Abstract
Background:
Fibroblast growth factor 21 (FGF21) has been suggested to be an endocrine signal of nutritional status and an active regulator of metabolism. However, there is no agreement on the effect of weight-loss therapies on circulating levels of FGF21 in humans.
Objective:
To assess FGF21 circulating levels in adiposity excess and after different weight-loss strategies prescribed in five different groups from four independent centers.
Subjects and methods:
Body composition, ketosis, insulin sensitivity and FGF21 were evaluated in 181 excess body weight and 14 normal-weight subjects. From the excess body weight patients, two independent groups (discovery cohort; n=20 and validation cohort; n=28) undertook a very low-calorie ketogenic (VLCK) diet, a third group followed a low-calorie (LC) diet (n=84) and other two groups underwent bariatric surgery (discovery cohort; n=24 and validation cohort; n=25). The follow-up was 4 to 6 or 12 months, respectively.
Results:
FGF21 levels were higher in excess body weight patients than in normal-weight subjects. The energy-restriction therapy to lose weight induced a significant decrease, with respect to baseline, in circulating levels of FGF21 (VLCK: −62.5 pg ml−1 or −14.8 pg ml−1 and LC diet: −67.9 pg ml−1). There were no differences in FGF21 levels between both energy-restriction treatments. On the contrary, after bariatric surgery morbidly obese patients showed a significant increase in FGF21, especially 1 month after surgery (148.8 pg ml−1 higher than baseline). The FGF21 differential changes occur concomitantly with a non-induced ketosis situation (0.66±0.56 mm) in bariatric surgery, and an improvement in adiposity and insulin sensitivity induced by the three therapies.
Conclusions:
FGF21 levels were reduced after energy-restricted treatments and severely increased after bariatric surgery, independently of the weight reduction magnitude, insulin sensitivity or ketosis. Therefore, FGF21 appears to be a marker of severe nutritional stress.
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References
Funk LM, Jolles SA, Voils CI . Obesity as a disease: has the AMA resolution had an impact on how physicians view obesity? Surg Obes Relat Dis 2016; 12: 1431–1435.
Collaboration NCDRF. Trends in adult body-mass index in 200 countries from 1975 to 2014: a pooled analysis of 1698 population-based measurement studies with 19.2 million participants. Lancet 2016; 387: 1377–1396.
Apovian CM, Aronne LJ, Bessesen DH, McDonnell ME, Murad MH, Pagotto U et al. Pharmacological management of obesity: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2015; 100: 342–362.
Bray GA, Fruhbeck G, Ryan DH, Wilding JP . Management of obesity. Lancet 2016; 387: 1947–1956.
Pi-Sunyer X, Obesity S, Prediabetes I . Liraglutide in weight management. N Engl J Med 2015; 373: 1781–1782.
Heymsfield SB, Wadden TA . Mechanisms, pathophysiology, and management of obesity. N Engl J Med 2017; 376: 254–266.
Crujeiras AB, Diaz-Lagares A, Moreno-Navarrete JM, Sandoval J, Hervas D, Gomez A et al. Genome-wide DNA methylation pattern in visceral adipose tissue differentiates insulin-resistant from insulin-sensitive obese subjects. Transl Res 2016; 178: e5.
Roman S, Agil A, Peran M, Alvaro-Galue E, Ruiz-Ojeda FJ, Fernandez-Vazquez G et al. Brown adipose tissue and novel therapeutic approaches to treat metabolic disorders. Transl Res 2015; 165: 464–479.
Bostrom P, Wu J, Jedrychowski MP, Korde A, Ye L, Lo JC et al. A PGC1-alpha-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature 2012; 481: 463–468.
Crujeiras AB, Zulet MA, Abete I, Amil M, Carreira MC, Martinez JA et al. Interplay of atherogenic factors, protein intake and betatrophin levels in obese-metabolic syndrome patients treated with hypocaloric diets. Int J Obes 2016; 40: 403–410.
Rodriguez A, Becerril S, Ezquerro S, Mendez-Gimenez L, Fruhbeck G . Cross-talk between adipokines and myokines in fat browning. Acta Physiol 2017; 2019: 362–381.
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.
Samms RJ, Fowler MJ, Cooper S, Emmerson P, Coskun T, Adams AC et al. Photoperiodic regulation of FGF21 production in the Siberian hamster. Hormon Behav 2014; 66: 180–185.
Kharitonenkov A, DiMarchi R . FGF21 revolutions: recent advances illuminating FGF21 biology and medicinal properties. Trends Endocrinol Metab 2015; 26: 608–617.
Laeger T, Henagan TM, Albarado DC, Redman LM, Bray GA, Noland RC et al. FGF21 is an endocrine signal of protein restriction. J Clin Invest 2014; 124: 3913–3922.
Zhang X, Yeung DC, Karpisek M, Stejskal D, Zhou ZG, Liu F et al. Serum FGF21 levels are increased in obesity and are independently associated with the metabolic syndrome in humans. Diabetes 2008; 57: 1246–1253.
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 USA 2010; 107: 12553–12558.
Giralt M, Gavalda-Navarro A, Villarroya F . Fibroblast growth factor-21, energy balance and obesity. Mol Cell Endocrinol 2015; 418 (Pt 1): 66–73.
Fazeli PK, Lun M, Kim SM, Bredella MA, Wright S, Zhang Y et al. FGF21 and the late adaptive response to starvation in humans. J Clin Invest 2015; 125: 4601–4611.
Kharitonenkov A, Larsen P . FGF21 reloaded: challenges of a rapidly growing field. Trends Endocrinol Metab 2011; 22: 81–86.
Solon-Biet SM, Cogger VC, Pulpitel T, Heblinski M, Wahl D, McMahon AC et al. Defining the nutritional and metabolic context of FGF21 using the geometric framework. Cell Metab 2016; 24: 555–565.
Fisher FM, Chui PC, Antonellis PJ, Bina HA, Kharitonenkov A, Flier JS et al. Obesity is a fibroblast growth factor 21 (FGF21)-resistant state. Diabetes 2010; 59: 2781–2789.
Gallego-Escuredo JM, Gomez-Ambrosi J, Catalan V, Domingo P, Giralt M, Fruhbeck G 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.
Lips MA, de Groot GH, Berends FJ, Wiezer R, van Wagensveld BA, Swank DJ et al. Calorie restriction and Roux-en-Y gastric bypass have opposing effects on circulating FGF21 in morbidly obese subjects. Clin Endocrinol 2014; 81: 862–870.
Gomez-Ambrosi J, Gallego-Escuredo JM, Catalan V, Rodriguez A, Domingo P, Moncada R 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 2017; 36: 861–868.
Mai K, Schwarz F, Bobbert T, Andres J, Assmann A, Pfeiffer AF et al. Relation between fibroblast growth factor-21, adiposity, metabolism, and weight reduction. Metabolism 2011; 60: 306–311.
Mraz M, Bartlova M, Lacinova Z, Michalsky D, Kasalicky M, Haluzikova D 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 2009; 71: 369–375.
de Luis D, Domingo JC, Izaola O, Casanueva FF, Bellido D, Sajoux I . Effect of DHA supplementation in a very low-calorie ketogenic diet in the treatment of obesity: a randomized clinical trial. Endocrine 2016; 54: 111–122.
Gomez-Arbelaez D, Bellido D, Castro AI, Ordonez-Mayan L, Carreira J, Galban C et al. Body composition changes after very low-calorie-ketogenic diet in obesity evaluated by three standardized methods. J Clin Endocrinol Metab 2016; 102: 488–498.
Moreno B, Bellido D, Sajoux I, Goday A, Saavedra D, Crujeiras AB et al. Comparison of a very low-calorie-ketogenic diet with a standard low-calorie diet in the treatment of obesity. Endocrine 2014; 47: 793–805.
Moreno B, Crujeiras AB, Bellido D, Sajoux I, Casanueva FF . Obesity treatment by very low-calorie-ketogenic diet at two years: reduction in visceral fat and on the burden of disease. Endocrine 2016; 54: 681–690.
EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA). Scientific opinion on the essential composition of total diet replacements for weight control. EFSA Journal 2015; 13: 3957.
Crujeiras AB, Cabia B, Carreira MC, Amil M, Cueva J, Andrade S et al. Secreted factors derived from obese visceral adipose tissue regulate the expression of breast malignant transformation genes. Int J Obes 2016; 40: 514–523.
Crujeiras AB, Pardo M, Arturo RR, Navas-Carretero S, Zulet MA, Martinez JA et al. Longitudinal variation of circulating irisin after an energy restriction-induced weight loss and following weight regain in obese men and women. Am J Hum Biol 2014; 26: 198–207.
Lopez-Legarrea P, de la Iglesia R, Abete I, Bondia-Pons I, Navas-Carretero S, Forga L et al. Short-term role of the dietary total antioxidant capacity in two hypocaloric regimes on obese with metabolic syndrome symptoms: the RESMENA randomized controlled trial. Nutr Metab (Lond) 2013; 10: 22.
Crujeiras AB, Goyenechea E, Abete I, Lage M, Carreira MC, Martinez JA et al. Weight regain after a diet-induced loss is predicted by higher baseline leptin and lower ghrelin plasma levels. J Clin Endocrinol Metab 2010; 95: 5037–5044.
Brolin RE, Gorman RC, Milgrim LM, Kenler HA . Multivitamin prophylaxis in prevention of post-gastric bypass vitamin and mineral deficiencies. Int J Obes 1991; 15: 661–667.
Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC . Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985; 28: 412–419.
de la Iglesia R, Lopez-Legarrea P, Abete I, Bondia-Pons I, Navas-Carretero S, Forga L et al. A new dietary strategy for long-term treatment of the metabolic syndrome is compared with the American Heart Association (AHA) guidelines: the MEtabolic Syndrome REduction in NAvarra (RESMENA) project. Br J Nutr 2014; 111: 643–652.
Badman MK, Koester A, Flier JS, Kharitonenkov A, Maratos-Flier E . Fibroblast growth factor 21-deficient mice demonstrate impaired adaptation to ketosis. Endocrinology 2009; 150: 4931–4940.
Jornayvaz FR, Jurczak MJ, Lee HY, Birkenfeld AL, Frederick DW, Zhang D et al. A high-fat, ketogenic diet causes hepatic insulin resistance in mice, despite increasing energy expenditure and preventing weight gain. Am J Physiol Endocrinol Metab 2010; 299: E808–E815.
Domouzoglou EM, Maratos-Flier E . Fibroblast growth factor 21 is a metabolic regulator that plays a role in the adaptation to ketosis. Am J Clin Nutr 2011; 93: 901 S–5.
Aminian A, Kashyap SR, Burguera B, Punchai S, Sharma G, Froylich D et al. Incidence and clinical features of diabetic ketoacidosis after bariatric and metabolic surgery. Diabetes Care 2016; 39: e50–e53.
Nicoletti CF, de Oliveira BA, Barbin R, Marchini JS, Salgado Junior W, Nonino CB . Red meat intolerance in patients submitted to gastric bypass: a 4-year follow-up study. Surg Obes Relat Dis 2015; 11: 842–846.
Schiavo L, Scalera G, Sergio R, De Sena G, Pilone V, Barbarisi A . Clinical impact of Mediterranean-enriched-protein diet on liver size, visceral fat, fat mass, and fat-free mass in patients undergoing sleeve gastrectomy. Surg Obes Relat Dis 2015; 11: 1164–1170.
Faintuch J, Matsuda M, Cruz ME, Silva MM, Teivelis MP, Garrido AB Jr et al. Severe protein-calorie malnutrition after bariatric procedures. Obes Surg 2004; 14: 175–181.
Moize V, Geliebter A, Gluck ME, Yahav E, Lorence M, Colarusso T et al. Obese patients have inadequate protein intake related to protein intolerance up to 1 year following Roux-en-Y gastric bypass. Obes Surg 2003; 13: 23–28.
Thibault R, Pichard C . Overview on nutritional issues in bariatric surgery. Curr Opin Clin Nutr Metab Care 2016; 19: 484–490.
Ozaki Y, Saito K, Nakazawa K, Konishi M, Itoh N, Hakuno F et al. Rapid increase in fibroblast growth factor 21 in protein malnutrition and its impact on growth and lipid metabolism—ERRATUM. Br J Nutr 2015; 114: 1535–1536.
Astrup A, Raben A, Geiker N . The role of higher protein diets in weight control and obesity-related comorbidities. Int J Obes 2015; 39: 721–726.
Khan FH, Shaw L, Zhang W, Salazar Gonzalez RM, Mowery S, Oehrle M et al. Fibroblast growth factor 21 correlates with weight loss after vertical sleeve gastrectomy in adolescents. Obesity 2016; 24: 2377–2383.
Crujeiras AB, Parra D, Milagro FI, Goyenechea E, Larrarte E, Margareto J et al. Differential expression of oxidative stress and inflammation related genes in peripheral blood mononuclear cells in response to a low-calorie diet: a nutrigenomics study. OMICS 2008; 12: 251–261.
Galman C, Lundasen T, Kharitonenkov A, Bina HA, Eriksson M, Hafstrom I et al. The circulating metabolic regulator FGF21 is induced by prolonged fasting and PPARalpha activation in man. Cell Metab 2008; 8: 169–174.
Domingo P, Gallego-Escuredo JM, Domingo JC, Gutierrez Mdel M, Mateo MG, Fernandez I et al. Serum FGF21 levels are elevated in association with lipodystrophy, insulin resistance and biomarkers of liver injury in HIV-1-infected patients. AIDS 2010; 24: 2629–2637.
Dushay J, Chui PC, Gopalakrishnan GS, Varela-Rey M, Crawley M, Fisher FM et al. Increased fibroblast growth factor 21 in obesity and nonalcoholic fatty liver disease. Gastroenterology 2010; 139: 456–463.
Mutanen A, Heikkila P, Lohi J, Raivio T, Jalanko H, Pakarinen MP . Serum FGF21 increases with hepatic fat accumulation in pediatric onset intestinal failure. J Hepatol 2014; 60: 183–190.
Shen J, Chan HL, Wong GL, Choi PC, Chan AW, Chan HY et al. Non-invasive diagnosis of non-alcoholic steatohepatitis by combined serum biomarkers. J Hepatol 2012; 56: 1363–1370.
Micanovic R, Raches DW, Dunbar JD, Driver DA, Bina HA, Dickinson CD et al. Different roles of N- and C- termini in the functional activity of FGF21. J Cell Physiol 2009; 219: 227–234.
Yie J, Hecht R, Patel J, Stevens J, Wang W, Hawkins N et al. FGF21 N- and C-termini play different roles in receptor interaction and activation. FEBS Lett 2009; 583: 19–24.
Coppage AL, Heard KR, DiMare MT, Liu Y, Wu W, Lai JH et al. Human FGF-21 Is a substrate of fibroblast activation protein. PLoS One 2016; 11: e0151269.
Dunshee DR, Bainbridge TW, Kljavin NM, Zavala-Solorio J, Schroeder AC, Chan R et al. Fibroblast activation protein cleaves and inactivates fibroblast growth factor 21. J Biol Chem 2016; 291: 5986–5996.
Acknowledgements
We thank all the subjects who participated in this study and the research group implicated in the project, especially the people who performed the field work (I Abete, R de la Iglesia, P Lopez-Legarrea, S Perez and BE Martinez de Morentin) as well as technical assistance (M Amil and V Ciaurriz). We also thank Prof Francesc Villarroya for his advice and encouragement. This work was supported by the PronoKal Group and grants from the Fondo de Investigacion Sanitaria, PE13/00024 and PI14/01012 research projects and CIBERobn (CB06/003) from the Instituto de Salud Carlos III (ISCIII)-Subdireccion General de Evaluacion y Fomento de la Investigación; Fondo Europeo de Desarrollo Regional (FEDER), the Health Department of the Xunta de Galicia (GRC2014/034), and the Health Department of the Government of Navarra (48/2009), Spain and Linea Especial ‘Nutrition, Obesity and Health’ (University of Navarra LE/97). DGA is grateful to the Colombian Department of Science, Technology and Innovation (COLCIENCIAS) as a recipient of their pre-doctoral scholarship to support his work.
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The funding source had no involvement in the study design, recruitment of patients, study interventions, data collection or interpretation of the results. The Pronokal personnel (IS) was involved in the study design and revised the final version of the manuscript, without intervention in the analysis of data, statistical evaluation and final interpretation of the results of this study.
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ABC, DB and FFC received advisory board fees and or research grants from Pronokal Protein Supplies Spain. IS is Medical Director of Pronokal Spain. The remaining authors declare no conflict of interest.
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Crujeiras, A., Gomez-Arbelaez, D., Zulet, M. et al. Plasma FGF21 levels in obese patients undergoing energy-restricted diets or bariatric surgery: a marker of metabolic stress?. Int J Obes 41, 1570–1578 (2017). https://doi.org/10.1038/ijo.2017.138
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DOI: https://doi.org/10.1038/ijo.2017.138
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