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Exp Clin Endocrinol Diabetes 2020; 128(11): 752-770
DOI: 10.1055/a-0879-2968
DOI: 10.1055/a-0879-2968
Review
Circulating FGF21 Levels in Human Health and Metabolic Disease
Abstract
Human fibroblast growth factor 21 (FGF21) is primarily produced and secreted by the liver as a hepatokine. This hormone circulates to its target tissues (e. g., brain, adipose tissue), which requires two components, one of the preferred FGF receptor isoforms (FGFR1c and FGFR3c) and the co-factor beta-Klotho (KLB) to trigger downstream signaling pathways. Although targeting FGF21 signaling in humans by analogues and receptor agonists results in beneficial effects, e. g., improvements in plasma lipids and decreased body weight, it failed to recapitulate the improvements in glucose handling shown for many mouse models. FGF21’s role and metabolic effects in mice and its therapeutic potential have extensively been reviewed elsewhere. In this review we focus on circulating FGF21 levels in humans and their associations with disease and clinical parameters, focusing primarily on obesity and obesity-associated diseases such as type-2 diabetes. We provide a comprehensive overview on human circulating FGF21 levels under normal physiology and metabolic disease. We discuss the emerging field of inactivating FGF21 in human blood by fibroblast activation protein (FAP) and its potential clinical implications.
* Current address: Department of Molecular Biosciences, The Wenner- Gren Institute, Stockholm University, 106 91 Stockholm, Sweden, email: michaela.keuper@su.se
Publication History
Received: 03 December 2018
Received: 13 March 2019
Accepted: 18 March 2019
Article published online:
20 May 2019
© 2020. Thieme. All rights reserved.
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References
- 1 Nishimura T, Nakatake Y, Konishi M. et al. Identification of a novel FGF, FGF-21, preferentially expressed in the liver1. Biochim Biophys Acta BBA - Gene Struct Expr 2000; 1492: 203-206
- 2 Kharitonenkov A, Shiyanova TL, Koester A. et al. FGF-21 as a novel metabolic regulator. J Clin Invest 2005; 115: 1627-1635
- 3 Zhang J, Li Y. Fibroblast growth factor 21 analogs for treating metabolic disorders. Front Endocrinol 2015; 6: 168
- 4 Degirolamo C, Sabbà C, Moschetta A. Therapeutic potential of the endocrine fibroblast growth factors FGF19, FGF21 and FGF23. Nat Rev Drug Discov 2016; 15: 51-69
- 5 Petryszak R, Keays M, Tang YA. et al. Expression Atlas update—an integrated database of gene and protein expression in humans, animals and plants. Nucleic Acids Res 2016; 44: D746-D752
- 6 Kharitonenkov A, Adams AC. Inventing new medicines: The FGF21 story. Mol Metab 2013; 3: 221-229
- 7 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
- 8 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
- 9 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
- 10 Coate KC, Hernandez G, Thorne CA. et al. FGF21 is an exocrine pancreas secretagogue. Cell Metab 2017; 25: 472-480
- 11 Lee P, Linderman JD, Smith S. et al. Irisin and FGF21 are cold-induced endocrine activators of brown fat function in humans. Cell Metab 2014; 19: 302-309
- 12 Ogawa Y, Kurosu H, Yamamoto M. et al. Beta-Klotho is required for metabolic activity of fibroblast growth factor 21. Proc Natl Acad Sci USA 2007; 104: 7432-7437
- 13 Kharitonenkov A, Dunbar JD, Bina HA. et al. FGF-21/FGF-21 receptor interaction and activation is determined by beta-Klotho. J Cell Physiol 2008; 215: 1-7
- 14 Suzuki M, Uehara Y, Motomura-Matsuzaka K. et al. Beta-Klotho is required for fibroblast growth factor (FGF) 21 signaling through FGF receptor (FGFR) 1c and FGFR3c. Mol Endocrinol Baltim. Md 2008; 22: 1006-1014
- 15 Ding X, Boney-Montoya J, Owen BM. et al. β-Klotho is required for fibroblast growth factor 21 effects on growth and metabolism. Cell Metab 2012; 16: 387-393
- 16 Adams AC, Cheng CC, Coskun T. et al. FGF21 Requires β-klotho to Act in vivo. PLoS ONE 2012; 7 (11) e49977
- 17
Ornitz DM,
Itoh N.
The Fibroblast Growth Factor signaling pathway. Wiley Interdiscip Rev Dev Biol 2015;
4: 215-266
MissingFormLabel
- 18 Zhang X, Ibrahimi OA, Olsen SK. et al. Receptor Specificity of the Fibroblast Growth Factor Family The complete mammalian fgf family. J Biol Chem 2006; 281: 15694-15700
- 19 Tan BK, Hallschmid M, Adya R. et al. Fibroblast Growth Factor 21 (FGF21) in Human Cerebrospinal Fluid. Diabetes 2011; 60: 2758-2762
- 20 Staiger H, Keuper M, Berti L. et al. Fibroblast Growth Factor 21—Metabolic Role in Mice and Men. Endocr Rev 2017; 38: 468-488
- 21 Erickson A, Moreau R. The regulation of FGF21 gene expression by metabolic factors and nutrients. Horm Mol Biol Clin Investig 2016; 30 (1) 20160016
- 22 Owen BM, Mangelsdorf DJ, Kliewer SA. Tissue-specific actions of the metabolic hormones FGF15/19 and FGF21. Trends Endocrinol Metab TEM 2015; 26: 22-29
- 23 Fisher FM, Maratos-Flier E. Understanding the Physiology of FGF21. Annu Rev Physiol 2016; 78: 223-241
- 24 Lin X, Liu YB, Hu H. Metabolic role of fibroblast growth factor 21 in liver, adipose and nervous system tissues (Review). Biomed Rep 2017; 6: 495-502
- 25 Kharitonenkov A, DiMarchi R. FGF21 Revolutions: Recent Advances Illuminating FGF21 Biology and Medicinal Properties. Trends Endocrinol Metab TEM 2015; 26: 608-617
- 26 Woo YC, Xu A, Wang Y. et al. Fibroblast growth factor 21 as an emerging metabolic regulator: clinical perspectives. Clin Endocrinol (Oxf) 2013; 78: 489-496
- 27 Gälman C, Lundåsen T, Kharitonenkov A. et al. The circulating metabolic regulator FGF21 is induced by prolonged fasting and PPARalpha activation in man. Cell Metab 2008; 8: 169-174
- 28 Fazeli PK, Lun M, Kim SM. et al. FGF21 and the late adaptive response to starvation in humans. J Clin Invest 2015; 125: 4601-4611
- 29 Zhang X, Yeung DCY, Karpisek M. et al. Serum FGF21 levels are increased in obesity and are independently associated with the metabolic syndrome in humans. Diabetes 2008; 57: 1246-1253
- 30 Li H, Bao Y, Xu A. et al. Serum fibroblast growth factor 21 is associated with adverse lipid profiles and gamma-glutamyltransferase but not insulin sensitivity in Chinese subjects. J Clin Endocrinol Metab 2009; 94: 2151-2156
- 31 Hanks LJ, Gutiérrez OM, Bamman MM. et al. Circulating levels of fibroblast growth factor-21 increase with age independently of body composition indices among healthy individuals. J Clin Transl Endocrinol 2015; 2: 77-82
- 32 Taniguchi H, Tanisawa K, Sun X. et al. Cardiorespiratory fitness and visceral fat are key determinants of serum fibroblast growth factor 21 concentration in Japanese men. J Clin Endocrinol Metab 2014; 99: E1877-E1884
- 33 Bisgaard A, Sørensen K, Johannsen TH. et al. Significant gender difference in serum levels of fibroblast growth factor 21 in Danish children and adolescents. Int J Pediatr Endocrinol 2014; 2014: 7
- 34 Kralisch S, Tönjes A, Krause K. et al. Fibroblast growth factor-21 serum concentrations are associated with metabolic and hepatic markers in humans. J Endocrinol 2013; 216: 135-143
- 35 Dushay J, Chui PC, Gopalakrishnan GS. et al. Increased fibroblast growth factor 21 in obesity and nonalcoholic fatty liver disease. Gastroenterology 2010; 139: 456-463
- 36 Tyynismaa H, Raivio T, Hakkarainen A. et al. Liver fat but not other adiposity measures influence circulating FGF21 levels in healthy young adult twins. J Clin Endocrinol Metab 2011; 96: E351-E355
- 37 Vinales KL, Begaye B, Bogardus C. et al. FGF21 is a Hormonal Mediator of the Human “Thrifty” Metabolic Phenotype. Diabetes September 2018; db180696
- 38 Nygaard EB, Ørskov C, Almdal TP. et al. Fasting decreases plasma FGF21 in obese subjects and the expression of FGF21 receptors in adipose tissue in both lean and obese subjects. J Endocrinol 2018; 239 (01) 73-80
- 39 Christodoulides C, Dyson P, Sprecher D. et al. Circulating fibroblast growth factor 21 is induced by peroxisome proliferator-activated receptor agonists but not ketosis in man. J Clin Endocrinol Metab 2009; 94: 3594-3601
- 40 Solon-Biet SM, Cogger VC, Pulpitel T. et al. Defining the nutritional and metabolic context of FGF21 using the geometric framework. Cell Metab 2016; 24: 555-565
- 41 Pérez-Martí A, Garcia-Guasch M, Tresserra-Rimbau A. et al. A low-protein diet induces body weight loss and browning of subcutaneous white adipose tissue through enhanced expression of hepatic fibroblast growth factor 21 (FGF21). Mol Nutr Food Res 2017; 61: 1600725
- 42 Markova M, Pivovarova O, Hornemann S. et al. Isocaloric diets high in animal or plant protein reduce liver fat and inflammation in individuals with type 2 diabetes. Gastroenterology 2017; 152: 571-585.e8
- 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 Fontana L, Cummings NE, Arriola Apelo SI. et al. Decreased consumption of branched-chain amino acids improves metabolic health. Cell Rep 2016; 16: 520-530
- 45 von Holstein-Rathlou S, BonDurant 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
- 46 Dushay JR, Toschi E, Mitten EK. et al. Fructose ingestion acutely stimulates circulating FGF21 levels in humans. Mol Metab 2015; 4: 51-57
- 47 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
- 48 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
- 49 Frayling TM, Beaumont RN, Jones SE. et al. 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 2018; 23: 327-336
- 50 Søberg S, Sandholt CH, Jespersen NZ. et al. FGF21 is a sugar-induced hormone associated with sweet intake and preference in humans. Cell Metab 2017; 25: 1045-1053.e6
- 51 Søberg S, Andersen ES, Dalgaard NB. et al. FGF21, a liver hormone that inhibits alcohol intake in mice, increases in human circulation after acute alcohol ingestion and sustained binge drinking at Oktoberfest. Mol Metab 2018; 11: 96-103
- 52 Desai BN, Singhal G, Watanabe M. et al. Fibroblast growth factor 21 (FGF21) is robustly induced by ethanol and has a protective role in ethanol associated liver injury. Mol Metab 2017; 6: 1395-1406
- 53 Song P, Zechner C, Hernandez G. et al. The hormone FGF21 stimulates water drinking in response to ketogenic diet and alcohol. Cell Metab 2018; 27: 1338-1347.e4
- 54 Schumann G, Liu C, O’Reilly P. et al. KLB is associated with alcohol drinking, and its gene product β-Klotho is necessary for FGF21 regulation of alcohol preference. Proc Natl Acad Sci 2016; 113: 14372-14377
- 55 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
- 56 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
- 57 Douris N, Stevanovic DM, Fisher ffolliott M. et al. Central fibroblast growth factor 21 browns white fat via sympathetic action in male mice. Endocrinology 2015; 156: 2470-2481
- 58 Santoso P, Nakata M, Shiizaki K. et al. Fibroblast growth factor 21, assisted by elevated glucose, activates paraventricular nucleus NUCB2/Nesfatin-1 neurons to produce satiety under fed states. Sci Rep 2017; 7: 45819
- 59 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
- 60 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
- 61 Tong X, Muchnik M, Chen Z. et al. Transcriptional repressor E4-binding protein 4 (E4BP4) regulates metabolic hormone fibroblast growth factor 21 (FGF21) during circadian cycles and feeding. J Biol Chem 2010; 285: 36401-36409
- 62 Oishi K, Uchida D, Ishida N. Circadian expression of FGF21 is induced by PPARalpha activation in the mouse liver. FEBS Lett 2008; 582: 3639-3642
- 63 Yu H, Xia F, Lam KSL. et al. Circadian rhythm of circulating fibroblast growth factor 21 is related to diurnal changes in fatty acids in humans. Clin Chem 2011; 57: 691-700
- 64 Mai K, Andres J, Biedasek K. et al. Free Fatty Acids Link Metabolism and Regulation of the Insulin-Sensitizing Fibroblast Growth Factor-21. Diabetes 2009; 58: 1532-1538
- 65 Andersen B, Beck-Nielsen H, Højlund K. Plasma FGF21 displays a circadian rhythm during a 72-h fast in healthy female volunteers. Clin Endocrinol (Oxf) 2011; 75: 514-519
- 66 Wang Y, Solt LA, Burris TP. Regulation of FGF21 expression and secretion by retinoic acid receptor-related orphan receptor alpha. J Biol Chem 2010; 285: 15668-15673
- 67 Lundberg J, Höybye C, Krusenstjerna-Hafstrøm T. et al. Influence of growth hormone on circulating fibroblast growth factor 21 levels in humans. J Intern Med 2013; 274: 227-232
- 68 Chen W, Hoo RL, Konishi M. et al. Growth hormone induces hepatic production of fibroblast growth factor 21 through a mechanism dependent on lipolysis in adipocytes. J Biol Chem 2011; 286: 34559-34566
- 69 Patel R, Bookout AL, Magomedova L. et al. Glucocorticoids regulate the metabolic hormone FGF21 in a feed-forward loop. Mol Endocrinol Baltim. Md 2015; 29: 213-223
- 70 Jelenik T, Dille M, Müller-Lühlhoff S. et al. FGF21 regulates insulin sensitivity following long-term chronic stress. Mol Metab 2018; 16: 126-138
- 71 Lynch L, Hogan AE, Duquette D. et al. iNKT Cells Induce FGF21 for Thermogenesis and Are Required for Maximal Weight Loss in GLP1 Therapy. Cell Metab 2016; 24: 510-519
- 72 Hojman P, Pedersen M, Nielsen AR. et al. Fibroblast growth factor-21 is induced in human skeletal muscles by hyperinsulinemia. Diabetes 2009; 58: 2797-2801
- 73 Vienberg SG, Brøns C, Nilsson E. et al. Impact of short-term high-fat feeding and insulin-stimulated FGF21 levels in subjects with low birth weight and controls. Eur J Endocrinol 2012; 167: 49-57
- 74 Mraz M, Bartlova M, Lacinova Z. et al. Serum concentrations and tissue expression of a novel endocrine regulator fibroblast growth factor-21 in patients with type 2 diabetes and obesity. Clin Endocrinol (Oxf) 2009; 71: 369-375
- 75 Samms RJ, Lewis JE, Norton L. et al. FGF21 Is an insulin-dependent postprandial hormone in adult humans. J Clin Endocrinol Metab 2017; 102: 3806-3813
- 76 Kruse R, Vienberg SG, Vind BF. et al. Effects of insulin and exercise training on FGF21, its receptors and target genes in obesity and type 2 diabetes. Diabetologia 2017; 60: 2042-2051
- 77 Kim KH, Kim SH, Min Y-K. et al. Acute exercise induces FGF21 expression in mice and in healthy humans. PloS One 2013; 8: e63517
- 78 Cuevas-Ramos D, Almeda-Valdés P, Meza-Arana CE. et al. Exercise increases serum fibroblast growth factor 21 (FGF21) levels. PloS One 2012; 7: e38022
- 79 Slusher AL, Whitehurst M, Zoeller RF. et al. Attenuated fibroblast growth factor 21 response to acute aerobic exercise in obese individuals. Nutr Metab Cardiovasc Dis NMCD 2015; 25: 839-845
- 80 Hansen JS, Clemmesen JO, Secher NH. et al. Glucagon-to-insulin ratio is pivotal for splanchnic regulation of FGF-21 in humans. Mol Metab 2015; 4: 551-560
- 81 Morville T, Sahl RE, Trammell SAJ. et al. Divergent effects of resistance and endurance exercise on plasma bile acids, FGF19, and FGF21 in humans. JCI Insight 2018; 3 (15) e122737
- 82 Hansen JS, Pedersen BK, Xu G. et al. Exercise-Induced secretion of fgf21 and follistatin are blocked by pancreatic clamp and impaired in type 2 diabetes. J Clin Endocrinol Metab 2016; 101: 2816-2825
- 83 Habegger KM, Stemmer K, Cheng C. et al. Fibroblast growth factor 21 mediates specific glucagon actions. Diabetes 2013; 62: 1453-1463
- 84 Arafat AM, Kaczmarek P, Skrzypski M. et al. Glucagon increases circulating fibroblast growth factor 21 independently of endogenous insulin levels: A novel mechanism of glucagon-stimulated lipolysis?. Diabetologia 2013; 56: 588-597
- 85 Inagaki T, Dutchak P, Zhao G. et al. Endocrine regulation of the fasting response by PPARalpha-mediated induction of fibroblast growth factor 21. Cell Metab 2007; 5: 415-425
- 86 Hotta Y, Nakamura H, Konishi M. et al. 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
- 87 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
- 88 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
- 89 Pan X, Shao Y, Wu F. et al. FGF21 Prevents Angiotensin II-Induced Hypertension and Vascular Dysfunction by Activation of ACE2/Angiotensin-(1–7) Axis in Mice. Cell Metab 2018; 27: 1323-1337.e5
- 90 Han SH, Choi SH, Cho BJ. et al. Serum fibroblast growth factor-21 concentration is associated with residual renal function and insulin resistance in end-stage renal disease patients receiving long-term peritoneal dialysis. Metabolism 2010; 59: 1656-1662
- 91 Semba RD, Crasto C, Strait J. et al. Elevated serum fibroblast growth factor 21 is associated with hypertension in community-dwelling adults. J Hum Hypertens 2013; 27: 397-399
- 92 Turner T, Chen X, Zahner M. et al. FGF21 increases water intake, urine output and blood pressure in rats. PLOS ONE 2018; 13: e0202182
- 93 Zhao C, Liu Y, Xiao J. et al. FGF21 mediates alcohol-induced adipose tissue lipolysis by activation of systemic release of catecholamine in mice. J Lipid Res 2015; 56: 1481-1491
- 94 Chartoumpekis DV, Habeos IG, Ziros PG. et al. Brown adipose tissue responds to cold and adrenergic stimulation by induction of FGF21. Mol Med Camb Mass 2011; 17: 736-740
- 95 Hanssen MJW, Broeders E, Samms RJ. et al. Serum FGF21 levels are associated with brown adipose tissue activity in humans. Sci Rep 2015; 5: 10275
- 96 Eto K, Tumenbayar B, Nagashima S. et al. Distinct association of serum FGF21 or adiponectin levels with clinical parameters in patients with type 2 diabetes. Diabetes Res Clin Pract 2010; 89: 52-57
- 97 Ong KL, Rye K-A, O’Connell R. et al. Long-term fenofibrate therapy increases fibroblast growth factor 21 and retinol-binding protein 4 in subjects with type 2 diabetes. J Clin Endocrinol Metab 2012; 97: 4701-4708
- 98 Araki E, Yamashita S, Arai H. et al. Effects of Pemafibrate, a Novel Selective PPARα Modulator, on Lipid and Glucose Metabolism in Patients With Type 2 Diabetes and Hypertriglyceridemia: A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Trial. Diabetes Care 2018; 41: 538-546
- 99 Ong K-L, Januszewski AS, O’Connell R. et al. The relationship of fibroblast growth factor 21 with cardiovascular outcome events in the Fenofibrate Intervention and Event Lowering in Diabetes study. Diabetologia 2015; 58: 464-473
- 100 Li K, Li L, Yang M. et al. Effects of rosiglitazone on fasting plasma fibroblast growth factor-21 levels in patients with type 2 diabetes mellitus. Eur J Endocrinol 2009; 161: 391-395
- 101 Kim KH, Jeong YT, Kim SH. et al. Metformin-induced inhibition of the mitochondrial respiratory chain increases FGF21 expression via ATF4 activation. Biochem Biophys Res Commun 2013; 440: 76-81
- 102 Fan H, Sun X, Zhang H. et al. Effect of metformin on fibroblast growth Factor-21 levels in patients with newly diagnosed type 2 diabetes. Diabetes Technol Ther 2016; 18: 120-126
- 103 Cuevas-Ramos D, Almeda-Valdes P, Gómez-Pérez FJ. et al. 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 2010; 163: 469-477
- 104 Reinehr T, Woelfle J, Wunsch R. et al. Fibroblast growth factor 21 (FGF-21) and its relation to obesity, metabolic syndrome, and nonalcoholic fatty liver in children: a longitudinal analysis. J Clin Endocrinol Metab 2012; 97: 2143-2150
- 105 Lee Y, Lim S, Hong E-S. et al. Serum FGF21 concentration is associated with hypertriglyceridaemia, hyperinsulinaemia and pericardial fat accumulation, independently of obesity, but not with current coronary artery status. Clin Endocrinol (Oxf) 2014; 80: 57-64
- 106 Akyildiz ZI, Polat S, Yurekli BS. et al. Epicardial fat, body mass index, and triglyceride are independent contributors of serum fibroblast growth factor 21 level in obese premenopausal women. J Endocrinol Invest 2015; 38: 361-366
- 107 Heilbronn LK, Campbell LV, Xu A. et al. Metabolically protective cytokines adiponectin and fibroblast growth factor-21 are increased by acute overfeeding in healthy humans. PloS One 2013; 8: e78864
- 108 Iggman D, Rosqvist F, Larsson A. et al. Role of dietary fats in modulating cardiometabolic risk during moderate weight gain: A randomized double-blind overfeeding trial (LIPOGAIN study). J Am Heart Assoc 2014; 3: e001095
- 109 Woelnerhanssen B, Peterli R, Steinert RE. et al. Effects of postbariatric surgery weight loss on adipokines and metabolic parameters: Comparison of laparoscopic Roux-en-Y gastric bypass and laparoscopic sleeve gastrectomy – a prospective randomized trial. Surg Obes Relat Dis Off J Am Soc Bariatr Surg 2011; 7: 561-568
- 110 Jansen PLM, van Werven J, Aarts E. et al. Alterations of hormonally active fibroblast growth factors after Roux-en-Y gastric bypass surgery. Dig Dis Basel Switz 2011; 29: 48-51
- 111 Crujeiras AB, Gomez-Arbelaez D, Zulet MA. et al. Plasma FGF21 levels in obese patients undergoing energy-restricted diets or bariatric surgery: A marker of metabolic stress?. Int J Obes 2005 2017; 41: 1570-1578
- 112 Lips MA, de Groot GH, Berends FJ. et al. Calorie restriction and Roux-en-Y gastric bypass have opposing effects on circulating FGF21 in morbidly obese subjects. Clin Endocrinol (Oxf) 2014; 81: 862-870
- 113 Gómez-Ambrosi J, Gallego-Escuredo JM, Catalán V. et al. FGF19 and FGF21 serum concentrations in human obesity and type 2 diabetes behave differently after diet- or surgically-induced weight loss. Clin Nutr Edinb Scotl 2017; 36: 861-868
- 114 BonDurant LD, Ameka M, Naber MC. et al. FGF21 regulates metabolism through adipose-dependent and -independent mechanisms. Cell Metab 2017; 25: 935-944.e4
- 115 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
- 116 Rodríguez A, Ezquerro S, Méndez-Giménez L. et al. Revisiting the adipocyte: A model for integration of cytokine signaling in the regulation of energy metabolism. Am J Physiol-Endocrinol Metab 2015; 309: E691-E714
- 117 Stefan N, Kantartzis K, Machann J. et al. Identification and characterization of metabolically benign obesity in humans. Arch Intern Med 2008; 168: 1609-1616
- 118 Böhm A, Halama A, Meile T. et al. Metabolic signatures of cultured human adipocytes from metabolically healthy versus unhealthy obese individuals. PloS One 2014; 9: e93148
- 119 Das SK, Ma L, Sharma NK. Adipose tissue gene expression and metabolic health of obese adults. Int J Obes 2005; 2015 39: 869-873
- 120 Hwang Y-C, Hayashi T, Fujimoto WY. et al. Visceral abdominal fat accumulation predicts the conversion of metabolically healthy obese subjects to an unhealthy phenotype. Int J Obes 2005 2015; 39: 1365-1370
- 121 Berti L, Irmler M, Zdichavsky M. et al. Fibroblast growth factor 21 is elevated in metabolically unhealthy obesity and affects lipid deposition, adipogenesis, and adipokine secretion of human abdominal subcutaneous adipocytes. Mol Metab 2015; 4: 519-527
- 122 Chen C, Cheung BMY, Tso AWK. et al. High plasma level of fibroblast growth factor 21 is an Independent predictor of type 2 diabetes: A 5.4-year population-based prospective study in Chinese subjects. Diabetes Care 2011; 34: 2113-2115
- 123 Cheng X, Zhu B, Jiang F. et al. Serum FGF-21 levels in type 2 diabetic patients. Endocr Res 2011; 36: 142-148
- 124 Semba RD, Sun K, Egan JM. et al. Relationship of serum fibroblast growth factor 21 with abnormal glucose metabolism and insulin resistance: The Baltimore Longitudinal Study of Aging. J Clin Endocrinol Metab 2012; 97: 1375-1382
- 125 Bobbert T, Schwarz F, Fischer-Rosinsky A. et al. Fibroblast growth factor 21 predicts the metabolic syndrome and type 2 diabetes in Caucasians. Diabetes Care 2013; 36: 145-149
- 126 Novotny D, Vaverkova H, Karasek D. et al. Evaluation of total adiponectin, adipocyte fatty acid binding protein and fibroblast growth factor 21 levels in individuals with metabolic syndrome. Physiol Res 2014; 63: 219-228
- 127 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
- 128 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
- 129 Giannini C, Feldstein AE, Santoro N. et al. Circulating levels of FGF-21 in obese youth: Associations with liver fat content and markers of liver damage. J Clin Endocrinol Metab 2013; 98: 2993-3000
- 130 Yilmaz Y, Eren F, Yonal O. et al. Increased serum FGF21 levels in patients with nonalcoholic fatty liver disease. Eur J Clin Invest 2010; 40: 887-892
- 131 Dasarathy S, Yang Y, McCullough AJ. et al. Elevated hepatic fatty acid oxidation, high plasma fibroblast growth factor 21, and fasting bile acids in nonalcoholic steatohepatitis. Eur J Gastroenterol Hepatol 2011; 23: 382-388
- 132 Braun LR, Feldpausch MN, Czerwonka N. et al. Fibroblast growth factor 21 decreases after liver fat reduction via growth hormone augmentation. Growth Horm IGF Res Off J Growth Horm Res Soc Int IGF Res Soc 2017; 37: 1-6
- 133 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 randomised controlled trial. Diabetologia 2011; 54: 3093-3100
- 134 Shen J, Chan HL-Y, Wong GL-H. et al. Non-invasive diagnosis of non-alcoholic steatohepatitis by combined serum biomarkers. J Hepatol 2012; 56: 1363-1370
- 135 Wu G, Li H, Fang Q. et al. Complementary Role of Fibroblast Growth Factor 21 and Cytokeratin 18 in Monitoring the Different Stages of Nonalcoholic Fatty Liver Disease. Sci Rep 2017; 7: 5095
- 136 Liu J, Xu Y, Hu Y. et al. The role of fibroblast growth factor 21 in the pathogenesis of non-alcoholic fatty liver disease and implications for therapy. Metabolism 2015; 64: 380-390
- 137 Stefan N, Kantartzis K, Häring H-U. Causes and metabolic consequences of Fatty liver. Endocr Rev 2008; 29: 939-960
- 138 Chow WS, Xu A, Woo YC. et al. Serum fibroblast growth factor-21 levels are associated with carotid atherosclerosis independent of established cardiovascular risk factors. Arterioscler Thromb Vasc Biol 2013; 33: 2454-2459
- 139 Kim WJ, Kim SS, Lee HC. et al. Association between serum fibroblast growth factor 21 and coronary artery disease in patients with type 2 diabetes. J Korean Med Sci 2015; 30: 586-590
- 140 Bellos I, Fitrou G, Pergialiotis V et al. Serum levels of adipokines in gestational
diabetes: A systematic review. J Endocrinol Invest November 2018
MissingFormLabel
- 141 Xiao Y, Liu L, Xu A. et al. Serum fibroblast growth factor 21 levels are related to subclinical atherosclerosis in patients with type 2 diabetes. Cardiovasc Diabetol 2015; 14: 72
- 142 Ulu SM, Yuksel S, Altuntaş A. et al. Associations between serum hepcidin level, FGF-21 level and oxidative stress with arterial stiffness in CAPD patients. Int Urol Nephrol 2014; 46: 2409-2414
- 143 Yang SJ, Hong HC, Choi HY. et al. Effects of a three-month combined exercise programme on fibroblast growth factor 21 and fetuin-A levels and arterial stiffness in obese women. Clin Endocrinol (Oxf) 2011; 75: 464-469
- 144 An S-Y, Lee MS, Yi S-A. et al. Serum fibroblast growth factor 21 was elevated in subjects with type 2 diabetes mellitus and was associated with the presence of carotid artery plaques. Diabetes Res Clin Pract 2012; 96: 196-203
- 145 Zhang X, Hu Y, Zeng H. et al. Serum fibroblast growth factor 21 levels is associated with lower extremity atherosclerotic disease in Chinese female diabetic patients. Cardiovasc Diabetol 2015; 14: 32
- 146 Lin Z, Wu Z, Yin X. et al. Serum levels of FGF-21 are increased in coronary heart disease patients and are independently associated with adverse lipid profile. PloS One 2010; 5: e15534
- 147 Shen Y, Ma X, Zhou J. et al. Additive relationship between serum fibroblast growth factor 21 level and coronary artery disease. Cardiovasc Diabetol 2013; 12: 124
- 148 Zhang W, Chu S, Ding W. et al. Serum level of fibroblast growth factor 21 is independently associated with acute myocardial infarction. PloS One 2015; 10: e0129791
- 149 Jin Q-R, Bando Y, Miyawaki K. et al. Correlation of fibroblast growth factor 21 serum levels with metabolic parameters in Japanese subjects. J Med Investig JMI 2014; 61: 28-34
- 150 Stepan H, Kley K, Hindricks J. et al. Serum levels of the adipokine fibroblast growth factor-21 are increased in preeclampsia. Cytokine 2013; 62: 322-326
- 151 Lee CH, Woo YC, Chow WS. et al. Role of Circulating Fibroblast Growth Factor 21 Measurement in Primary Prevention of Coronary Heart Disease Among Chinese Patients With Type 2 Diabetes Mellitus. J Am Heart Assoc 2017; 6: e005344
- 152 Lakhani I, Gong M, Wong WT. et al. Fibroblast growth factor 21 in cardio-metabolic disorders: a systematic review and meta-analysis. Metabolism 2018; 83: 11-17
- 153 Stein S, Stepan H, Kratzsch J. et al. Serum fibroblast growth factor 21 levels in gestational diabetes mellitus in relation to insulin resistance and dyslipidemia. Metabolism 2010; 59: 33-37
- 154 Gómez-Sámano MÁ, Grajales-Gómez M, Zuarth-Vázquez JM. et al. Fibroblast growth factor 21 and its novel association with oxidative stress. Redox Biol 2017; 11: 335-341
- 155 Anuwatmatee S, Tang S, Wu BJ. et al. Fibroblast growth factor 21 in chronic kidney disease. Clin Chim Acta Int. J Clin Chem 2019; 489: 196-202
- 156 Esteghamati A, Khandan A, Momeni A. et al. Circulating levels of fibroblast growth factor 21 in early-stage diabetic kidney disease. Ir J Med Sci 2017; 186: 785-794
- 157 Lee CH, Hui EYL, Woo YC. et al. Circulating fibroblast growth factor 21 levels predict progressive kidney disease in subjects with type 2 diabetes and normoalbuminuria. J Clin Endocrinol Metab 2015; 100: 1368-1375
- 158 Li S, Wang N, Guo X. et al. Fibroblast growth factor 21 regulates glucose metabolism in part by reducing renal glucose reabsorption. Biomed Pharmacother 2018; 108: 355-366
- 159 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
- 160 Kharitonenkov A, Wroblewski VJ, Koester A. et al. The metabolic state of diabetic monkeys is regulated by fibroblast growth factor-21. Endocrinology 2007; 148: 774-781
- 161 Huang J, Ishino T, Chen G. et al. Development of a novel long-acting antidiabetic FGF21 mimetic by targeted conjugation to a scaffold antibody. J Pharmacol Exp Ther 2013; 346: 270-280
- 162 Mu J, Pinkstaff J, Li Z. et al. FGF21 Analogs of sustained action enabled by orthogonal biosynthesis demonstrate enhanced antidiabetic pharmacology in rodents. Diabetes 2012; 61: 505-512
- 163 Christoffersen B, Straarup EM, Lykkegaard K. et al. FGF21 decreases food intake and body weight in obese Göttingen minipigs. Diabetes Obes Metab 2019; 21: 592-600
- 164 Stein S, Bachmann A, Lössner U. et al. Serum levels of the adipokine fgf21 depend on renal function. Diabetes Care 2009; 32: 126-128
- 165 Lin Z, Zhou Z, Liu Y. et al. Circulating FGF21 levels are progressively increased from the early to end stages of chronic kidney diseases and are associated with renal function in Chinese. PloS One 2011; 6: e18398
- 166 Kharitonenkov A, Beals JM, Micanovic R. et al. Rational design of a fibroblast growth factor 21-based clinical candidate, LY2405319. PloS One 2013; 8: e58575
- 167 Gaich G, Chien JY, Fu H. et al. The Effects of LY2405319, an FGF21 analog, in obese human subjects with type 2 diabetes. Cell Metab 2013; 18: 333-340
- 168 Dong JQ, Rossulek M, Somayaji VR. et al. Pharmacokinetics and pharmacodynamics of PF-05231023, a novel long-acting FGF21 mimetic, in a first-in-human study. Br J Clin Pharmacol 2015; 80: 1051-1063
- 169 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
- 170 Kim AM, Somayaji VR, Dong JQ. et al. 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 2017; 19: 1762-1772
- 171 Zhen EY, Jin Z, Ackermann BL. et al. Circulating FGF21 proteolytic processing mediated by fibroblast activation protein. Biochem J 2016; 473: 605-614
- 172 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
- 173 Coppage AL, Heard KR, DiMare MT. et al. Human FGF-21 Is a substrate of fibroblast activation protein. PloS One 2016; 11: e0151269
- 174 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
- 175 Micanovic R, Raches DW, Dunbar JD. et al. Different roles of N- and C- termini in the functional activity of FGF21. J Cell Physiol 2009; 219: 227-234
- 176 Agrawal A, Parlee S, Perez-Tilve D. et al. Molecular elements in FGF19 and FGF21 defining KLB/FGFR activity and specificity. Mol Metab 2018; 13: 45-55
- 177 Adams AC, Coskun T, Rovira ARI. et al. Fundamentals of FGF19 & FGF21 action in vitro and in vivo. PloS One 2012; 7: e38438
- 178 Parmar B, Lewis JE, Samms RJ. et al. Eccentric exercise increases circulating fibroblast activation protein α but not bioactive fibroblast growth factor 21 in healthy humans. Exp Physiol 2018; 103: 876-883
- 179 Sánchez-Garrido MA, Habegger KM, Clemmensen C. et al. Fibroblast activation protein (FAP) as a novel metabolic target. Mol Metab 2016; 5: 1015-1024
- 180 Panaro BL, Coppage AL, Beaudry JL. et al. Fibroblast activation protein is dispensable for control of glucose homeostasis and body weight in mice. Mol Metab 2019; 19: 65-74
- 181 Keane FM, Yao T-W, Seelk S. et al. Quantitation of fibroblast activation protein (FAP)-specific protease activity in mouse, baboon and human fluids and organs. FEBS Open Bio 2013; 4: 43-54
- 182 Hamson EJ, Keane FM, Tholen S. et al. Understanding fibroblast activation protein (FAP): Substrates, activities, expression and targeting for cancer therapy. PROTEOMICS - Clin Appl 2014; 8: 454-463
- 183 Park JE, Lenter MC, Zimmermann RN. et al. Fibroblast activation protein, a dual specificity serine protease expressed in reactive human tumor stromal fibroblasts. J Biol Chem 1999; 274: 36505-36512
- 184 Christiansen VJ, Jackson KW, Lee KN. et al. Effect of fibroblast activation protein and α2-antiplasmin cleaving enzyme on collagen Types I, III, and IV. Arch Biochem Biophys 2007; 457: 177-186
- 185 Keane FM, Nadvi NA, Yao T-W. et al. Neuropeptide Y, B-type natriuretic peptide, substance P and peptide YY are novel substrates of fibroblast activation protein-α. FEBS J 2011; 278: 1316-1332
- 186 Garin-Chesa P, Old LJ, Rettig WJ. Cell surface glycoprotein of reactive stromal fibroblasts as a potential antibody target in human epithelial cancers. Proc Natl Acad Sci 1990; 87: 7235-7239
- 187 Brennen WN, Isaacs JT, Denmeade SR. Rationale behind targeting fibroblast activation protein–expressing carcinoma-associated fibroblasts as a novel chemotherapeutic strategy. Mol Cancer Ther 2012; 11: 257-266
- 188 Wen Y, Wang C-T, Ma T-T. et al. Immunotherapy targeting fibroblast activation protein inhibits tumor growth and increases survival in a murine colon cancer model. Cancer Sci 2010; 101: 2325-2332
- 189 Roberts EW, Deonarine A, Jones JO. et al. Depletion of stromal cells expressing fibroblast activation protein-α from skeletal muscle and bone marrow results in cachexia and anemia. J Exp Med 2013; 210: 1137-1151
- 190 Tran E, Chinnasamy D, Yu Z. et al. Immune targeting of fibroblast activation protein triggers recognition of multipotent bone marrow stromal cells and cachexia. J Exp Med 2013; 210: 1125-1135
- 191 Uitte de Willige S, Malfliet JJMC, Janssen HLA. et al. Increased N-terminal cleavage of alpha-2-antiplasmin in patients with liver cirrhosis. J Thromb Haemost JTH 2013; 11: 2029-2036
- 192 Williams KH, Ribeiro de AJV, Prakoso E. et al. Lower serum fibroblast activation protein shows promise in the exclusion of clinically significant liver fibrosis due to non-alcoholic fatty liver disease in diabetes and obesity. Diabetes Res Clin Pract 2015; 108: 466-472
- 193 Uitte de Willige S, Keane FM, Bowen DG. et al. Circulating fibroblast activation protein activity and antigen levels correlate strongly when measured in liver disease and coronary heart disease. PLoS ONE 2017; 12 (06) e0178987
- 194 Wong PF, Gall MG, Bachovchin WW. et al. Neuropeptide Y is a physiological substrate of fibroblast activation protein: Enzyme kinetics in blood plasma and expression of Y2R and Y5R in human liver cirrhosis and hepatocellular carcinoma. Peptides 2016; 75: 80-95
- 195 Umberger TS, Sloan JH, Chen J. et al. Novel sandwich immunoassays for the measurement of total and active FGF21. Bioanalysis 2014; 6: 3283-3293
- 196 Migdal A, Comte S, Rodgers M. et al. Fibroblast growth factor 21 and fructose dynamics in humans: FGF21 fructose dose response. Obes Sci Pract 2018; 4: 483-489
- 197 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 2005 2015; 39: 121-129
- 198 Fisher FM, Chui PC, Antonellis PJ. et al. Obesity is a fibroblast growth factor 21 (FGF21)-resistant state. Diabetes 2010; 59: 2781-2789
- 199 Markan KR. Defining “FGF21 Resistance” during obesity: Controversy, criteria and unresolved questions. F1000Research 2018; 7: 289
- 200 Tanajak P. Letter to the Editor: Parameters, Characteristics, and Criteria for Defining the Term ‘FGF21 Resistance’. Endocrinology 2017; 158: 1523-1524
- 201 Hale C, Chen MM, Stanislaus S. et al. Lack of overt FGF21 resistance in two mouse models of obesity and insulin resistance. Endocrinology 2012; 153: 69-80