 55. Bartelt A, Heeren J. Adipose tissue browning and metabolic health. Nat Rev Endocrinol 2014;10:24-36. ArticlePubMedPDF
• 56. Hondares E, Iglesias R, Giralt A, Gonzalez FJ, Giralt M, Mampel T, Villarroya F. Thermogenic activation induces FGF21 expression and release in brown adipose tissue. J Biol Chem 2011;286:12983-12990. ArticlePubMedPMC

Fig. 1

The functional role of fibroblast growth factor 21 (FGF21) induction due to diverse stressors. FGF21 expression is increased in multiple major metabolic organs, including the liver, skeletal muscle, white adipose tissue and brown adipose tissue (as illustrated in the middle column of the figure from the above), in response to diverse stressors. Consequently, elevated FGF21 induces various metabolic effects on the major metabolic organs which help adapt to these stressors. mtDNA, mitochondrial DNA.

Figure & Data

References

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  Current Diabetes Reviews.2025;[Epub]     CrossRef
• The Impact of Human Liver Transplantation on the Concentration of Fibroblast Growth Factors: FGF19 and FGF21
  Marta Budkowska, Ewa Ostrycharz-Jasek, Elżbieta Cecerska-Heryć, Katarzyna Dołęgowska, Aldona Siennicka, Łukasz Nazarewski, Paweł Rykowski, Barbara Dołęgowska
  International Journal of Molecular Sciences.2025; 26(3): 1299.     CrossRef
• Adipokines as Cardioprotective Factors: BAT Steps Up to the Plate
  Keely McLeod, Victoria Datta, Scott Fuller
  Biomedicines.2025; 13(3): 710.     CrossRef
• Effects of Grape By-Products on Oxidative Stress and Inflammation in Farm Animals: An Overview of Studies Performed in Pigs, Chickens, and Cattle
  Klaus Eder, Robert Ringseis, Denise K. Gessner
  Animals.2025; 15(11): 1536.     CrossRef
• Decoding the Liver-Heart Axis in Cardiometabolic Diseases
  Federico Capone, Antonio Vacca, Guillaume Bidault, Dylan Sarver, Dorota Kaminska, Stefano Strocchi, Antonio Vidal-Puig, Carolina M. Greco, Aldons J. Lusis, Gabriele G. Schiattarella
  Circulation Research.2025; 136(11): 1335.     CrossRef
• Fibroblast growth factor 21: An emerging pleiotropic regulator of lipid metabolism and the metabolic network
  Shuo Li, Tiande Zou, Jun Chen, Jiaming Li, Jinming You
  Genes & Diseases.2024; 11(3): 101064.     CrossRef
• From Beats to Metabolism: the Heart at the Core of Interorgan Metabolic Cross Talk
  Rafael Romero-Becera, Ayelén M. Santamans, Alba C. Arcones, Guadalupe Sabio
  Physiology.2024; 39(2): 98.     CrossRef
• Beneficial Effects of Low-Grade Mitochondrial Stress on Metabolic Diseases and Aging
  Se Hee Min, Gil Myoung Kang, Jae Woo Park, Min-Seon Kim
  Yonsei Medical Journal.2024; 65(2): 55.     CrossRef
• GDF15 is a dynamic biomarker of the integrated stress response in the central nervous system
  Jyoti Asundi, Chunlian Zhang, Diana Donnelly‐Roberts, Josè Zavala Solorio, Malleswari Challagundla, Caitlin Connelly, Christina Boch, Jun Chen, Mario Richter, Mohammad Mehdi Maneshi, Andrew M. Swensen, Lauren Lebon, Raphael Schiffmann, Subhabrata Sanyal,
  CNS Neuroscience & Therapeutics.2024;[Epub]     CrossRef
• Deciphering adipose development: Function, differentiation and regulation
  Ge Guo, Wanli Wang, Mengjie Tu, Binbin Zhao, Jiayang Han, Jiali Li, Yanbing Pan, Jie Zhou, Wen Ma, Yi Liu, Tiantian Sun, Xu Han, Yang An
  Developmental Dynamics.2024; 253(11): 956.     CrossRef
• Inflammatory liver diseases and susceptibility to sepsis
  Hong Lu
  Clinical Science.2024; 138(7): 435.     CrossRef
• Ketogenic diet with aerobic exercise can induce fat browning: potential roles of β-hydroxybutyrate
  Sujin Kim, Dong-Ho Park, Sohee Moon, Bonsang Gu, Keren Esther Kristina Mantik, Hyo-Bum Kwak, Ji-Kan Ryu, Ju-Hee Kang
  Frontiers in Nutrition.2024;[Epub]     CrossRef
• Deficiency of GPR10 and NPFFR2 receptors leads to sex-specific prediabetic syndrome and late-onset obesity in mice
  Alena Morgan, Nivasini Shekhar, Veronika Strnadová, Zdenko Pirník, Eliška Haasová, Jan Kopecký, Andrea Pačesová, Blanka Železná, Jaroslav Kuneš, Kristina Bardová, Lenka Maletínská
  Bioscience Reports.2024;[Epub]     CrossRef
• ChREBP-mediated up-regulation of Them1 coordinates thermogenesis with glycolysis and lipogenesis in response to chronic stress
  Xu Xu, Arturo Mendoza, Christopher S. Krumm, Shi Su, Mariana Acuña, Curtis J. Bare, Corey D. Holman, Marissa Cortopassi, Hayley T. Nicholls, Vincent Dartigue, Anthony N. Hollenberg, Ann-Hwee Lee, Susan J. Hagen, David E. Cohen
  Science Signaling.2024;[Epub]     CrossRef
• Fibroblast growth factor 21 and bone homeostasis
  Yan Tang, Mei Zhang
  Biomedical Journal.2023; 46(4): 100548.     CrossRef
• Chronic docosahexaenoic acid supplementation improves metabolic plasticity in subcutaneous adipose tissue of aged obese female mice
  Elisa Félix-Soriano, Neira Sáinz, Marta Fernández-Galilea, Eva Gil-Iturbe, Jon Celay, José A. Martínez-Climent, María J. Moreno-Aliaga
  The Journal of Nutritional Biochemistry.2023; 111: 109153.     CrossRef
• Fibroblast Growth Factor–Based Pharmacotherapies for the Treatment of Obesity-Related Metabolic Complications
  Leigang Jin, Ranyao Yang, Leiluo Geng, Aimin Xu
  Annual Review of Pharmacology and Toxicology.2023; 63(1): 359.     CrossRef
• The effect of FGF21 gene polymorphism (g. 940C/T) on biochemical metabolic parameters in blood serum of holstein cattle
  N. Yu. Safina, Sh. K. Shakrov, E. R. Gaynutdinova, Z. F. Fattakhova
  International Journal of Veterinary Medicine.2023; (4): 314.     CrossRef
• Fibroblast growth factor 21 is expressed and secreted from skeletal muscle following electrical stimulation via extracellular ATP activation of the PI3K/Akt/mTOR signaling pathway
  Manuel Arias-Calderón, Mariana Casas, Julián Balanta-Melo, Camilo Morales-Jiménez, Nadia Hernández, Paola Llanos, Enrique Jaimovich, Sonja Buvinic
  Frontiers in Endocrinology.2023;[Epub]     CrossRef
• Fibroblast growth factor 21 as a potential master regulator in metabolic disorders
  Aayushi Velingkar, Sugunakar Vuree, Pranav Kumar Prabhakar, Rajender Rao Kalashikam, Aparna Banerjee, Suresh Kondeti
  American Journal of Physiology-Endocrinology and Metabolism.2023; 324(5): E409.     CrossRef
• Association of NAFLD with FGF21 Polygenic Hazard Score, and Its Interaction with Protein Intake Level in Korean Adults
  Hae Jin Lee, Jinyoung Shon, Yoon Jung Park
  Nutrients.2023; 15(10): 2385.     CrossRef
• Blood and liver telomere length, mitochondrial DNA copy number, and hepatic gene expression of mitochondrial dynamics in mid-lactation cows supplemented with l-carnitine under systemic inflammation
  S. Häussler, M.H. Ghaffari, K. Seibt, H. Sadri, M. Alaedin, K. Huber, J. Frahm, S. Dänicke, H. Sauerwein
  Journal of Dairy Science.2023; 106(12): 9822.     CrossRef
• Pharmacological Effects of Fibroblast Growth Factor 21 (FGF21) оn Carbohydrate-Lipid Metabolism: Sex Dependence
  N. M. Bazhan, E. N. Makarova
  Успехи физиологических наук.2023; 54(4): 93.     CrossRef
• The Nuanced Metabolic Functions of Endogenous FGF21 Depend on the Nature of the Stimulus, Tissue Source, and Experimental Model
  Redin A. Spann, Christopher D. Morrison, Laura J. den Hartigh
  Frontiers in Endocrinology.2022;[Epub]     CrossRef
• Long-Term Dietary Taurine Lowers Plasma Levels of Cholesterol and Bile Acids
  Ryoma Tagawa, Masaki Kobayashi, Misako Sakurai, Maho Yoshida, Hiroki Kaneko, Yuhei Mizunoe, Yuka Nozaki, Naoyuki Okita, Yuka Sudo, Yoshikazu Higami
  International Journal of Molecular Sciences.2022; 23(3): 1793.     CrossRef
• Endocrine Fibroblast Growth Factors in Relation to Stress Signaling
  Makoto Shimizu, Ryuichiro Sato
  Cells.2022; 11(3): 505.     CrossRef
• Histone Deacetylases as Modulators of the Crosstalk Between Skeletal Muscle and Other Organs
  Alessandra Renzini, Marco D’Onghia, Dario Coletti, Viviana Moresi
  Frontiers in Physiology.2022;[Epub]     CrossRef
• Multidimensional Biomarker Analysis Including Mitochondrial Stress Indicators for Nonalcoholic Fatty Liver Disease
  Eunha Chang, Jae Seung Chang, In Deok Kong, Soon Koo Baik, Moon Young Kim, Kyu-Sang Park
  Gut and Liver.2022; 16(2): 171.     CrossRef
• FGF21: A Novel Regulator of Glucose and Lipid Metabolism and Whole-Body Energy Balance
  Ewa Szczepańska, Małgorzata Gietka-Czernel
  Hormone and Metabolic Research.2022; 54(04): 203.     CrossRef
• Exercise, Mitohormesis, and Mitochondrial ORF of the 12S rRNA Type-C (MOTS-c)
  Tae Kwan Yoon, Chan Hee Lee, Obin Kwon, Min-Seon Kim
  Diabetes & Metabolism Journal.2022; 46(3): 402.     CrossRef
• Counteracting health risks by Modulating Homeostatic Signaling
  Junqiang J. Tian, Mark Levy, Xuekai Zhang, Robert Sinnott, Rolando Maddela
  Pharmacological Research.2022; 182: 106281.     CrossRef
• Hesperidin abrogates bisphenol A endocrine disruption through binding with fibroblast growth factor 21 (FGF-21), α-amylase and α-glucosidase: an in silico molecular study
  P.M. Aja, J.N. Awoke, P.C. Agu, A.E. Adegboyega, E.M. Ezeh, I.O. Igwenyi, O.U. Orji, O.G. Ani, B.A. Ale, U.A. Ibiam
  Journal of Genetic Engineering and Biotechnology.2022; 20(1): 84.     CrossRef
• Circulating FGF21 vs. Stress Markers in Girls during Childhood and Adolescence, and in Their Caregivers: Intriguing Inter-Relations between Overweight/Obesity, Emotions, Behavior, and the Cared-Caregiver Relationship
  Eirini V. Christaki, Panagiota Pervanidou, Ioannis Papassotiriou, Aimilia Mantzou, Giorgos Giannakakis, Dario Boschiero, George P. Chrousos
  Children.2022; 9(6): 821.     CrossRef
• α‐Lipoic acid up‐regulates gene expression but reduces protein levels of fibroblast growth factor 21 in HepG2 cells
  Xiaochun Zhang, Yanyan Zhao, Xiangyan Liang, Lijun Zhang, Ke Li, Zhuo Sun, Yu‐Feng Zhao
  Basic & Clinical Pharmacology & Toxicology.2022; 131(4): 270.     CrossRef
• Multi-organ FGF21-FGFR1 signaling in metabolic health and disease
  Namrita Kaur, Sanskruti Ravindra Gare, Jiahan Shen, Rida Raja, Oveena Fonseka, Wei Liu
  Frontiers in Cardiovascular Medicine.2022;[Epub]     CrossRef
• Management of patients with neuropathic pain
  Eun Joo Choi
  Journal of the Korean Medical Association.2022; 65(8): 505.     CrossRef
• FGF21–Sirtuin 3 Axis Confers the Protective Effects of Exercise Against Diabetic Cardiomyopathy by Governing Mitochondrial Integrity
  Leigang Jin, Leiluo Geng, Lei Ying, Lingling Shu, Kevin Ye, Ranyao Yang, Yan Liu, Yao Wang, Yin Cai, Xue Jiang, Qin Wang, Xingqun Yan, Boya Liao, Jie Liu, Fuyu Duan, Gary Sweeney, Connie Wai Hong Woo, Yu Wang, Zhengyuan Xia, Qizhou Lian, Aimin Xu
  Circulation.2022; 146(20): 1537.     CrossRef
• Performance and Metabolic, Inflammatory, and Oxidative Stress-Related Parameters in Early Lactating Dairy Cows with High and Low Hepatic FGF21 Expression
  Denise K. Gessner, Lena M. Sandrock, Erika Most, Christian Koch, Robert Ringseis, Klaus Eder
  Animals.2022; 13(1): 131.     CrossRef
• Relationship between FGF21 and drug or nondrug therapy of type 2 diabetes mellitus
  Chang Guo, Li Zhao, Yanyan Li, Xia Deng, Guoyue Yuan
  Journal of Cellular Physiology.2021; 236(1): 55.     CrossRef
• Skeletal Muscle and Bone – Emerging Targets of Fibroblast Growth Factor-21
  Hui Sun, Matthew Sherrier, Hongshuai Li
  Frontiers in Physiology.2021;[Epub]     CrossRef
• Transthyretin contributes to insulin resistance and diminishes exercise-induced insulin sensitivity in obese mice by inhibiting AMPK activity in skeletal muscle
  Yingzi He, Ruojun Qiu, Beibei Wu, Weiwei Gui, Xihua Lin, Hong Li, Fenping Zheng
  American Journal of Physiology-Endocrinology and Metabolism.2021; 320(4): E808.     CrossRef
• Metabolic Messengers: FGF21
  Kyle H. Flippo, Matthew J. Potthoff
  Nature Metabolism.2021; 3(3): 309.     CrossRef
• Circulating Fibroblast Growth Factor-21 Levels in Rheumatoid Arthritis: Associations With Disease Characteristics, Body Composition, and Physical Functioning
  Patrick W. Gould, Babette S. Zemel, Elena G. Taratuta, Joshua F. Baker
  The Journal of Rheumatology.2021; 48(4): 504.     CrossRef
• The transcription factors CREBH, PPARa, and FOXO1 as critical hepatic mediators of diet-induced metabolic dysregulation
  Zhao Yang, Katherine Roth, Manisha Agarwal, Wanqing Liu, Michael C. Petriello
  The Journal of Nutritional Biochemistry.2021; 95: 108633.     CrossRef
• Low‐Level Radiofrequency Exposure Induces Vasoconstriction in Rats
  Thi Cuc Mai, Anne Braun, Veronique Bach, Amandine Pelletier, Rene de Seze
  Bioelectromagnetics.2021; 42(6): 455.     CrossRef
• Anterograde regulation of mitochondrial genes and FGF21 signaling by hepatic LSD1
  Yang Cao, Lingyi Tang, Kang Du, Kitt Paraiso, Qiushi Sun, Zhengxia Liu, Xiaolong Ye, Yuan Fang, Fang Yuan, Hank Chen, Yumay Chen, Xiaorong Wang, Clinton Yu, Ira L. Blitz, Ping H. Wang, Lan Huang, Haibo Cheng, Xiang Lu, Ken W.Y. Cho, Marcus Seldin, Zhuyuan
  JCI Insight.2021;[Epub]     CrossRef
• Fibroblast growth factor 21 attenuates iron overload-induced liver injury and fibrosis by inhibiting ferroptosis
  Aimin Wu, Bin Feng, Jie Yu, Lijun Yan, Lianqiang Che, Yong Zhuo, Yuheng Luo, Bing Yu, De Wu, Daiwen Chen
  Redox Biology.2021; 46: 102131.     CrossRef
• Stress-induced FGF21 and GDF15 in obesity and obesity resistance
  Susanne Keipert, Mario Ost
  Trends in Endocrinology & Metabolism.2021; 32(11): 904.     CrossRef
• Fibroblast growth factor 21 in dairy cows: current knowledge and potential relevance
  Klaus Eder, Denise K. Gessner, Robert Ringseis
  Journal of Animal Science and Biotechnology.2021;[Epub]     CrossRef
• Weight regain after bariatric surgery: Promoters and potential predictors
  Hala Mourad Demerdash
  World Journal of Meta-Analysis.2021; 9(5): 438.     CrossRef
• αKlotho attenuates cardiac hypertrophy and increases myocardial fibroblast growth factor 21 expression in uremic rats
  Paulo Giovani de Albuquerque Suassuna, Paula Marocolo Cherem, Bárbara Bruna de Castro, Edgar Maquigussa, Marco Antonio Cenedeze, Júlio Cesar Moraes Lovisi, Melani Ribeiro Custódio, Helady Sanders-Pinheiro, Rogério Baumgratz de Paula
  Experimental Biology and Medicine.2020; 245(1): 66.     CrossRef
• Effect of Fibroblast Growth Factor 21 on the Development of Atheromatous Plaque and Lipid Metabolic Profiles in an Atherosclerosis-Prone Mouse Model
  Hyo Jin Maeng, Gha Young Lee, Jae Hyun Bae, Soo Lim
  International Journal of Molecular Sciences.2020; 21(18): 6836.     CrossRef
• A Land of Controversy: Fibroblast Growth Factor-23 and Uremic Cardiac Hypertrophy
  Jing-Fu Bao, Pan-Pan Hu, Qin-Ying She, Aiqing Li
  Journal of the American Society of Nephrology.2020; 31(7): 1423.     CrossRef
• Possible associations between plasma fibroblast growth factor 21 levels and cognition in bipolar disorder
  Favour Omileke, Sayuri Ishiwata, Junko Matsuo, Fuyuko Yoshida, Shinsuke Hidese, Kotaro Hattori, Hiroshi Kunugi
  Neuropsychopharmacology Reports.2020; 40(2): 175.     CrossRef
• FGF21-protection against fructose-induced lipid accretion and oxidative stress is influenced by maternal nutrition in male progeny
  Elena Fauste, Silvia Rodrigo, Lourdes Rodríguez, Cristina Donis, Antonia García, Coral Barbas, Juan J. Álvarez-Millán, María I. Panadero, Paola Otero, Carlos Bocos
  Journal of Functional Foods.2020; 64: 103676.     CrossRef
• Fibroblast growth factor 21 and grow differentiation factor 15 are sensitive biomarkers of mitochondrial diseases due to mitochondrial transfer-RNA mutations and mitochondrial DNA deletions
  Patrizia Formichi, Nastasia Cardone, Ilaria Taglia, Elena Cardaioli, Simona Salvatore, Annalisa Lo Gerfo, Costanza Simoncini, Vincenzo Montano, Gabriele Siciliano, Michelangelo Mancuso, Alessandro Malandrini, Antonio Federico, Maria Teresa Dotti
  Neurological Sciences.2020; 41(12): 3653.     CrossRef
• Novel Medicinal Mushroom Blend as a Promising Supplement in Integrative Oncology: A Multi-Tiered Study using 4T1 Triple-Negative Mouse Breast Cancer Model
  Elisa Roda, Fabrizio De Luca, Carmine Di Iorio, Daniela Ratto, Stella Siciliani, Beatrice Ferrari, Filippo Cobelli, Giuseppina Borsci, Erica Cecilia Priori, Silvia Chinosi, Andrea Ronchi, Renato Franco, Raffaele Di Francia, Massimiliano Berretta, Carlo Al
  International Journal of Molecular Sciences.2020; 21(10): 3479.     CrossRef
• High‐protein diet more effectively reduces hepatic fat than low‐protein diet despite lower autophagy and FGF21 levels
  Chenchen Xu, Mariya Markova, Nicole Seebeck, Anne Loft, Silke Hornemann, Thomas Gantert, Stefan Kabisch, Kathleen Herz, Jennifer Loske, Mario Ost, Verena Coleman, Frederick Klauschen, Anke Rosenthal, Volker Lange, Jürgen Machann, Susanne Klaus, Tilman Gru
  Liver International.2020; 40(12): 2982.     CrossRef
• Recharacterizing the Metabolic State of Energy Balance in Thrifty and Spendthrift Phenotypes
  Tim Hollstein, Alessio Basolo, Takafumi Ando, Susanne B Votruba, Mary Walter, Jonathan Krakoff, Paolo Piaggi
  The Journal of Clinical Endocrinology & Metabolism.2020; 105(5): 1375.     CrossRef
• Targeting of Secretory Proteins as a Therapeutic Strategy for Treatment of Nonalcoholic Steatohepatitis (NASH)
  Kyeongjin Kim, Kook Hwan Kim
  International Journal of Molecular Sciences.2020; 21(7): 2296.     CrossRef
• Discovery of a novel fibroblast activation protein (FAP) inhibitor, BR103354, with anti-diabetic and anti-steatotic effects
  Jae Min Cho, Eun Hee Yang, Wenying Quan, Eun Hye Nam, Hyae Gyeong Cheon
  Scientific Reports.2020;[Epub]     CrossRef
• Spontaneous ketonuria and risk of incident diabetes: a 12 year prospective study
  Gyuri Kim, Sang-Guk Lee, Byung-Wan Lee, Eun Seok Kang, Bong-Soo Cha, Ele Ferrannini, Yong-ho Lee, Nam H. Cho
  Diabetologia.2019; 62(5): 779.     CrossRef
• Combined docosahexaenoic acid and thyroid hormone supplementation as a protocol supporting energy supply to precondition and afford protection against metabolic stress situations
  Luis A. Videla
  IUBMB Life.2019; 71(9): 1211.     CrossRef
• Effects of exercise on brown and beige adipocytes
  Revati S. Dewal, Kristin I. Stanford
  Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids.2019; 1864(1): 71.     CrossRef
• Manipulating mtDNA in vivo reprograms metabolism via novel response mechanisms
  Diana Bahhir, Cagri Yalgin, Liina Ots, Sampsa Järvinen, Jack George, Alba Naudí, Tatjana Krama, Indrikis Krams, Mairi Tamm, Ana Andjelković, Eric Dufour, Jose M. González de Cózar, Mike Gerards, Mikael Parhiala, Reinald Pamplona, Howard T. Jacobs, Priit J
  PLOS Genetics.2019; 15(10): e1008410.     CrossRef
• The Level of FGF 21 as a New Risk Factor for the Occurrence of Cardiometabolic Disorders amongst the Psoriatic Patients
  Paulina Kiluk, Anna Baran, Tomasz W. Kaminski, Magdalena Maciaszek, Iwona Flisiak
  Journal of Clinical Medicine.2019; 8(12): 2206.     CrossRef
• Docosahexaenoic acid‐thyroid hormone combined protocol as a novel approach to metabolic stress disorders: Relation to mitochondrial adaptation via liver PGC‐1α and sirtuin1 activation
  Romina Vargas, Bárbara Riquelme, Javier Fernández, Daniela Álvarez, Ignacio F. Pérez, Pamela Cornejo, Virginia Fernández, Luis A. Videla
  BioFactors.2019; 45(2): 271.     CrossRef
• Fibroblast growth factor 21 predicts outcome in community-acquired pneumonia: secondary analysis of two randomised controlled trials
  Fahim Ebrahimi, Carole Wolffenbuttel, Claudine A. Blum, Christine Baumgartner, Beat Mueller, Philipp Schuetz, Christian Meier, Marius Kraenzlin, Mirjam Christ-Crain, Matthias Johannes Betz
  European Respiratory Journal.2019; 53(2): 1800973.     CrossRef
• Fibroblast growth factor 21 increases insulin sensitivity through specific expansion of subcutaneous fat
  Huating Li, Guangyu Wu, Qichen Fang, Mingliang Zhang, Xiaoyan Hui, Bin Sheng, Liang Wu, Yuqian Bao, Peng Li, Aimin Xu, Weiping Jia
  Nature Communications.2018;[Epub]     CrossRef
• Effects of supplementing rumen-protected niacin on fiber composition and metabolism of skeletal muscle in dairy cows during early lactation
  J.O. Zeitz, A. Weber, E. Most, W. Windisch, C. Bolduan, J. Geyer, F.-J. Romberg, C. Koch, K. Eder
  Journal of Dairy Science.2018; 101(9): 8004.     CrossRef
• The mitochondrial unfolded protein response and mitohormesis: a perspective on metabolic diseases
  Hyon-Seung Yi, Joon Young Chang, Minho Shong
  Journal of Molecular Endocrinology.2018; 61(3): R91.     CrossRef
• Berberine-induced activation of AMPK increases hepatic FGF21 expression via NUR77
  Feiye Zhou, Mengyao Bai, Yuqing Zhang, Qin Zhu, Linlin Zhang, Qi Zhang, Shushu Wang, Kecheng Zhu, Yun Liu, Xiao Wang, Libin Zhou
  Biochemical and Biophysical Research Communications.2018; 495(2): 1936.     CrossRef
• FGF21 Attenuates High-Fat Diet-Induced Cognitive Impairment via Metabolic Regulation and Anti-inflammation of Obese Mice
  Qingzhi Wang, Jing Yuan, Zhanyang Yu, Li Lin, Yinghua Jiang, Zeyuan Cao, Pengwei Zhuang, Michael J. Whalen, Bo Song, Xiao-Jie Wang, Xiaokun Li, Eng H. Lo, Yuming Xu, Xiaoying Wang
  Molecular Neurobiology.2018; 55(6): 4702.     CrossRef
• Leptin Mediates a Glucose-Fatty Acid Cycle to Maintain Glucose Homeostasis in Starvation
  Rachel J. Perry, Yongliang Wang, Gary W. Cline, Aviva Rabin-Court, Joongyu D. Song, Sylvie Dufour, Xian Man Zhang, Kitt Falk Petersen, Gerald I. Shulman
  Cell.2018; 172(1-2): 234.     CrossRef
• Improvement of Lipid and Glucose Metabolism by Capsiate in Palmitic Acid-Treated HepG2 Cells via Activation of the AMPK/SIRT1 Signaling Pathway
  Yufan Zang, Li Fan, Jihua Chen, Ruixue Huang, Hong Qin
  Journal of Agricultural and Food Chemistry.2018; 66(26): 6772.     CrossRef
• Fibroblast growth factor 21 as a biomarker for long‐term complications in organic acidemias
  F. Molema, E. H. Jacobs, W. Onkenhout, G. C. Schoonderwoerd, J. G. Langendonk, Monique Williams
  Journal of Inherited Metabolic Disease.2018; 41(6): 1179.     CrossRef
• The mitochondrial UPR: mechanisms, physiological functions and implications in ageing
  Tomer Shpilka, Cole M. Haynes
  Nature Reviews Molecular Cell Biology.2018; 19(2): 109.     CrossRef
• FGF21 Is Associated with Metabolic Effects and Treatment Response in Depressed Bipolar II Disorder Patients Treated with Valproate
  Hui Hua Chang, Po See Chen, Yung Wen Cheng, Tzu-Yun Wang, Yen Kuang Yang, Ru-Band Lu
  International Journal of Neuropsychopharmacology.2018; 21(4): 319.     CrossRef
• Circulating Fibroblast Growth Factor 21 is Associated with Subsequent Renal Injury Events in Patients Undergoing Coronary Angiography
  Cheng-Hsueh Wu, Ruey-Hsing Chou, Chin-Sung Kuo, Po-Hsun Huang, Chun-Chin Chang, Hsin-Bang Leu, Chin-Chou Huang, Jaw-Wen Chen, Shing-Jong Lin
  Scientific Reports.2018;[Epub]     CrossRef
• Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis
  Lucas D. BonDurant, Matthew J. Potthoff
  Annual Review of Nutrition.2018; 38(1): 173.     CrossRef
• Endocrine Regulator rFGF21 (Recombinant Human Fibroblast Growth Factor 21) Improves Neurological Outcomes Following Focal Ischemic Stroke of Type 2 Diabetes Mellitus Male Mice
  Yinghua Jiang, Ning Liu, Qingzhi Wang, Zhanyang Yu, Li Lin, Jing Yuan, Shuzhen Guo, Bum Ju Ahn, Xiao-Jie Wang, Xiaokun Li, Eng H. Lo, Xiaochuan Sun, Xiaoying Wang
  Stroke.2018; 49(12): 3039.     CrossRef
• Restricting branched‐chain amino acids: an approach to improve metabolic health
  Jacob G. Anderson, Kenzie Hintze, Erik D. Marchant
  The Journal of Physiology.2018; 596(13): 2469.     CrossRef
• Dietary Manipulations That Induce Ketosis Activate the HPA Axis in Male Rats and Mice: A Potential Role for Fibroblast Growth Factor-21
  Karen K Ryan, Amy E B Packard, Karlton R Larson, Jayna Stout, Sarah M Fourman, Abigail M K Thompson, Kristen Ludwick, Kirk M Habegger, Kerstin Stemmer, Nobuyuki Itoh, Diego Perez-Tilve, Matthias H Tschöp, Randy J Seeley, Yvonne M Ulrich-Lai
  Endocrinology.2018; 159(1): 400.     CrossRef
• Mitochondrial dysfunction in cancer: Potential roles of ATF5 and the mitochondrial UPR
  Pan Deng, Cole M. Haynes
  Seminars in Cancer Biology.2017; 47: 43.     CrossRef
• Modulation of energy balance by fibroblast growth factor 21
  Daniel Cuevas-Ramos, Carlos A. Aguilar-Salinas
  Hormone Molecular Biology and Clinical Investigation.2017;[Epub]     CrossRef
• Fibroblast Growth Factor 21 Mimetics for Treating Atherosclerosis
  Kelvin H. M. Kwok, Karen S. L. Lam
  Endocrinology and Metabolism.2017; 32(2): 145.     CrossRef
• The U-shaped relationship between fibroblast growth factor 21 and microvascular complication in type 2 diabetes mellitus
  Chan-Hee Jung, Sang-Hee Jung, Bo-Yeon Kim, Chul-Hee Kim, Sung-Koo Kang, Ji-Oh Mok
  Journal of Diabetes and its Complications.2017; 31(1): 134.     CrossRef
• A combined docosahexaenoic acid–thyroid hormone protocol upregulates rat liver β-Klotho expression and downstream components of FGF21 signaling as a potential novel approach to metabolic stress conditions
  R. Vargas, B. Riquelme, J. Fernández, L. A. Videla
  Food & Function.2017; 8(11): 3980.     CrossRef
• Anti-inflammatory effects of exercise training in adipose tissue do not require FGF21
  Jay W Porter, Joe L Rowles, Justin A Fletcher, Terese M Zidon, Nathan C Winn, Leighton T McCabe, Young-Min Park, James W Perfield, John P Thyfault, R Scott Rector, Jaume Padilla, Victoria J Vieira-Potter
  Journal of Endocrinology.2017; 235(2): 97.     CrossRef
• Hepatic FXR/SHP axis modulates systemic glucose and fatty acid homeostasis in aged mice
  Kang Ho Kim, Sungwoo Choi, Ying Zhou, Eun Young Kim, Jae Man Lee, Pradip K. Saha, Sayeepriyadarshini Anakk, David D. Moore
  Hepatology.2017; 66(2): 498.     CrossRef
• Association between circulating fibroblast growth factor 21 and mortality in end-stage renal disease
  Marina Kohara, Takahiro Masuda, Kazuhiro Shiizaki, Tetsu Akimoto, Yuko Watanabe, Sumiko Honma, Chuji Sekiguchi, Yasuharu Miyazawa, Eiji Kusano, Yoshinobu Kanda, Yasushi Asano, Makoto Kuro-o, Daisuke Nagata, Tatsuo Shimosawa
  PLOS ONE.2017; 12(6): e0178971.     CrossRef
• Analysis of hepatic transcript profile and plasma lipid profile in early lactating dairy cows fed grape seed and grape marc meal extract
  Denise K. Gessner, Anne Winkler, Christian Koch, Georg Dusel, Gerhard Liebisch, Robert Ringseis, Klaus Eder
  BMC Genomics.2017;[Epub]     CrossRef
• The FGF21-CCL11 Axis Mediates Beiging of White Adipose Tissues by Coupling Sympathetic Nervous System to Type 2 Immunity
  Zhe Huang, Ling Zhong, Jimmy Tsz Hang Lee, Jialiang Zhang, Donghai Wu, Leiluo Geng, Yu Wang, Chi-Ming Wong, Aimin Xu
  Cell Metabolism.2017; 26(3): 493.     CrossRef
• Fibroblast growth factor 21 and its novel association with oxidative stress
  Miguel Ángel Gómez-Sámano, Mariana Grajales-Gómez, Julia María Zuarth-Vázquez, Ma. Fernanda Navarro-Flores, Mayela Martínez-Saavedra, Óscar Alfredo Juárez-León, Mariana G. Morales-García, Víctor Manuel Enríquez-Estrada, Francisco J. Gómez-Pérez, Daniel Cu
  Redox Biology.2017; 11: 335.     CrossRef
• FGF21 activates AMPK signaling: impact on metabolic regulation and the aging process
  Antero Salminen, Anu Kauppinen, Kai Kaarniranta
  Journal of Molecular Medicine.2017; 95(2): 123.     CrossRef
• The Role of Autophagy in Critical Illness-induced Liver Damage
  Steven E. Thiessen, Inge Derese, Sarah Derde, Thomas Dufour, Lies Pauwels, Youri Bekhuis, Isabel Pintelon, Wim Martinet, Greet Van den Berghe, Ilse Vanhorebeek
  Scientific Reports.2017;[Epub]     CrossRef
• Implication of hepatokines in metabolic disorders and cardiovascular diseases
  Tae Woo Jung, Hye Jin Yoo, Kyung Mook Choi
  BBA Clinical.2016; 5: 108.     CrossRef
• Upregulation of rat liver PPARα‐FGF21 signaling by a docosahexaenoic acid and thyroid hormone combined protocol
  Luis A. Videla, Virginia Fernández, Romina Vargas, Pamela Cornejo, Gladys Tapia, Nelson Varela, Rodrigo Valenzuela, Allan Arenas, Javier Fernández, María C. Hernández‐Rodas, Bárbara Riquelme
  BioFactors.2016; 42(6): 638.     CrossRef
• Fibroblast Growth Factor 21 Protects against Atherosclerosis via Fine-Tuning the Multiorgan Crosstalk
  Leigang Jin, Zhuofeng Lin, Aimin Xu
  Diabetes & Metabolism Journal.2016; 40(1): 22.     CrossRef
• Hepatic Fgf21 Expression Is Repressed after Simvastatin Treatment in Mice
  Panos Ziros, Zoi Zagoriti, George Lagoumintzis, Venetsana Kyriazopoulou, Ralitsa P. Iskrenova, Evagelia I. Habeos, Gerasimos P. Sykiotis, Dionysios V. Chartoumpekis, Ioannis G Habeos, Kostas Pantopoulos
  PLOS ONE.2016; 11(9): e0162024.     CrossRef
• Metabolic fibroblast growth factors (FGFs): Mediators of energy homeostasis
  Kathleen R. Markan, Matthew J. Potthoff
  Seminars in Cell & Developmental Biology.2016; 53: 85.     CrossRef
• miR‐212 downregulation contributes to the protective effect of exercise against non‐alcoholic fatty liver via targeting FGF‐21
  Junjie Xiao, Yihua Bei, Jingqi Liu, Jasmina Dimitrova‐Shumkovska, Dapeng Kuang, Qiulian Zhou, Jin Li, Yanning Yang, Yang Xiang, Fei Wang, Changqing Yang, Wenzhuo Yang
  Journal of Cellular and Molecular Medicine.2016; 20(2): 204.     CrossRef
• Fibroblast growth factor 21 and exercise-induced hepatic mitochondrial adaptations
  Justin A. Fletcher, Melissa A. Linden, Ryan D. Sheldon, Grace M. Meers, E. Matthew Morris, Anthony Butterfield, James W. Perfield, John P. Thyfault, R. Scott Rector
  American Journal of Physiology-Gastrointestinal and Liver Physiology.2016; 310(10): G832.     CrossRef
• New adipokines
  Bruno Fève, Claire Bastard, Soraya Fellahi, Jean-Philippe Bastard, Jacqueline Capeau
  Annales d'Endocrinologie.2016; 77(1): 49.     CrossRef
• Stress Signaling Between Organs in Metazoa
  Edward Owusu-Ansah, Norbert Perrimon
  Annual Review of Cell and Developmental Biology.2015; 31(1): 497.     CrossRef
• Dietary restriction in obese children and its relation with eating behavior, fibroblast growth factor 21 and leptin: a prospective clinical intervention study
  Lorena del Rocío Ibarra-Reynoso, Liudmila Pisarchyk, Elva Leticia Pérez-Luque, Ma. Eugenia Garay-Sevilla, Juan Manuel Malacara
  Nutrition & Metabolism.2015;[Epub]     CrossRef
• FGF21 as a mediator of adaptive responses to stress and metabolic benefits of anti-diabetic drugs
  Kook Hwan Kim, Myung-Shik Lee
  Journal of Endocrinology.2015; 226(1): R1.     CrossRef
• Effects of a plant product consisting of green tea and curcuma extract on milk production and the expression of hepatic genes involved in endoplasmic stress response and inflammation in dairy cows
  Anne Winkler, Denise K. Gessner, Christian Koch, Franz-Josef Romberg, Georg Dusel, Eva Herzog, Erika Most, Klaus Eder
  Archives of Animal Nutrition.2015; 69(6): 425.     CrossRef
• The effect of grape seed and grape marc meal extract on milk performance and the expression of genes of endoplasmic reticulum stress and inflammation in the liver of dairy cows in early lactation
  D.K. Gessner, C. Koch, F.-J. Romberg, A. Winkler, G. Dusel, E. Herzog, E. Most, K. Eder
  Journal of Dairy Science.2015; 98(12): 8856.     CrossRef
• Vascular protection with fibroblast growth factor 21 in diabetes: Its potential beyond glucose and lipid control
  Mi-Hua Liu
  International Journal of Cardiology.2015; 199: 403.     CrossRef
• The acute pancreatitis severity prediction using adiponectin, adipocyte fatty acid binding protein and fibroblast growth factor 21 levels in day 4 after admission
  D Novotný, P Malina, P Krumpholcová, I Tozzi, V Procházka
  Klinická biochemie a metabolismus.2015; 23(1): 9.     CrossRef

About this article

Kim KH, Lee MS. FGF21 as a Stress Hormone: The Roles of FGF21 in Stress Adaptation and the Treatment of Metabolic Diseases. Diabetes Metab J. 2014;38(4):245-251.

DOI: https://doi.org/10.4093/dmj.2014.38.4.245.

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