Fgf21, Fibroblast growth factor 21, is a peptide hormone synthesized by multiple organs. It regulates energy homeostasis, glucose and lipid metabolism, and is involved in pathways related to energy balance [1,2,3]. It acts via a heterodimeric receptor complex of FGF receptor 1 (FGFR1) and β -klotho [2]. Fgf21 has shown potential as a biomarker and therapeutic target in various metabolic and cardiovascular diseases [2,3]. Genetic models, especially KO/CKO mouse models, are valuable tools for studying its functions.

In PTEC-specific fgf21-deficient mice, different effects on autophagy were observed depending on age and diet. Young fgf21-deficient mice had increased autophagic flux, while aged or obese fgf21-deficient mice had exacerbated autophagy stagnation. This indicates that Fgf21 is induced by autophagy deficiency and protects against chronic kidney disease progression during aging and obesity by alleviating autophagy stagnation [4]. In adiponectin knockout mice, several therapeutic benefits of FGF21, such as alleviating obesity-associated hyperglycemia, hypertriglyceridemia, insulin resistance, and hepatic steatosis, were lost, suggesting that adiponectin mediates the systemic effects of FGF21 on energy metabolism and insulin sensitivity [5]. Mice lacking FGF21 or its signaling in the brain fail to adaptively shift macronutrient preference in response to dietary protein restriction, indicating that FGF21 mediates the physiological regulation of macronutrient preference [6].

In conclusion, Fgf21 plays essential roles in energy homeostasis, glucose and lipid metabolism, and macronutrient preference regulation. Mouse models, especially KO/CKO models, have revealed its significance in diseases like chronic kidney disease, obesity-related metabolic complications, and in the regulation of macronutrient preference, providing insights into potential therapeutic applications for metabolic and related diseases [4,5,6].

References:

1. Fisher, Ffolliott Martin, Maratos-Flier, Eleftheria. 2015. Understanding the Physiology of FGF21. In Annual review of physiology, 78, 223-41. doi:10.1146/annurev-physiol-021115-105339. https://pubmed.ncbi.nlm.nih.gov/26654352/

2. Geng, Leiluo, Lam, Karen S L, Xu, Aimin. 2020. The therapeutic potential of FGF21 in metabolic diseases: from bench to clinic. In Nature reviews. Endocrinology, 16, 654-667. doi:10.1038/s41574-020-0386-0. https://pubmed.ncbi.nlm.nih.gov/32764725/

3. Tan, Huiling, Yue, Tong, Chen, Zhengfang, Xu, Suowen, Weng, Jianping. 2023. Targeting FGF21 in cardiovascular and metabolic diseases: from mechanism to medicine. In International journal of biological sciences, 19, 66-88. doi:10.7150/ijbs.73936. https://pubmed.ncbi.nlm.nih.gov/36594101/

4. Minami, Satoshi, Sakai, Shinsuke, Yamamoto, Takeshi, Matsui, Isao, Isaka, Yoshitaka. 2023. FGF21 and autophagy coordinately counteract kidney disease progression during aging and obesity. In Autophagy, 20, 489-504. doi:10.1080/15548627.2023.2259282. https://pubmed.ncbi.nlm.nih.gov/37722816/

5. Lin, Zhuofeng, Tian, Haishan, Lam, Karen S L, Xu, Aimin, Li, Xiaokun. . Adiponectin mediates the metabolic effects of FGF21 on glucose homeostasis and insulin sensitivity in mice. In Cell metabolism, 17, 779-89. doi:10.1016/j.cmet.2013.04.005. https://pubmed.ncbi.nlm.nih.gov/23663741/

6. Hill, Cristal M, Qualls-Creekmore, Emily, Berthoud, Hans-Rudolf, Münzberg, Heike, Morrison, Christopher D. . FGF21 and the Physiological Regulation of Macronutrient Preference. In Endocrinology, 161, . doi:10.1210/endocr/bqaa019. https://pubmed.ncbi.nlm.nih.gov/32047920/