Klb, encoding β-Klotho, is a co-receptor for fibroblast growth factor 15/19 (FGF15/19) and FGF21. It is involved in the FGF21-KLB-FGFR signaling pathway, which regulates multiple metabolic systems in the liver, such as lipid metabolism, and is crucial for normal muscle development [1,2,3,4]. Animal models are valuable for studying Klb's functions.

In a pig model of intrauterine growth restriction (IUGR), increased KLB in fetal muscle was associated with reduced myogenic capacity. Transfection of fetal muscle progenitor cells with KLB small interfering RNA promoted myogenesis, indicating that KLB inhibits muscle development through suppressing mechanistic target of rapamycin signaling [1]. In mice, lack of Klb led to delayed puberty, altered estrous cyclicity, and subfertility due to a hypothalamic defect in GnRH neuron response to FGF21, suggesting a role of the FGF21/KLB/FGFR1 signaling in linking metabolism with reproduction [5]. Also, in high-fat diet-fed mice, increased DNA methylation at the Klb promoter mediated by DNMT1 and 3A led to down-regulation of Klb expression and development of hepatic steatosis. Liver-specific deletion of Dnmt1 or 3a increased Klb expression and ameliorated hepatic steatosis [2].

In conclusion, Klb plays essential roles in muscle development, metabolism-reproduction connection, and hepatic lipid metabolism. Mouse and pig models have significantly contributed to understanding Klb's role in IUGR-related muscle development impairment, hypothalamic-related reproductive defects, and diet-induced hepatic steatosis. [1,2,5]

References:

1. Cortes-Araya, Yennifer, Stenhouse, Claire, Salavati, Mazdak, Esteves, Cristina L, Donadeu, F Xavier. 2022. KLB dysregulation mediates disrupted muscle development in intrauterine growth restriction. In The Journal of physiology, 600, 1771-1790. doi:10.1113/JP281647. https://pubmed.ncbi.nlm.nih.gov/35081669/

2. Wang, Shirong, Zha, Lin, Cui, Xin, Xue, Bingzhong, Shi, Hang. 2023. Epigenetic Regulation of Hepatic Lipid Metabolism by DNA Methylation. In Advanced science (Weinheim, Baden-Wurttemberg, Germany), 10, e2206068. doi:10.1002/advs.202206068. https://pubmed.ncbi.nlm.nih.gov/37282749/

3. Lu, Weiqin, Li, Xiaokun, Luo, Yongde. 2020. FGF21 in obesity and cancer: New insights. In Cancer letters, 499, 5-13. doi:10.1016/j.canlet.2020.11.026. https://pubmed.ncbi.nlm.nih.gov/33264641/

4. Ji, Fang, Liu, Ye, Hao, Jun-Gui, Shen, Gui-Fang, Yan, Xue-Bing. 2019. KLB gene polymorphism is associated with obesity and non-alcoholic fatty liver disease in the Han Chinese. In Aging, 11, 7847-7858. doi:10.18632/aging.102293. https://pubmed.ncbi.nlm.nih.gov/31548436/

5. Xu, Cheng, Messina, Andrea, Somm, Emmanuel, Prevot, Vincent, Pitteloud, Nelly. . KLB, encoding β-Klotho, is mutated in patients with congenital hypogonadotropic hypogonadism. In EMBO molecular medicine, 9, 1379-1397. doi:10.15252/emmm.201607376. https://pubmed.ncbi.nlm.nih.gov/28754744/