The Role and Potential Therapeutic Implications of the Fibroblast Growth Factors in Energy Balance and Type 2 Diabetes
- 920 Downloads
Purpose of Review
Obesity and its associated metabolic diseases have reached epidemic proportions worldwide, reducing life expectancy and quality of life. Several drugs have been tested to treat these diseases but many of them have damaging side effects. Consequently, there is an urgent need to develop more effective therapies. Recently, endocrine fibroblast growth factors (FGFs) have become attractive targets in the treatment of metabolic diseases. This review summarizes their most important functions as well as FGF-based therapies for the treatment of obesity and type 2 diabetes (T2D).
Recent studies demonstrate that circulating levels of FGF19 are reduced in obesity. In fact, exogenous FGF19 administration is associated with a reduction in food intake as well as with improvements in glycaemia. In contrast, FGF21 levels are elevated in subjects with abdominal obesity, insulin resistance and T2D, probably representing a compensatory response. Additionally, elevated levels of circulating FGF23 in individuals with obesity and T2D are reported in most clinical studies. Finally, increased FGF1 levels in obese patients associated with adipogenesis have been described.
FGFs constitute important molecules in the treatment of metabolic diseases due to their beneficial effects on glucose and lipid metabolism. Among all members, FGF19 and FGF21 have demonstrated the ability to improve glucose, lipid and energy homeostasis, along with FGF1, which was recently discovered to have beneficial effects on metabolic homeostasis. Additionally, FGF23 may also play a role in insulin resistance or energy homeostasis beyond mineral metabolism control. These results highlight the relevant use of FGFs as potential biomarkers for the early diagnosis of metabolic diseases. In this regard, notable progress has been made in the development of FGF-based therapies and different approaches are being tested in different clinical trials. However, further studies are needed to determine their potential therapeutic use in the treatment of obesity and obesity-related comorbidities.
KeywordsFGF FGFR α-Klotho β-Klotho T2D Obesity Energy balance
This work was supported by ISCIII-Subdirección General de Evaluación y FEDER (PI13/00460 and PI16/01217; Plan Estatal I + D + I/2013-2016) and by Fundación Caja Navarra (20-2014). CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN) is an initiative of the ISCIII, Spain.
The authors gratefully acknowledge the valuable collaboration of all the members of the Multidisciplinary Obesity Team, Clinica Universidad de Navarra, Pamplona, Spain.
Compliance with Ethical Standards
Conflict of Interest
Maitane Izaguirre, María J. Gil, Ignacio Monreal, Fabrizio Montecucco, Gema Frühbeck, and Victoria Catalán declare that they have no conflict of interest.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
- 29.• Marcelin G, Jo YH, Li X, et al. Central action of FGF19 reduces hypothalamic AGRP/NPY neuron activity and improves glucose metabolism. Mol Metab. 2014;3:19–28. This study provides evidence that FGF19 can signal in the hypothalamic arcuate nucleus improving peripheral insulin signaling through the induction of ERK1/2 signaling and the suppression of AGRP/NPY neurons activity in obese and insulin-resistant states PubMedCrossRefGoogle Scholar
- 81.• Gallego-Escuredo JM, Gómez-Ambrosi J, Catalán 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;39:121–9. This study reports that obesity is associated with an increase in FGF21 as well as with a decrease in FGF19 circulating levels. Moreover, opposite changes in β-klotho expression in fat and liver indicate potential tissue-specific alterations in the responsiveness to endocrine FGF-s in obesity CrossRefGoogle Scholar
- 83.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. 2016; doi: 10.1016/j.clnu.2016.04.027
- 90.•• 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;18:333–40. This study examines that daily administration of LY, a human FGF21 analog, provides clear evidence of its clinically meaningful effects on several metabolic comorbidities associated with type 2 diabetes PubMedCrossRefGoogle Scholar
- 91.Chavez AO, Molina-Carrion M, Abdul-Ghani MA, Folli F, Defronzo RA, Tripathy D. 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. 2009;32:1542–6.PubMedPubMedCentralCrossRefGoogle Scholar
- 125.•• Suh JM, Jonker JW, Ahmadian M, et al. Endocrinization of FGF1 produces a neomorphic and potent insulin sensitizer. Nature. 2014;513:436–9. This study demonstrates that recombinant FGF1 (rFGF1) produces glucose lowering and insulin sensitization without mitogenic effects, indicating that rFGF1 and its derivates may hold therapeutic promises PubMedPubMedCentralCrossRefGoogle Scholar