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 associated with pathways like those involving its heterodimeric receptor complex of FGF receptor 1 (FGFR1) and β -klotho [1,2]. Genetic models, such as KO/CKO mouse models, have been essential in studying its functions [3].

In PTEC-specific fgf21-deficient young mice, increased autophagic flux was observed due to heightened autophagy demand, while in aged or obese fgf21-deficient mice, autophagy stagnation was exacerbated. This indicates that Fgf21 is induced by autophagy disturbance and protects against chronic kidney disease (CKD) progression during aging and obesity by alleviating autophagy stagnation and maintaining mitochondrial homeostasis [3]. In adiponectin knockout mice, several therapeutic benefits of FGF21, like alleviating obesity-associated hyperglycemia and insulin resistance, were lost, suggesting adiponectin mediates FGF21's systemic effects on energy metabolism and insulin sensitivity [4]. Mice lacking FGF21 or its signaling in the brain fail to adaptively shift macronutrient preference in response to dietary protein restriction, showing FGF21 mediates shifts in macronutrient preference to maintain protein intake [5].

In conclusion, Fgf21 plays diverse and essential roles in regulating metabolism, autophagy, and macronutrient preference. Model-based research, especially using Fgf21 KO/CKO mouse models, has provided insights into its functions in diseases such as CKD, obesity-related metabolic complications, and in the regulation of macronutrient intake, which may help in developing new therapeutic strategies for these conditions.