Investigating the Involvement of Fibroblast Growth Factors in Adipose Tissue Thermogenesis

Year 2024, , 60 - 66, 30.05.2024

Serkan Kır

https://doi.org/10.26650/EurJBiol.2024.1415673

Abstract

Objective: Thermogenesis in white and brown adipose tissues can be induced by various stimuli, including cold exposure, β-adrenergic stimulation, and tumor growth. Fibroblast growth factor (FGF) 21 has emerged as an important mediator of thermogenesis. This study investigated the involvement of other FGF family members in the regulation of adipose tissue thermogenesis.
Materials and Methods: Mice were exposed to cold and administrated a β-adrenergic agonist (CL-316,243) to stimulate a thermogenic response in adipose tissues. Stromavascular fractions isolated from white and brown adipose tissues were cultured and differentiated into primary adipocytes. These cells were treated with recombinant FGFs. Changes in the expression levels of thermogenic genes and FGFs were determined by real-time quantitative PCR.
Results: Cold exposure stimulated thermogenic gene expression in the adipose tissue, which was accompanied by the upregulation of certain FGFs. Ffg9 and Fgf21 were prominently induced in white and brown adipose tissues. β-adrenergic stimulation also upregulated thermogenic genes in adipocytes. Fgf21 was identified as the main responder to the β-adrenergic pathway. The administration of recombinant FGFs to cultured primary white and brown adipocytes induced thermogenic genes, including uncoupling protein-1 (Ucp1). FGF2, FGF9, and FGF21 triggered the most significant Ucp1-inducing effects in these cells.
Conclusion: FGF21 is as a prominent inducer of thermogenesis in adipose tissue and a promising therapeutic target against cardiovascular and metabolic diseases. FGF2 and FGF9 potently promote thermogenic gene expression in adipocytes. Therefore, their therapeutic targeting should be considered to enhance energy metabolism in adipose tissues.

Keywords

Adipose tissue thermogenesis, Browning, Fibroblast growth factors, FGF2, FGF9, FGF21

Ethical Statement

All experimental procedures were conducted in the Koç University Animal Research Facility in accordance with institutional policies and animal care ethics guidelines. All animal protocols were approved by the Institutional Animal Care and Use Committee of Koc University.

Supporting Institution

This work was supported by the EMBO installation grant (#4162) to S.K.

References

• Peirce V, Carobbio S, Vidal-Puig A. The different shades of fat. Nature. 2014;510(7503):76-83. google scholar
• Lidell ME. Brown adipose tissue in human infants. Handb Exp Pharmacol. 2019;251:107-123. google scholar
• Virtanen KA, Lidell ME, Orava J, et al. Functional brown adipose tissue in healthy adults. N Engl J Med. 2009;360(15):1518-1525. google scholar
• Cypess AM, White AP, Vernochet C, et al. Anatomical localiza-tion, gene expression profiling and functional characterization of adult human neck brown fat. Nature Med. 2013;19(5):635-639. google scholar
• van Marken Lichtenbelt WD, Vanhommerig JW, Smulders NM, et al. Cold-activated brown adipose tissue in healthy men. N Engl J Med. 2009;360(15):1500-1508. google scholar
• Kir S, White JP, Kleiner S, et al. Tumour-derived PTH-related protein triggers adipose tissue browning and cancer cachexia. Nature. 2014;513(7516):100-104. google scholar
• Petruzzelli M, Schweiger M, Schreiber R, et al. A switch from white to brown fat increases energy expenditure in cancer-associated cachexia. Cell Metab. 2014;20(3):433-447. google scholar
• Kir S, Spiegelman BM. Cachexia and brown fat: A burning issue in cancer. Trends Cancer. 2016;2(9):461-463. google scholar
• Cohen P, Spiegelman BM. Brown and beige fat: Molecular parts of a thermogenic machine. Diabetes. 2015;64(7):2346-2351. google scholar
• Kir S, Komaba H, Garcia AP, et al. PTH/PTHrP receptor mediates cachexia in models of kidney failure and cancer. Cell Metab. 2016;23(2):315-323. google scholar
• Cuevas-Ramos D, Mehta R, Aguilar-Salinas CA. Fibroblast growth factor 21 and browning of white adipose tissue. Front Physiol. 2019;10:37. doi:10.3389/fphys.2019.00037 google scholar
• Szczepanska E, Gietka-Czernel M. FGF21: A Novel regulator of glucose and lipid metabolism and whole-body energy balance. Horm Metab Res. 2022;54(4):203-211. google scholar
• Lu W, Li X, Luo Y. FGF21 in obesity and cancer: New insights. Cancer Lett. 2021;499:5-13. google scholar
• Chartoumpekis DV, Habeos IG, Ziros PG, Psyrogiannis AI, Kyri-azopoulou VE, Papavassiliou AG. Brown adipose tissue responds to cold and adrenergic stimulation by induction of FGF21. Mol Med. 2011;17(7-8):736-740. google scholar
• Fisher FM, Kleiner S, Douris N, et al. FGF21 regulates PGC-1alpha and browning of white adipose tissues in adaptive thermogenesis. Genes Dev. 2012;26(3):271-281. google scholar
• Abu-Odeh M, Zhang Y, Reilly SM, et al. FGF21 promotes ther-mogenic gene expression as an autocrine factor in adipocytes. Cell Rep. 2021;35(13):109331. doi:10.1016/j.celrep.2021.109331 google scholar
• Keipert S, Kutschke M, Ost M, et al. Long-term cold adaptation does not require FGF21 or UCP1. Cell Metab. 2017;26(2):437-446 e5. doi:10.1016/j.cmet.2017.07.016 google scholar
• Beenken A, Mohammadi M. The FGF family: Biology, patho-physiology and therapy. Nat Rev Drug Discov. 2009;8(3):235-253. google scholar
• Hui Q, Jin Z, Li X, Liu C, Wang X. FGF family: From drug de-velopment to clinical application. Int J Mol Sci. 2018;19(7):1875. doi:10.3390/ijms19071875 google scholar
• Li X. The FGF metabolic axis. Front Med. 2019;13(5):511-530. google scholar
• Bilgic SN, Domaniku A, Toledo B, et al. EDA2R-NIK signalling promotes muscle atrophy linked to cancer cachexia. Nature. 2023;617(7962):827-834. google scholar
• Tan H, Yue T, Chen Z, Wu W, Xu S, Weng J. Targeting FGF21 in cardiovascular and metabolic diseases: From mechanism to medicine. Int J Biol Sci. 2023;19(1):66-88. google scholar
• Dolegowska K, Marchelek-Mysliwiec M, Nowosiad-Magda M, Slawinski M, Dolegowska B. FGF19 subfamily members: FGF19 and FGF21. J Physiol Biochem. 2019;75(2):229-240. google scholar
• Harmer NJ. Insights into the role of heparan sulphate in fibroblast growth factor signalling. Biochem Soc Trans. 2006;34(Pt 3):442-445. google scholar
• Kwon MM, O’Dwyer SM, Baker RK, Covey SD, Kieffer TJ. FGF21-mediated improvements in glucose clearance require un-coupling protein 1. Cell Rep. 2015;13(8):1521-1527. google scholar
• Keipert S, Lutter D, Schroeder BO, et al. Author Correction: Endogenous FGF21-signaling controls paradoxical obesity resis-tance of UCP1-deficient mice. Nat Commun. 2021;12(1):1804. doi:10.1038/s41467-021-22119-x google scholar
• Charoenphandhu N, Suntornsaratoon P, Krishnamra N, et al. Fi-broblast growth factor-21 restores insulin sensitivity but induces aberrant bone microstructure in obese insulin-resistant rats. J Bone Miner Metab. 2017;35(2):142-149. google scholar
• Sun Y, Wang R, Zhao S, et al. FGF9 inhibits browning program of white adipocytes and associates with human obesity. J Mol Endocrinol. 2019;62(2):79-90. google scholar
• Li H, Zhang X, Huang C, et al. FGF2 disruption enhances thermogenesis in brown and beige fat to protect against adi-posity and hepatic steatosis. Mol Metab. 2021;54:101358. doi:10.1016/j.molmet.2021.101358 google scholar
• Shamsi F, Xue R, Huang TL, et al. FGF6 and FGF9 regulate UCP1 expression independent of brown adipogenesis. Nat Commun. 2020;11(1):1421. doi:10.1038/s41467-020-15055-9 google scholar
• Goetz R, Ohnishi M, Kir S, et al. Conversion of a paracrine fibroblast growth factor into an endocrine fibroblast growth factor. The J Biol Chem. 2012;287(34):29134-29146. google scholar
• Zhao L, Niu J, Lin H, et al. Paracrine-endocrine FGF chimeras as potent therapeutics for metabolic diseases. EBioMedicine. 2019;48:462-477. google scholar