FGF21: A Novel Regulator of Glucose and Lipid Metabolism and
                    Whole-Body Energy Balance

Ewa Szczepańska; Małgorzata Gietka-Czernel

doi:10.1055/a-1778-4159

Hormone and Metabolic Research, Inhaltsverzeichnis

Horm Metab Res 2022; 54(04): 203-211
DOI: 10.1055/a-1778-4159

Review

FGF21: A Novel Regulator of Glucose and Lipid Metabolism and Whole-Body Energy Balance

Ewa Szczepańska

¹Department of Endocrinology, Centre of Postgraduate Medical Education, Warsaw, Poland

,

Małgorzata Gietka-Czernel

¹Department of Endocrinology, Centre of Postgraduate Medical Education, Warsaw, Poland

› Institutsangaben

Abstract

Fibroblast growth factor (FGF) 21 is a recently recognized metabolic regulator that evokes interest due to its beneficial action of maintaining whole-body energy balance and protecting the liver from excessive triglyceride production and storage. Together with FGF19 and FGF23, FGF21 belongs to the FGF family with hormone-like activity. Serum FGF21 is generated primarily in the liver under nutritional stress stimuli like prolonged fasting or the lipotoxic diet, but also during increased mitochondrial and endoplasmic reticulum stress. FGF21 exerts its endocrine action in the central nervous system and adipose tissue. Acting in the ventromedial hypothalamus, FGF21 diminishes simple sugar intake. In adipose tissue, FGF21 promotes glucose utilization and increases energy expenditure by enhancing adipose tissue insulin sensitivity and brown adipose tissue thermogenesis. Therefore, FGF21 favors glucose consumption for heat production instead of energy storage. Furthermore, FGF21 specifically acts in the liver, where it protects hepatocytes from metabolic stress caused by lipid overload. FGF21 stimulates hepatic fatty acid oxidation and reduces lipid flux into the liver by increasing peripheral lipoprotein catabolism and reducing adipocyte lipolysis. Paradoxically, and despite its beneficial action, FGF21 is elevated in insulin resistance states, that is, fatty liver, obesity, and type 2 diabetes.

Key words

FGF21 - insulin sensitivity - appetite - blood glucose - triglycerides - NAFLD

Volltext

Referenzen

References
1 von Holstein-Rathlou S, Bon Durant LD, Peltekian L. et al. FGF21 mediates endocrine control of simple sugar intake and sweet taste preference by the liver. Cell Metab 2016; 23: 335-343
2 Talukdar S, Owen BM, Song P. et al. FGF21 regulates sweet and alcohol preference. Cell Metab 2016; 23: 344-349
3 Baruch A, Wong C, China LW. et al. Antibody-mediated activation of the FGFR1/Klothoβ complex corrects metabolic dysfunction and alters food preference in obese humans. Proc Natl Acad Sci USA 2020; 117: 28992-29000
4 Owen BM, Ding X, Morgan DA. et al. FGF21 acts centrally to induce sympathetic nerve activity, energy expenditure, and weight loss. Cell Metab 2014; 20: 670-677
5 Douris N, Stevanovic DM, Fisher FM. et al. Central fibroblast growth factor 21 browns white fat via sympathetic action in male mice. Endocrinology 2015; 156: 2470-2481
6 Xu J, Lloyd DJ, Hale C. et al. Fibroblast growth factor 21 reverses hepatic steatosis, increases energy expenditure, and improves insulin sensitivity in diet-induced obese mice. Diabetes 2009; 58: 250-259
7 Kharitonenkov A, Wroblewski VJ, Koester A. et al. The metabolic state of diabetic monkey is regulated by fibroblast growth factor-21. Endocrinology 2007; 148: 774-781
8 Talukdar S, Zhou Y, Li D. et al. 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 2016; 23: 427-440
9 Kaufman A, Abuqayyas L, Denney WS. et al. AKR-001, an Fc-FGF21 analog, showed sustained pharmacodynamic effects on insulin sensitivity and lipid metabolism in type 2 diabetes patients. Cell Rep Med 2020; 1: 100057
10 Sanyal A, Charles ED, Neuschwander-Tetri BA. et al. Pegbelfermin (BMS-986036), a PEGylated fibroblast growth factor 21 analogue, in patients with non-alcoholic steatohepatitis: a randomised, double-blind, placebo-controlled, phase 2a trial. Lancet 2019; 392: 2705-2717
11 Ameka M, Markan KR, Morgan DA. et al. Liver derived FGF21 maintains core body temperature during acute cold exposure. Sci Rep 2019; 9: 630
12 Turer AT, Scherer PE. Adiponectin: mechanistic impacts and clinical implications. Diabetologia 2012; 55: 2319-2326
13 Arner P, Pettersson A, Mitchell PJ. et al. FGF21 attenuates lipolysis in human adipocytes: a possible link to improved insulin sensitivity. FEBS Lett 2008; 582: 1725-1730
14 BonDurant LD, Pothoff MJ. Fibroblast growth factor 21: a versatile regulator of metabolic homeostasis. Annu Rev Nutr 2018; 38: 173-196
15 Satapi S, He TT, Inagaki T. et al. Partial resistance to peroxisome proliferator-activated receptor-alpha agonists in ZDF rats is associated with defective hepatic mitochondrial metabolism. Diabetes 2008; 57: 2012-2021
16 Fisher FM, Chui PC, Antonellis PJ. et al. Obesity is a fibroblast growth factor 21 (FGF21)- resistant state. Diabetes 2010; 59: 2781-2789
17 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: 245-251
18 Beenken A, Mohammadi M. The FGF family: biology, pathophysiology and therapy. Nat Rev Drug Discov 2009; 8: 235-253
19 Beenken A, Mohammadi M. The structural biology of the FGF19 subfamily. Adv Exp Med Biol 2012; 728: 1-24
20 Kurosu H, Choi M, Ogawa Y. et al. Tissue specific expression of bKlotho and fibroblast growth factor (FGF) receptor isoforms determines metabolic activity of FGF19 and FGF21. J Biol Chem 2007; 282: 26687-26695
21 Suzuki M, Uehara Y, Motomura-Matsuzaka K. et al. bKlotho is required for fibroblast growth factor (FGF) 21 signaling through FGF receptor (FGFR) 1c and FGFR3c. Mol Endocrinol 2008; 22: 1006-1014
22 Martin A, David V, Quarles LD. Regulation and function of the FGF23/klotho endocrine pathways. Phys Rev 2012; 92: 131-155
23 Kharitonenkov A, Shiyanova TL, Koester A. et al. FGF21 as a novel metabolic regulator. J Clin Invest 2005; 115: 1627-1635
24 Yie J, Wang W, Deng L. et al. Understanding the physical interactions in the FGF21/FGFR/b-Klotho complex: structural requirements and implications in FGF21 signaling. Chem Biol Drug Des 2012; 79: 398-410
25 Chau MDL, Gao J, Yang Q. et al. Fibroblast growth factor 21 regulates energy metabolism by activating the AMPK-SIRT1-PGC-1a pathway. Proc Natl Acad Sci USA 2010; 107: 12553-12558
26 Díaz-Delfín J, Hondares E, Iglesias R. et al. TNF-a represses b-Klotho expression and impairs FGF21 action in adipose cells: involvement of JNK1 in the FGF21pathway. Endocrinology 2012; 153: 4238-4245
27 Gallego-Escuredo JM, Gómez-Ambrosi J, Catalan V. et al. Opposite alterations in FGF21 and FGF19 levels and disturbed expression of the receptor machinery for endocrine FGFs in obese patients. Int J Obes 2015; 39: 121-129
28 Adams AC, Coskun T, Cheng CC. et al. Fibroblast growth factor 21 is not required for the anti-diabetic actions of the thiazoladinediones. Mol Metab 2013; 2: 205-214
29 Samson SL, Sathyanarayana P, Jogi M. et al. Exenatide decreases hepatic fibroblast growth factor 21 resistance in non-alcoholic fatty liver disease in a mouse model of obesity and in a randomized controlled trial. Diabetologia 2011; 54: 3093-3100
30 Wang L, Mazagova M, Pan C. et al. YIPF6 controls sorting of FGF21 into COPII vesicles and promotes obesity. Proc Natl Acad Sci USA 2019; 116: 15184-15193
31 Dunshee DR, Bainbridge TW, Kljavin NM. et al. Fibroblast activation protein cleaves and inactivates fibroblast growth factor 21. J Biol Chem 2016; 291: 5986-5996
32 Yie J, Hecht R, Patel J. et al. FGF21 N- and C-termini play different roles in receptor interaction and activation. FEBS Lett 2009; 583: 19-24
33 Izumiya Y, Bina HA, Ouchi N. et al. FGF21 is an Akt-regulated myokine. FEBS Lett 2008; 582: 3805-3810
34 Tezze C, Romanello V, Desbats MA. et al. Age-associated loss of OPA1 in muscle impacts muscle mass, metabolic homeostasis, systemic inflammation, and epithelial senescence. Cell Metab 2017; 25: 1374-1389.e6
35 Keipert S, Ost M, Johann K. et al. Skeletal muscle mitochondrial uncoupling drives endocrine cross-talk through the induction of FGF21 as a myokine. Am J Physiol Endocrinol Metab 2014; 306: E469-E482
36 Keipert S, Kutschke M, Lamp D. et al. Genetic disruption of uncoupling protein 1 in mice renders brown adipose tissue a significant source of FGF21 secretion. Mol Metab 2015; 4: 537-542
37 Restelli LM, Oettinghaus B, Halliday M. et al. Neuronal mitochondrial dysfunction activates the integrated stress response to induce fibroblast growth factor 21. Cell Rep 2018; 24: 1407-1414
38 Lehtonen JM, Forsström S, Bottani E. et al. FGF21 is a biomarker for mitochondrial translation and mtDNA maintenance disorders. Neurology 2016; 87: 2290-2299
39 Markan KR, Naber MC, Ameka MK. et al. Circulating FGF21 is liver derived and enhances glucose uptake during refeeding and overfeeding. Diabetes 2014; 63: 4057-4063
40 Dushay JR, Toschi E, Mitten EK. et al. Fructose ingestion acutely stimulates circulating FGF21 levels in humans. Mol Metab 2014; 4: 51-57
41 Lundsgaard AM, Fritzen AM, Sjøberg KA. et al. Circulating FGF21 in humans is potently induced by short term overfeeding of carbohydrates. Mol Metab 2016; 6: 22-29
42 Gälman C, Lundåsen T, Kharitonenkov A. et al. The circulating metabolic regulator FGF21 is induced by prolonged fasting and PPARα activation in man. Cell Metab 2008; 8: 169-174
43 Laeger T, Henagan TM, Albarado DC. et al. FGF21 is an endocrine signal of protein restriction. J Clin Invest 2014; 124: 3913-3922
44 Inagaki T, Dutchak P, Zhao G. et al. Endocrine regulation of the fasting response by PPARα-mediated induction of fibroblast growth factor 21. Cell Metab 2007; 5: 415-425
45 Badman MK, Pissios P, Kennedy AR. et al. Hepatic fibroblast growth factor 21 is regulated by PPARa and is a key mediator of hepatic lipid metabolism in ketotic states. Cell Metab 2007; 5: 426-437
46 Badman MK, Koester A, Flier JS. et al. Fibroblast growth factor 21-deficient mice demonstrate impaired adaptation to ketosis. Endocrinology 2009; 150: 4931-4940
47 Pothoff MJ, Inagaki T, Satapati S. et al. FGF21 induces PGC-1a and regulates carbohydrate and fatty acid metabolism during the adaptive starvation response. Proc Natl Acad Sci U S A 2009; 106: 10853-10858
48 Fisher FM, Estall JL, Adams AC. et al. Integrated regulation of hepatic metabolism by fibroblast growth factor 21 (FGF21) in vivo. Endocrinology 2011; 152: 2996-3004
49 DeSousa-Coehlo AL, Marrero PF, Haro D. Activating transcription factor 4-dependent induction of FGF21 during amino acid deprivation. Biochem J 2012; 443: 165-171
50 Shimuzu N, Maruyama T, Yoshikawa N. et al. A muscle-liver-fat signalling axis is essential for central control of adaptive adipose remodeling. Nat Commun 2015; 6: 6693
51 Fisher FM, Chui PC, Nasser IA. et al. Fibroblast growth factor 21 limits lipotoxicity by promoting hepatic fatty acid activation in mice on methionine and choline-deficient diets. Gastroenterology 2014; 147: 1073-1083.e6
52 Tanaka N, Takahashi S, Zhang Y. et al. Role of fibroblast growth factor 21 in the early stage of NASH induced by methionine- and choline-deficient diet. Biochim Biophys Acta 2015; 1852: 1242-1252
53 Maida A, Zota A, Sjøberg KA. et al. A liver stress-endocrine nexus promotes metabolic integrity during dietary protein dilution. J Clin Invest 2016; 126: 3263-3278
54 Iron A, Montagner A, Benhamed F. et al. A specific ChREBP and PPARα cross-talk is required for the glucose-mediated FGF21 response. Cell Rep 2017; 21: 403-416
55 Jizuka K, Takeda J, Horikawa Y. Glucose induces FGF21 mRNA expression through ChREBP activation in rat hepatocytes. FEBS Lett 2009; 583: 2882-2886
56 Sánchez J, Palou A, Picó C. 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 2009; 150: 5341-5350
57 Geng L, Lam KSL, Xu A. The therapeutic potential of FGF21 in metabolic diseases: from bench to clinic. Nat Rev Endocrinol 2020; 16: 654-667
58 Ye D, Wang Y, Li H. et al. Fibroblast growth factor 21 protects against acetaminophen-induced hepatotoxicity by potentiating peroxisome proliferator-activated receptor coactivator protein-1a-mediated antioxidant capacity in mice. Hepatology 2014; 60: 977-989
59 Kim SH, Kim KH, Kim HK. et al. Fibroblast growth factor 21 participates in adaptation to endoplasmic reticulum stress and attenuates obesity-induced hepatic metabolic stress. Diabetologia 2015; 58: 809-818
60 Schlein C, Talukdar S, Heine M. et al. FGF21 lowers plasma triglycerides by accelerating lipoprotein catabolism in white and brown adipose tissues. Cell Metab 2016; 23: 441-453
61 Gong Q, Hu Z, Zhang F. et al. Fibroblast growth factor 21 improves hepatic insulin sensitivity by inhibiting mammalian target of rapamycin complex 1 in mice. Hepatology 2016; 64: 425-438
62 Liang Q, Zhong L, Zhang J. et al. FGF21 maintains glucose homeostasis by mediating the cross talk between liver and brain during prolonged fasting. Diabetes 2014; 63: 4064-4075
63 Foltz IN, Hu S, King C. et al. Treating diabetes and obesity with an FGF21-mimetic antibody activating the βKlotho/FGFR1c receptor complex. Sci Transl Med 2012; 4: 162ra153
64 Kan M, Wu X, Wang F, McKeehan WL. Specificity for fibroblast growth factors determined by heparan sulfate in a binary complex with the receptor kinase. J Biol Chem 1999; 274: 15947-15952
65 Huang X, Yang C, Jin C. et al. Resident hepatocyte fibroblast growth factor receptor 4 limits hepatocarcinogenesis. Mol Carcinog 2009; 48: 553-562
66 Lan T, Morgan DA, Rahmouni K. et al. FGF19, FGF21, and an FGFR1/beta-Klotho-activating antibody act on the nervous system to regulate body weight and glycemia. Cell Metab 2017; 26: 709-718.e703
67 Holland WL, Adams AC, Brozinick JT. et al. An FGF21-adiponectin-ceramide axis controls energy expenditure and insulin action in mice. Cell Metab 2013; 17: 790-797
68 Lin Z, Tian H, Lam KSL. et al. Adiponectin mediates the metabolic effects of FGF21 on glucose homeostasis and insulin sensitivity in mice. Cell Metab 2013; 17: 779-789
69 BonDurant LD, Ameka M, Naber MC. et al. FGF21 regulates metabolism through adipose-dependent and -independent mechanisms. Cell Metab 2017; 25: 935-944.e4
70 Gaich G, Chien JY, Fu H. et al. The effects of LY2405319, an FGF21 analogue, in obese human subjects with type 2 diabetes. Cell Metab 2013; 18: 333-340
71 Li H, Fang Q, Gao F. et al. Fibroblast growth factor 21 levels are increased in nonalcoholic fatty liver disease patients and are correlated with hepatic triglyceride. J Hepatol 2010; 53: 934-940
72 Yan H, Xia M, Chang X. et al. Circulating fibroblast growth factor 21 levels are closely associated with hepatic fat content: a cross-sectional study. PLoS One 2011; 6: e24895
73 Ge X, Chen C, Hui X, Wang Y. et al. Fibroblast growth factor 21 induces glucose transporter-1 expression through activation of the serum response factor/Ets-like protein-1 in adipocytes. J Biol Chem 2011; 286: 34533-34541
74 Xu J, Stanislaus S, Chinookoswong N. et al. 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
75 Ding X, Boney-Montoya J, Owen BM. et al. βKlotho is required for fibroblast growth factor 21 effects on growth and metabolism. Cell Metab 2012; 16: 387-393
76 Véniant MM, Hale C, Helmering J. et al. FGF21 promotes metabolic homeostasis via white adipose and leptin in mice. PLoS One 2012; 7: e40164
77 Bartlet A, Bruns OT, Reimer R. et al. Brown adipose tissue activity controls triglyceride clearance. Nat Med 2011; 17: 200-205
78 Orava J, Nuutila P, Lidell ME. et al. Different metabolic responses of human brown adipose tissue to activation by cold and insulin. Cell Metab 2011; 14: 272-279
79 Hondares E, Rosell M, Gonzalez FJ. et al. Hepatic FGF21 expression is induced at birth via PPARα in response to milk intake and contributes to thermogenic activation of neonatal brown fat. Cell Metab 2010; 11: 206-212
80 Kwon MM, O’Dwyer SM, Baker RK. et al. FGF21-mediated improvements in glucose clearance require uncoupling protein 1. Cell Rep 2015; 13: 1521-1527
81 Li X, Ge H, Weiszmann J. et al. Inhibition of lipolysis may contribute to the acute regulation of plasma FFA and glucose by FGF21 in ob/ob mice. FEBS Lett 2009; 583: 3230-3234
82 Berglund ED, Li CY, Bina HA. et al. Fibroblast growth factor 21 controls glycemia via regulation of hepatic glucose flux and insulin sensitivity. Endocrinology 2009; 150: 4084-4093
83 Adams AC, Yang C, Coscun T. et.al. The breadth of FGF21’s metabolic actions are governed by FGFR1 in adipose tissue. Mol Met 2012; 2: 31-37
84 Han MS, Perry RJ, Camporez JP. et al. A feed-forward regulatory loop in adipose tissue promotes signalling by the hepatokine FGF21. Genes Dev 2021; 35: 133-146
85 Jensen-Cody SO, Flippo KH, Claflin KE. et al. FGF21 signals to glutamatergic neurons in the ventromedial hypothalamus to suppress carbohydrate intake. Cell Metab 2020; 32: 273-286.e276
86 Bookout AL, de Groot MHM, Owen BM. et al. FGF21 regulates metabolism and circadian behavior by acting on the nervous system. Nat Med 2013; 19: 1147-1152
87 Flippo KH, Pothoff MJ. Metabolic messengers: FGF21. Nat Met 2021; 3: 309-317
88 Samms RJ, Smith DP, Cheng CC. et al. Discrete aspects of FGF21 in vivo pharmacology do not require UCP1. Cell Rep 2015; 11: 991-999
89 Véniant MM, Sivits G, Helmering J. et al. Pharmacologic effects of FGF21 are independent of the “browning” of white adipose tissue. Cell Metab 2015; 21: 731-738
90 Chu AY, Workalemahu T, Paynter NP. et al. Novel locus including FGF21 is associated with dietary macronutrient intake. Hum Mol Genet 2013; 22: 1895-1902
91 Tanaka T, Ngwa JS, van Rooij FJA. et al. Genome-wide meta-analysis of observational studies shows common genetic variants associated with macronutrient intake. Am J Clin Nutr 2013; 97: 1395-1402
92 Søberg S, Sandholt CH, Jespersen NJ. et al. FGF21 is a sugar-induced hormone associated with sweet intake and preference in humans. Cell Metab 2017; 25: 1045-1053.e6
93 Hondares E, Iglesias R, Giralt A. et al. Thermogenic activation induces FGF21 expression and release in brown adipose tissue. J Biol Chem 2011; 286: 12983-12990
94 Chartoumpekis DV, Habeos IG, Ziros PG. et al. Brown adipose tissue responds to cold and adrenergic stimulation by induction of FGF21. Mol Med 2011; 17: 736-740
95 Lee P, Brychta RJ, Linderman J. et al. Mild cold exposure modulates fibroblast growth factor 21 (FGF21) diurnal rhythm in humans: relationship between FGF21 levels, lipolysis, and cold-induced thermogenesis. J Clin Endocrinol Metab 2013; 98: E98-E102
96 Fisher FM, Kleiner S, Douris N. et al. FGF21 regulates PGC-1a and browning of white adipose tissues in adaptive thermogenesis. Genes Dev 2012; 26: 271-281
97 Dutchak PA, Katafuchi T, Bookout AL. et al. Fibroblast growth factor-21 regulates PPARγ activity and the antidiabetic actions of thiazolidinediones. Cell 2012; 148: 556-567
98 Charles ED, Neuschwander-Tetri BA, Frias JP. et al. Pegbelfermin (BMS-98036)PEGylated FGF21, in patients with obesity and type 2 diabetes: results from a randomized phase 2 study. Obesity 2019; 27: 41-49
99 Depaoli A, Phung V, Bashir MR. et al. NGM313, a novel activator of beta- klotho/FGFR1c, improves insulin resistance and reduces hepatic fat in obese, nondiabetic subjects [abstract 140-LB]. Diabetes 2019; 68: 140-1
100 Charoenphandhu N, Suntornsaratoon P, Krishnamra N. et al. Fibroblast growth factor-21 restores insulin sensitivity but induces aberrant bone microstructure in obese insulin-resistant rats. J. Bone Min Metab 2017; 35: 142-149