M. Yang, Y. Guo, J. Du, C. Li, H. Bai, Y. Guo, Y. Tan, X. Li, D. Ren, J. Li, X. Zhang, P. Zhang, et al. (2026). Impaired hepatic BMAL1-FGF21 signaling drives adverse metabolic outcomes of ketogenic diet. Life sciences, 393, 124324. https://doi.org/10.1016/j.lfs.2026.124324

PubMed 41862050

[Abstract]
Aims The ketogenic diet (KD) has gained popularity for its metabolic benefits; however, its effects vary markedly across physiological and pathological conditions. This study aimed to determine the mechanisms underlying differential metabolic responses to KD. Materials and Methods Db/db, liver-specific fibroblast growth factor 21 (FGF21) knockdown mice, and liver-specific brain and muscle aryl hydrocarbon receptor nuclear translocator-like 1 (BMAL1) knockout mice were treated with isocaloric KD for 8 weeks. Patients with alcoholic fatty liver disease were enrolled and subjected to an acute KD challenge. Liver function and lipid metabolism were evaluated post KD feeding. Key findings Isocaloric KD feeding for 8 weeks induces weight loss and maintains metabolic homeostasis in wild-type (WT) mice, but paradoxically promotes weight gain, aggravating lipid metabolic disorder and impairing exercise capacity in db/db mice. Mechanistically, hepatic responsiveness of FGF21 to lipid flux, regulated by the BMAL1, emerges as a determinant of KD outcomes. Db/db mice exhibit impaired FGF21 responsiveness due to hepatic BMAL1 deficiency, leading to KD intolerance. Liver-specific FGF21 knockdown or BMAL1 knockout recapitulates the adverse effects of KD observed in db/db mice, while FGF21 supplementation ameliorates lipid dysregulation. Importantly, db/db mice and patients with alcoholic fatty liver disease display blunted FGF21 responsiveness during acute KD challenge, inducing lipid metabolic disorder and liver injury. Significance These findings identify hepatic BMAL1-FGF21 axis as a pivotal regulator of metabolic adaptation to KD dietary, highlighting an important role of maintaining circadian health for optimal metabolic outcome of dietary interventions in lifestyle medicine.