Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis

Literature Cited

1. 1.  Abdul-Wahed A, Guilmeau S, Postic C 2017. Sweet sixteenth for ChREBP: established roles and future goals. Cell Metab 26:324–41
   [Google Scholar]
2. 2.  Adams AC, Cheng CC, Coskun T, Kharitonenkov A 2012. FGF21 requires βklotho to act in vivo. PLOS ONE 7:e49977
   [Google Scholar]
3. 3.  Adams AC, Coskun T, Rovira AR, Schneider MA, Raches DW et al. 2012. Fundamentals of FGF19 & FGF21 action in vitro and in vivo. PLOS ONE 7:e38438
   [Google Scholar]
4. 4.  Adams AC, Yang C, Coskun T, Cheng CC, Gimeno RE et al. 2012. The breadth of FGF21’s metabolic actions are governed by FGFR1 in adipose tissue. Mol. Metab. 2:31–37
   [Google Scholar]
5. 5.  Arner P, Pettersson A, Mitchell PJ, Dunbar JD, Kharitonenkov A, Ryden M 2008. FGF21 attenuates lipolysis in human adipocytes—a possible link to improved insulin sensitivity. FEBS Lett 582:1725–30
   [Google Scholar]
6. 6.  Badman MK, Koester A, Flier JS, Kharitonenkov A, Maratos-Flier E 2009. Fibroblast growth factor 21–deficient mice demonstrate impaired adaptation to ketosis. Endocrinology 150:4931–40
   [Google Scholar]
7. 7.  Badman MK, Pissios P, Kennedy AR, Koukos G, Flier JS, Maratos-Flier E 2007. Hepatic fibroblast growth factor 21 is regulated by PPARα and is a key mediator of hepatic lipid metabolism in ketotic states. Cell Metab 5:426–37
   [Google Scholar]
8. 8.  Beenken A, Mohammadi M 2009. The FGF family: biology, pathophysiology and therapy. Nat. Rev. Drug Discov. 8:235–53
   [Google Scholar]
9. 9.  Beenken A, Mohammadi M 2012. The structural biology of the FGF19 subfamily. Adv. Exp. Med. Biol. 728:1–24
   [Google Scholar]
10. 10.  Bertholet AM, Kazak L, Chouchani ET, Bogaczynska MG, Paranjpe I et al. 2017. Mitochondrial patch clamp of beige adipocytes reveals UCP1-positive and UCP1-negative cells both exhibiting futile creatine cycling. Cell Metab 25:811–22.e4
    [Google Scholar]
11. 11.  BonDurant LD, Ameka M, Naber MC, Markan KR, Idiga SO et al. 2017. FGF21 regulates metabolism through adipose-dependent and -independent mechanisms. Cell Metab 25:935–44.e4
    [Google Scholar]
12. 12.  Bookout AL, de Groot MH, Owen BM, Lee S, Gautron L et al. 2013. FGF21 regulates metabolism and circadian behavior by acting on the nervous system. Nat. Med. 19:1147–52
    [Google Scholar]
13. 13.  Camilleri M 2015. Bile acid diarrhea: prevalence, pathogenesis, and therapy. Gut Liver 9:332–39
    [Google Scholar]
14. 14.  Camporez JP, Jornayvaz FR, Petersen MC, Pesta D, Guigni BA et al. 2013. Cellular mechanisms by which FGF21 improves insulin sensitivity in male mice. Endocrinology 154:3099–109
    [Google Scholar]
15. 15.  Chartoumpekis DV, Habeos IG, Ziros PG, Psyrogiannis AI, Kyriazopoulou VE, Papavassiliou AG 2011. Brown adipose tissue responds to cold and adrenergic stimulation by induction of FGF21. Mol. Med. 17:736–40
    [Google Scholar]
16. 16.  Chavez AO, Molina-Carrion M, Abdul-Ghani MA, Folli F, Defronzo RA, Tripathy D 2009. Circulating fibroblast growth factor-21 is elevated in impaired glucose tolerance and type 2 diabetes and correlates with muscle and hepatic insulin resistance. Diabetes Care 32:1542–46
    [Google Scholar]
17. 17.  Chen MZ, Chang JC, Zavala-Solorio J, Kates L, Thai M et al. 2017. FGF21 mimetic antibody stimulates UCP1-independent brown fat thermogenesis via FGFR1/βKlotho complex in non-adipocytes. Mol. Metab. 6:1454–67
    [Google Scholar]
18. 18.  Chen WW, Li L, Yang GY, Li K, Qi XY et al. 2008. Circulating FGF-21 levels in normal subjects and in newly diagnosed patients with type 2 diabetes mellitus. Exp. Clin. Endocrinol. Diabetes 116:65–68
    [Google Scholar]
19. 19.  Christodoulides C, Dyson P, Sprecher D, Tsintzas K, Karpe F 2009. Circulating fibroblast growth factor 21 is induced by peroxisome proliferator–activated receptor agonists but not ketosis in man. J. Clin. Endocrinol. Metab. 94:3594–601
    [Google Scholar]
20. 20.  Chu AY, Workalemahu T, Paynter NP, Rose LM, Giulianini F et al. 2013. Novel locus including FGF21 is associated with dietary macronutrient intake. Hum. Mol. Genet. 22:1895–902
    [Google Scholar]
21. 21.  Coskun T, Bina HA, Schneider MA, Dunbar JD, Hu CC et al. 2008. Fibroblast growth factor 21 corrects obesity in mice. Endocrinology 149:6018–27
    [Google Scholar]
22. 22.  Cuevas-Ramos D, Almeda-Valdes P, Gomez-Perez FJ, Meza-Arana CE, Cruz-Bautista I et al. 2010. Daily physical activity, fasting glucose, uric acid, and body mass index are independent factors associated with serum fibroblast growth factor 21 levels. Eur. J. Endocrinol. 163:469–77
    [Google Scholar]
23. 23.  Dashti HM, Mathew TC, Khadada M, Al-Mousawi M, Talib H et al. 2007. Beneficial effects of ketogenic diet in obese diabetic subjects. Mol. Cell. Biochem. 302:249–56
    [Google Scholar]
24. 24.  De Sousa-Coelho AL, Marrero PF, Haro D 2012. Activating transcription factor 4–dependent induction of FGF21 during amino acid deprivation. Biochem. J. 443:165–71
    [Google Scholar]
25. 25.  De Sousa-Coelho AL, Relat J, Hondares E, Perez-Marti A, Ribas F et al. 2013. FGF21 mediates the lipid metabolism response to amino acid starvation. J. Lipid Res. 54:1786–97
    [Google Scholar]
26. 26.  Desai BN, Singhal G, Watanabe M, Stevanovic D, Lundasen T et al. 2017. Fibroblast growth factor 21 (FGF21) is robustly induced by ethanol and has a protective role in ethanol associated liver injury. Mol. Metab. 6:1395–406
    [Google Scholar]
27. 27.  Ding X, Boney-Montoya J, Owen BM, Bookout AL, Coate KC et al. 2012. βKlotho is required for fibroblast growth factor 21 effects on growth and metabolism. Cell Metab 16:387–93
    [Google Scholar]
28. 28.  Douris N, Stevanovic DM, Fisher FM, Cisu TI, Chee MJ et al. 2015. Central fibroblast growth factor 21 browns white fat via sympathetic action in male mice. Endocrinology 156:2470–81
    [Google Scholar]
29. 29.  Dunshee DR, Bainbridge TW, Kljavin NM, Zavala-Solorio J, Schroeder AC et al. 2016. Fibroblast activation protein cleaves and inactivates fibroblast growth factor 21. J. Biol. Chem. 291:5986–96
    [Google Scholar]
30. 30.  Dushay JR, Chui PC, Gopalakrishnan GS, Varela-Rey M, Crawley M et al. 2010. Increased fibroblast growth factor 21 in obesity and nonalcoholic fatty liver disease. Gastroenterology 139:456–63
    [Google Scholar]
31. 31.  Dushay JR, Toschi E, Mitten EK, Fisher FM, Herman MA, Maratos-Flier E 2015. Fructose ingestion acutely stimulates circulating FGF21 levels in humans. Mol. Metab. 4:51–57
    [Google Scholar]
32. 32.  Dutchak PA, Katafuchi T, Bookout AL, Choi JH, Yu RT et al. 2012. Fibroblast growth factor-21 regulates PPARγ activity and the antidiabetic actions of thiazolidinediones. Cell 148:556–67
    [Google Scholar]
33. 33.  Fazeli PK, Lun M, Kim SM, Bredella MA, Wright S et al. 2015. FGF21 and the late adaptive response to starvation in humans. J. Clin. Investig. 125:4601–11
    [Google Scholar]
34. 34.  Fisher FM, Chui PC, Antonellis PJ, Bina HA, Kharitonenkov A et al. 2010. Obesity is a fibroblast growth factor 21 (FGF21)-resistant state. Diabetes 59:2781–89
    [Google Scholar]
35. 35.  Fisher FM, Kim M, Doridot L, Cunniff JC, Parker TS et al. 2017. A critical role for ChREBP-mediated FGF21 secretion in hepatic fructose metabolism. Mol. Metab. 6:14–21
    [Google Scholar]
36. 36.  Fisher FM, Kleiner S, Douris N, Fox EC, Mepani RJ et al. 2012. FGF21 regulates PGC-1α and browning of white adipose tissues in adaptive thermogenesis. Genes Dev 26:271–81
    [Google Scholar]
37. 37.  Fisher FM, Maratos-Flier E 2016. Understanding the physiology of FGF21. Annu. Rev. Physiol. 78:223–41
    [Google Scholar]
38. 38.  Foltz IN, Hu S, King C, Wu X, Yang C et al. 2012. Treating diabetes and obesity with an FGF21-mimetic antibody activating the βKlotho/FGFR1c receptor complex. Sci. Transl. Med. 4:162ra53
    [Google Scholar]
39. 39.  Fon Tacer K, Bookout AL, Ding X, Kurosu H, John GB et al. 2010. Research resource: comprehensive expression atlas of the fibroblast growth factor system in adult mouse. Mol. Endocrinol. 24:2050–64
    [Google Scholar]
40. 40.  Frayling TM, Beaumont RN, Jones SE, Yaghootkar H, Tuke MA et al. 2018. A common allele in FGF21 associated with sugar intake is associated with body shape, lower total body-fat percentage, and higher blood pressure. Cell Rep 23:327–36
    [Google Scholar]
41. 41.  Gaich G, Chien JY, Fu H, Glass LC, Deeg MA et al. 2013. The effects of LY2405319, an FGF21 analog, in obese human subjects with type 2 diabetes. Cell Metab 18:333–40
    [Google Scholar]
42. 42.  Galman C, Lundasen T, Kharitonenkov A, Bina HA, Eriksson M et al. 2008. The circulating metabolic regulator FGF21 is induced by prolonged fasting and PPARα activation in man. Cell Metab 8:169–74
    [Google Scholar]
43. 43.  Gillum MP, Potthoff MJ 2016. FAP finds FGF21 easy to digest. Biochem. J. 473:1125–27
    [Google Scholar]
44. 44.  Gimeno RE, Moller DE 2014. FGF21-based pharmacotherapy—potential utility for metabolic disorders. Trends Endocrinol. Metab. 25:303–11
    [Google Scholar]
45. 45.  Hale C, Chen MM, Stanislaus S, Chinookoswong N, Hager T et al. 2012. Lack of overt FGF21 resistance in two mouse models of obesity and insulin resistance. Endocrinology 153:69–80
    [Google Scholar]
46. 46.  Hansen JS, Clemmesen JO, Secher NH, Hoene M, Drescher A et al. 2015. Glucagon-to-insulin ratio is pivotal for splanchnic regulation of FGF-21 in humans. Mol. Metab. 4:551–60
    [Google Scholar]
47. 47.  Harno E, Cottrell EC, White A 2013. Metabolic pitfalls of CNS Cre-based technology. Cell Metab 18:21–28
    [Google Scholar]
48. 48.  Holland WL, Adams AC, Brozinick JT, Bui HH, Miyauchi Y et al. 2013. An FGF21–adiponectin–ceramide axis controls energy expenditure and insulin action in mice. Cell Metab 17:790–97
    [Google Scholar]
49. 49.  Hondares E, Iglesias R, Giralt A, Gonzalez FJ, Giralt M et al. 2011. Thermogenic activation induces FGF21 expression and release in brown adipose tissue. J. Biol. Chem. 286:12983–90
    [Google Scholar]
50. 50.  Hsuchou H, Pan W, Kastin AJ 2007. The fasting polypeptide FGF21 can enter brain from blood. Peptides 28:2382–86
    [Google Scholar]
51. 51.  Huang J, Ishino T, Chen G, Rolzin P, Osothprarop TF et al. 2013. Development of a novel long-acting antidiabetic FGF21 mimetic by targeted conjugation to a scaffold antibody. J. Pharmacol. Exp. Ther. 346:270–80
    [Google Scholar]
52. 52.  Huang Z, Zhong L, Lee JTH, Zhang J, Wu D et al. 2017. The FGF21–CCL11 axis mediates beiging of white adipose tissues by coupling sympathetic nervous system to type 2 immunity. Cell Metab 26:493–508.e4
    [Google Scholar]
53. 53.  Iizuka K, Takeda J, Horikawa Y 2009. Glucose induces FGF21 mRNA expression through ChREBP activation in rat hepatocytes. FEBS Lett 583:2882–86
    [Google Scholar]
54. 54.  Inagaki T, Dutchak P, Zhao G, Ding X, Gautron L et al. 2007. Endocrine regulation of the fasting response by PPARα-mediated induction of fibroblast growth factor 21. Cell Metab 5:415–25
    [Google Scholar]
55. 55.  Iroz A, Montagner A, Benhamed F, Levavasseur F, Polizzi A et al. 2017. A specific ChREBP and PPARα cross-talk is required for the glucose-mediated FGF21 response. Cell Rep 21:403–16
    [Google Scholar]
56. 56.  Izumiya Y, Bina HA, Ouchi N, Akasaki Y, Kharitonenkov A, Walsh K 2008. FGF21 is an Akt-regulated myokine. FEBS Lett 582:3805–10
    [Google Scholar]
57. 57.  Kang JG, Park CY 2012. Anti-obesity drugs: a review about their effects and safety. Diabetes Metab. J. 36:13–25
    [Google Scholar]
58. 58.  Kazak L, Chouchani ET, Jedrychowski MP, Erickson BK, Shinoda K et al. 2015. A creatine-driven substrate cycle enhances energy expenditure and thermogenesis in beige fat. Cell 163:643–55
    [Google Scholar]
59. 59.  Keipert S, Kutschke M, Lamp D, Brachthauser L, Neff F et al. 2015. Genetic disruption of uncoupling protein 1 in mice renders brown adipose tissue a significant source of FGF21 secretion. Mol. Metab. 4:537–42
    [Google Scholar]
60. 60.  Keipert S, Kutschke M, Ost M, Schwarzmayr T, van Schothorst EM et al. 2017. Long-term cold adaptation does not require FGF21 or UCP1. Cell Metab 26:437–46.e5
    [Google Scholar]
61. 61.  Keipert S, Ost M, Johann K, Imber F, Jastroch M et al. 2014. Skeletal muscle mitochondrial uncoupling drives endocrine cross-talk through the induction of FGF21 as a myokine. Am. J. Physiol. Endocrinol. Metab. 306:E469–82
    [Google Scholar]
62. 62.  Kersten S, Seydoux J, Peters JM, Gonzalez FJ, Desvergne B, Wahli W 1999. Peroxisome proliferator-activated receptor α mediates the adaptive response to fasting. J. Clin. Investig. 103:1489–98
    [Google Scholar]
63. 63.  Kharitonenkov A, DiMarchi R 2017. Fibroblast growth factor 21 night watch: advances and uncertainties in the field. J. Intern. Med. 281:233–46
    [Google Scholar]
64. 64.  Kharitonenkov A, Shiyanova TL, Koester A, Ford AM, Micanovic R et al. 2005. FGF-21 as a novel metabolic regulator. J. Clin. Investig. 115:1627–35
    [Google Scholar]
65. 65.  Kharitonenkov A, Wroblewski VJ, Koester A, Chen YF, Clutinger CK et al. 2007. The metabolic state of diabetic monkeys is regulated by fibroblast growth factor-21. Endocrinology 148:774–81
    [Google Scholar]
66. 66.  Kim AM, Somayaji VR, Dong JQ, Rolph TP, Weng Y et al. 2017. Once-weekly administration of a long-acting fibroblast growth factor 21 analogue modulates lipids, bone turnover markers, blood pressure and body weight differently in obese people with hypertriglyceridaemia and in non-human primates. Diabetes Obes. Metab. 19:1762–72
    [Google Scholar]
67. 67.  Kim HW, Lee JE, Cha JJ, Hyun YY, Kim JE et al. 2013. Fibroblast growth factor 21 improves insulin resistance and ameliorates renal injury in db/db mice. Endocrinology 154:3366–76
    [Google Scholar]
68. 68.  Kim KH, Jeong YT, Oh H, Kim SH, Cho JM et al. 2013. Autophagy deficiency leads to protection from obesity and insulin resistance by inducing Fgf21 as a mitokine. Nat. Med. 19:83–92
    [Google Scholar]
69. 69.  Kim KH, Lee MS 2014. FGF21 as a stress hormone: the roles of FGF21 in stress adaptation and the treatment of metabolic diseases. Diabetes Metab. J. 38:245–51
    [Google Scholar]
70. 70.  Kolumam G, Chen MZ, Tong R, Zavala-Solorio J, Kates L et al. 2015. Sustained brown fat stimulation and insulin sensitization by a humanized bispecific antibody agonist for fibroblast growth factor receptor 1/βKlotho complex. EBioMedicine 2:730–43
    [Google Scholar]
71. 71.  Kurosu H, Choi M, Ogawa Y, Dickson AS, Goetz R et al. 2007. Tissue-specific expression of βKlotho and fibroblast growth factor (FGF) receptor isoforms determines metabolic activity of FGF19 and FGF21. J. Biol. Chem. 282:26687–95
    [Google Scholar]
72. 72.  Laeger T, Albarado DC, Burke SJ, Trosclair L, Hedgepeth JW et al. 2016. Metabolic responses to dietary protein restriction require an increase in FGF21 that is delayed by the absence of GCN2. Cell Rep 16:707–16
    [Google Scholar]
73. 73.  Laeger T, Henagan TM, Albarado DC, Redman LM, Bray GA et al. 2014. FGF21 is an endocrine signal of protein restriction. J. Clin. Investig. 124:3913–22
    [Google Scholar]
74. 74.  Lan T, Morgan DA, Rahmouni K, Sonoda J, Fu X et al. 2017. FGF19, FGF21, and an FGFR1/β-Klotho-activating antibody act on the nervous system to regulate body weight and glycemia. Cell Metab 26:709–18.e3
    [Google Scholar]
75. 75.  Lee KY, Russell SJ, Ussar S, Boucher J, Vernochet C et al. 2013. Lessons on conditional gene targeting in mouse adipose tissue. Diabetes 62:864–74
    [Google Scholar]
76. 76.  Lee P, Linderman JD, Smith S, Brychta RJ, Wang J et al. 2014. Irisin and FGF21 are cold-induced endocrine activators of brown fat function in humans. Cell Metab 19:302–9
    [Google Scholar]
77. 77.  Lee S, Choi J, Mohanty J, Sousa LP, Tome F et al. 2018. Structures of β-klotho reveal a ‘zip code’-like mechanism for endocrine FGF signalling. Nature 553:501–5
    [Google Scholar]
78. 78.  Lehtonen JM, Forsstrom S, Bottani E, Viscomi C, Baris OR et al. 2016. FGF21 is a biomarker for mitochondrial translation and mtDNA maintenance disorders. Neurology 87:2290–99
    [Google Scholar]
79. 79.  Li H, Fang Q, Gao F, Fan J, Zhou J et al. 2010. Fibroblast growth factor 21 levels are increased in nonalcoholic fatty liver disease patients and are correlated with hepatic triglyceride. J. Hepatol. 53:934–40
    [Google Scholar]
80. 80.  Li X, Stanislaus S, Asuncion F, Niu QT, Chinookoswong N et al. 2017. FGF21 is not a major mediator for bone homeostasis or metabolic actions of PPARα and PPARγ agonists. J. Bone Miner. Res. 32:834–45
    [Google Scholar]
81. 81.  Liang Q, Zhong L, Zhang J, Wang Y, Bornstein SR et al. 2014. FGF21 maintains glucose homeostasis by mediating the cross talk between liver and brain during prolonged fasting. Diabetes 63:4064–75
    [Google Scholar]
82. 82.  Lin Z, Tian H, Lam KS, Lin S, Hoo RC et al. 2013. Adiponectin mediates the metabolic effects of FGF21 on glucose homeostasis and insulin sensitivity in mice. Cell Metab 17:779–89
    [Google Scholar]
83. 83.  Liu Y, Zhao C, Xiao J, Liu L, Zhang M et al. 2016. Fibroblast growth factor 21 deficiency exacerbates chronic alcohol-induced hepatic steatosis and injury. Sci. Rep. 6:31026
    [Google Scholar]
84. 84.  Lundsgaard AM, Fritzen AM, Sjoberg KA, Myrmel LS, Madsen L et al. 2017. Circulating FGF21 in humans is potently induced by short term overfeeding of carbohydrates. Mol. Metab. 6:22–29
    [Google Scholar]
85. 85.  Maida A, Zota A, Sjoberg KA, Schumacher J, Sijmonsma TP et al. 2016. A liver stress–endocrine nexus promotes metabolic integrity during dietary protein dilution. J. Clin. Investig. 126:3263–78
    [Google Scholar]
86. 86.  Markan KR, Naber MC, Ameka MK, Anderegg MD, Mangelsdorf DJ et al. 2014. Circulating FGF21 is liver derived and enhances glucose uptake during refeeding and overfeeding. Diabetes 63:4057–63
    [Google Scholar]
87. 87.  Markan KR, Naber MC, Small SM, Peltekian L, Kessler RL, Potthoff MJ 2017. FGF21 resistance is not mediated by downregulation of β-klotho expression in white adipose tissue. Mol. Metab. 6:602–10
    [Google Scholar]
88. 88.  Markan KR, Potthoff MJ 2016. Metabolic fibroblast growth factors (FGFs): mediators of energy homeostasis. Semin. Cell Dev. Biol. 53:85–93
    [Google Scholar]
89. 89.  Micanovic R, Raches DW, Dunbar JD, Driver DA, Bina HA et al. 2009. Different roles of N- and C-termini in the functional activity of FGF21. J. Cell. Physiol. 219:227–34
    [Google Scholar]
90. 90.  Morrison CD, Laeger T 2015. Protein-dependent regulation of feeding and metabolism. Trends Endocrinol. Metab. 26:256–62
    [Google Scholar]
91. 91.  Morrison SF, Nakamura K 2011. Central neural pathways for thermoregulation. Front. Biosci. 16:74–104
    [Google Scholar]
92. 92.  Morton GJ, Cummings DE, Baskin DG, Barsh GS, Schwartz MW 2006. Central nervous system control of food intake and body weight. Nature 443:289–95
    [Google Scholar]
93. 93.  Mraz M, Bartlova M, Lacinova Z, Michalsky D, Kasalicky M et al. 2009. Serum concentrations and tissue expression of a novel endocrine regulator fibroblast growth factor-21 in patients with type 2 diabetes and obesity. Clin. Endocrinol. 71:369–75
    [Google Scholar]
94. 94.  Muise ES, Azzolina B, Kuo DW, El-Sherbeini M, Tan Y et al. 2008. Adipose fibroblast growth factor 21 is up-regulated by peroxisome proliferator-activated receptor γ and altered metabolic states. Mol. Pharmacol. 74:403–12
    [Google Scholar]
95. 95.  Muise ES, Souza S, Chi A, Tan Y, Zhao X et al. 2013. Downstream signaling pathways in mouse adipose tissues following acute in vivo administration of fibroblast growth factor 21. PLOS ONE 8:e73011
    [Google Scholar]
96. 96.  Muller TD, Sullivan LM, Habegger K, Yi CX, Kabra D et al. 2012. Restoration of leptin responsiveness in diet-induced obese mice using an optimized leptin analog in combination with exendin-4 or FGF21. J. Pept. Sci. 18:383–93
    [Google Scholar]
97. 97.  Murata Y, Nishio K, Mochiyama T, Konishi M, Shimada M et al. 2013. Fgf21 impairs adipocyte insulin sensitivity in mice fed a low-carbohydrate, high-fat ketogenic diet. PLOS ONE 8:e69330
    [Google Scholar]
98. 98.  Nishimura T, Nakatake Y, Konishi M, Itoh N 2000. Identification of a novel FGF, FGF-21, preferentially expressed in the liver. Biochim. Biophys. Acta 1492:203–6
    [Google Scholar]
99. 99.  Ogawa Y, Kurosu H, Yamamoto M, Nandi A, Rosenblatt KP et al. 2007. βKlotho is required for metabolic activity of fibroblast growth factor 21. PNAS 104:7432–37
    [Google Scholar]
100. 100.  Owen BM, Bookout AL, Ding X, Lin VY, Atkin SD et al. 2013. FGF21 contributes to neuroendocrine control of female reproduction. Nat. Med. 19:1153–56
     [Google Scholar]
101. 101.  Owen BM, Ding X, Morgan DA, Coate KC, Bookout AL et al. 2014. FGF21 acts centrally to induce sympathetic nerve activity, energy expenditure, and weight loss. Cell Metab 20:670–77
     [Google Scholar]
102. 102.  Owen BM, Mangelsdorf DJ, Kliewer SA 2015. Tissue-specific actions of the metabolic hormones FGF15/19 and FGF21. Trends Endocrinol. Metab. 26:22–29
     [Google Scholar]
103. 103.  Pereira RO, Tadinada SM, Zasadny FM, Oliveira KJ, Pires KMP et al. 2017. OPA1 deficiency promotes secretion of FGF21 from muscle that prevents obesity and insulin resistance. EMBO J 36:2126–45
     [Google Scholar]
104. 104.  Potthoff MJ 2017. FGF21 and metabolic disease in 2016: a new frontier in FGF21 biology. Nat. Rev. Endocrinol. 13:74–76
     [Google Scholar]
105. 105.  Potthoff MJ, Inagaki T, Satapati S, Ding X, He T et al. 2009. FGF21 induces PGC-1α and regulates carbohydrate and fatty acid metabolism during the adaptive starvation response. PNAS 106:10853–58
     [Google Scholar]
106. 106.  Potthoff MJ, Kliewer SA, Mangelsdorf DJ 2012. Endocrine fibroblast growth factors 15/19 and 21: from feast to famine. Genes Dev 26:312–24
     [Google Scholar]
107. 107.  Rankinen T, Bouchard C 2006. Genetics of food intake and eating behavior phenotypes in humans. Annu. Rev. Nutr. 26:413–34
     [Google Scholar]
108. 108.  Rosen ED, Spiegelman BM 2014. What we talk about when we talk about fat. Cell 156:20–44
     [Google Scholar]
109. 109.  Samms RJ, Cheng CC, Kharitonenkov A, Gimeno RE, Adams AC 2016. Overexpression of β-klotho in adipose tissue sensitizes male mice to endogenous FGF21 and provides protection from diet-induced obesity. Endocrinology 157:1467–80
     [Google Scholar]
110. 110.  Samms RJ, Lewis JE, Norton L, Stephens FB, Gaffney CJ et al. 2017. FGF21 is an insulin-dependent postprandial hormone in adult humans. J. Clin. Endocrinol. Metab. 102:3806–13
     [Google Scholar]
111. 111.  Samms RJ, Smith DP, Cheng CC, Antonellis PP, Perfield JW, 2nd., et al. 2015. Discrete aspects of FGF21 in vivo pharmacology do not require UCP1. Cell Rep 11:991–99
     [Google Scholar]
112. 112.  Sanchez J, Palou A, Pico C 2009. Response to carbohydrate and fat refeeding in the expression of genes involved in nutrient partitioning and metabolism: striking effects on fibroblast growth factor-21 induction. Endocrinology 150:5341–50
     [Google Scholar]
113. 113.  Sanchez-Garrido MA, Habegger KM, Clemmensen C, Holleman C, Muller TD et al. 2016. Fibroblast activation protein (FAP) as a novel metabolic target. Mol. Metab. 5:1015–24
     [Google Scholar]
114. 114.  Schaefer EJ, Gleason JA, Dansinger ML 2009. Dietary fructose and glucose differentially affect lipid and glucose homeostasis. J. Nutr. 139:1257S–62S
     [Google Scholar]
115. 115.  Schlein C, Talukdar S, Heine M, Fischer AW, Krott LM et al. 2016. FGF21 lowers plasma triglycerides by accelerating lipoprotein catabolism in white and brown adipose tissues. Cell Metab 23:441–53
     [Google Scholar]
116. 116.  Schumann G, Liu C, O'Reilly P, Gao H, Song P et al. 2016. KLB is associated with alcohol drinking, and its gene product β-klotho is necessary for FGF21 regulation of alcohol preference. PNAS 113:14372–77
     [Google Scholar]
117. 117.  Shenoy VK, Beaver KM, Fisher FM, Singhal G, Dushay JR et al. 2016. Elevated serum fibroblast growth factor 21 in humans with acute pancreatitis. PLOS ONE 11:e0164351
     [Google Scholar]
118. 118.  Simpson SJ, Raubenheimer D 2005. Obesity: the protein leverage hypothesis. Obes. Rev. 6:133–42
     [Google Scholar]
119. 119.  Singhal G, Douris N, Fish AJ, Zhang X, Adams AC et al. 2016. Fibroblast growth factor 21 has no direct role in regulating fertility in female mice. Mol. Metab. 5:690–98
     [Google Scholar]
120. 120.  Soberg S, Sandholt CH, Jespersen NZ, Toft U, Madsen AL et al. 2017. FGF21 is a sugar-induced hormone associated with sweet intake and preference in humans. Cell Metab 25:1045–53.e6
     [Google Scholar]
121. 121.  Solon-Biet SM, Cogger VC, Pulpitel T, Heblinski M, Wahl D et al. 2016. Defining the nutritional and metabolic context of FGF21 using the Geometric Framework. Cell Metab 24:555–65
     [Google Scholar]
122. 122.  Solon-Biet SM, McMahon AC, Ballard JW, Ruohonen K, Wu LE et al. 2014. The ratio of macronutrients, not caloric intake, dictates cardiometabolic health, aging, and longevity in ad libitum–fed mice. Cell Metab 19:418–30
     [Google Scholar]
123. 123.  Stemmer K, Zani F, Habegger KM, Neff C, Kotzbeck P et al. 2015. FGF21 is not required for glucose homeostasis, ketosis or tumour suppression associated with ketogenic diets in mice. Diabetologia 58:2414–23
     [Google Scholar]
124. 124.  Suzuki M, Uehara Y, Motomura-Matsuzaka K, Oki J, Koyama Y et al. 2008. βKlotho is required for fibroblast growth factor (FGF) 21 signaling through FGF receptor (FGFR) 1c and FGFR3c. Mol. Endocrinol. 22:1006–14
     [Google Scholar]
125. 125.  Talukdar S, Owen BM, Song P, Hernandez G, Zhang Y et al. 2016. FGF21 regulates sweet and alcohol preference. Cell Metab 23:344–49
     [Google Scholar]
126. 126.  Talukdar S, Zhou Y, Li D, Rossulek M, Dong J et al. 2016. A long-acting FGF21 molecule, PF-05231023, decreases body weight and improves lipid profile in non-human primates and type 2 diabetic subjects. Cell Metab 23:427–40
     [Google Scholar]
127. 127.  Tanaka T, Ngwa JS, van Rooij FJ, Zillikens MC, Wojczynski MK et al. 2013. Genome-wide meta-analysis of observational studies shows common genetic variants associated with macronutrient intake. Am. J. Clin. Nutr. 97:1395–402
     [Google Scholar]
128. 128.  Tezze C, Romanello V, Desbats MA, Fadini GP, Albiero M et al. 2017. Age-associated loss of OPA1 in muscle impacts muscle mass, metabolic homeostasis, systemic inflammation, and epithelial senescence. Cell Metab 25:1374–89.e6
     [Google Scholar]
129. 129.  Thomou T, Mori MA, Dreyfuss JM, Konishi M, Sakaguchi M et al. 2017. Adipose-derived circulating miRNAs regulate gene expression in other tissues. Nature 542:450–55
     [Google Scholar]
130. 130.  Uebanso T, Taketani Y, Yamamoto H, Amo K, Ominami H et al. 2011. Paradoxical regulation of human FGF21 by both fasting and feeding signals: Is FGF21 a nutritional adaptation factor?. PLOS ONE 6:e22976
     [Google Scholar]
131. 131.  Veniant MM, Hale C, Helmering J, Chen MM, Stanislaus S et al. 2012. FGF21 promotes metabolic homeostasis via white adipose and leptin in mice. PLOS ONE 7:e40164
     [Google Scholar]
132. 132.  Veniant MM, Sivits G, Helmering J, Komorowski R, Lee J et al. 2015. Pharmacologic effects of FGF21 are independent of the “browning” of white adipose tissue. Cell Metab 21:731–38
     [Google Scholar]
133. 133.  von Holstein-Rathlou S, BonDurant LD, Peltekian L, Naber MC, Yin TC et al. 2016. FGF21 mediates endocrine control of simple sugar intake and sweet taste preference by the liver. Cell Metab 23:335–43
     [Google Scholar]
134. 134.  Wang X, Wei W, Krzeszinski JY, Wang Y, Wan Y 2015. A liver–bone endocrine relay by IGFBP1 promotes osteoclastogenesis and mediates FGF21-induced bone resorption. Cell Metab 22:811–24
     [Google Scholar]
135. 135.  Wei W, Dutchak PA, Wang X, Ding X, Wang X et al. 2012. Fibroblast growth factor 21 promotes bone loss by potentiating the effects of peroxisome proliferator-activated receptor γ. PNAS 109:3143–48
     [Google Scholar]
136. 136.  Wek SA, Zhu S, Wek RC 1995. The histidyl-tRNA synthetase-related sequence in the eIF-2α protein kinase GCN2 interacts with tRNA and is required for activation in response to starvation for different amino acids. Mol. Cell Biol. 15:4497–506
     [Google Scholar]
137. 137.  Wente W, Efanov AM, Brenner M, Kharitonenkov A, Koster A et al. 2006. Fibroblast growth factor-21 improves pancreatic β-cell function and survival by activation of extracellular signal-regulated kinase 1/2 and Akt signaling pathways. Diabetes 55:2470–78
     [Google Scholar]
138. 138.  Wilson GJ, Lennox BA, She P, Mirek ET, Al Baghdadi RJ et al. 2015. GCN2 is required to increase fibroblast growth factor 21 and maintain hepatic triglyceride homeostasis during asparaginase treatment. Am. J. Physiol. Endocrinol. Metab. 308:E283–93
     [Google Scholar]
139. 139.  Wu AL, Coulter S, Liddle C, Wong A, Eastham-Anderson J et al. 2011. FGF19 regulates cell proliferation, glucose and bile acid metabolism via FGFR4-dependent and independent pathways. PLOS ONE 6:e17868
     [Google Scholar]
140. 140.  Wu X, Ge H, Gupte J, Weiszmann J, Shimamoto G et al. 2007. Co-receptor requirements for fibroblast growth factor-19 signaling. J. Biol. Chem. 282:29069–72
     [Google Scholar]
141. 141.  Xu J, Lloyd DJ, Hale C, Stanislaus S, Chen M et al. 2009. Fibroblast growth factor 21 reverses hepatic steatosis, increases energy expenditure, and improves insulin sensitivity in diet-induced obese mice. Diabetes 58:250–59
     [Google Scholar]
142. 142.  Xu J, Stanislaus S, Chinookoswong N, Lau YY, Hager T et al. 2009. 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. 297:E1105–14
     [Google Scholar]
143. 143.  Yan Z, Kronemberger A, Blomme J, Call JA, Caster HM et al. 2017. Exercise leads to unfavourable cardiac remodelling and enhanced metabolic homeostasis in obese mice with cardiac and skeletal muscle autophagy deficiency. Sci. Rep. 7:7894
     [Google Scholar]
144. 144.  Yie J, Hecht R, Patel J, Stevens J, Wang W et al. 2009. FGF21 N- and C-termini play different roles in receptor interaction and activation. FEBS Lett 583:19–24
     [Google Scholar]
145. 145.  Yie J, Wang W, Deng L, Tam LT, Stevens J et al. 2012. Understanding the physical interactions in the FGF21/FGFR/β-Klotho complex: structural requirements and implications in FGF21 signaling. Chem. Biol. Drug Des. 79:398–410
     [Google Scholar]
146. 146.  Yilmaz Y, Eren F, Yonal O, Kurt R, Aktas B et al. 2010. Increased serum FGF21 levels in patients with nonalcoholic fatty liver disease. Eur. J. Clin. Investig. 40:887–92
     [Google Scholar]
147. 147.  Zhang J, Gupte J, Gong Y, Weiszmann J, Zhang Y et al. 2017. Chronic over-expression of fibroblast growth factor 21 increases bile acid biosynthesis by opposing FGF15/19 action. EBioMedicine 15:173–83
     [Google Scholar]
148. 148.  Zhang Y, Xie Y, Berglund ED, Coate KC, He TT et al. 2012. The starvation hormone, fibroblast growth factor-21, extends lifespan in mice. eLife 1:e00065
     [Google Scholar]
149. 149.  Zhao C, Liu Y, Xiao J, Liu L, Chen S et al. 2015. FGF21 mediates alcohol-induced adipose tissue lipolysis by activation of systemic release of catecholamine in mice. J. Lipid Res. 56:1481–91
     [Google Scholar]
150. 150.  Zhen EY, Jin Z, Ackermann BL, Thomas MK, Gutierrez JA 2016. Circulating FGF21 proteolytic processing mediated by fibroblast activation protein. Biochem. J. 473:605–14
     [Google Scholar]
151. 151.  Zimmerman CA, Leib DE, Knight ZA 2017. Neural circuits underlying thirst and fluid homeostasis. Nat. Rev. Neurosci. 18:459–69
     [Google Scholar]