Fgf21, or Fibroblast growth factor 21, is a peptide hormone synthesized by multiple organs. It plays a crucial role in regulating energy homeostasis, glucose and lipid metabolism, and is involved in pathways related to energy balance. It acts through a heterodimeric receptor complex of FGF receptor 1 (FGFR1) and β -klotho [1,2]. Its diverse functions in multiple target organs, acting as an autocrine, paracrine, and endocrine factor, make it an important player in various biological processes, suggesting the value of genetic models like KO/CKO mouse models for in-depth functional studies [1].

In PTEC-specific fgf21-deficient young mice, autophagic flux increased due to higher autophagy demand, while in aged or obese fgf21-deficient mice, autophagy stagnation was exacerbated because of more severe lysosomal overburden. In aged or obese PTEC-specific fgf21-and atg5-double-deficient mice, renal histology deteriorated, mitochondrial function was severely disturbed, and oxidative stress was exacerbated compared to atg5-deficient mice. This indicates that Fgf21, induced by autophagy deficiency, protects against chronic kidney disease (CKD) progression during aging and obesity by alleviating autophagy stagnation and maintaining mitochondrial homeostasis [3].

Adiponectin knockout mice were refractory to several therapeutic benefits of FGF21, including alleviation of obesity-associated hyperglycemia, hypertriglyceridemia, insulin resistance, and hepatic steatosis, suggesting that adiponectin mediates the systemic effects of FGF21 on energy metabolism and insulin sensitivity [4].

Mice lacking either FGF21 or FGF21 signaling in the brain fail to adaptively shift macronutrient preference and increase protein intake in response to dietary protein restriction, showing that FGF21 mediates adaptive shifts in macronutrient preference to maintain protein intake during protein restriction [5].

In conclusion, Fgf21 is essential for regulating energy and macronutrient metabolism, as well as for maintaining autophagy and mitochondrial homeostasis. Gene-knockout mouse models have revealed its role in metabolic diseases such as obesity-related complications, chronic kidney disease, and the regulation of macronutrient preference, providing insights into its potential as a therapeutic target for these diseases.