Nobiletin Enhances Skeletal Muscle Mass and Modulates Bile Acid Composition in Diet-Induced Obese Mice

Obesity and its associated metabolic disorders─including muscle atrophy─pose significant health challenges, particularly with the increasing prevalence of high-fat diets. This study investigates the effects of nobiletin, a citrus flavonoid, on high-fat-diet-induced obesity-related muscle atrophy and its regulatory role in bile acid metabolism, aiming to determine whether nobiletin supplementation can enhance muscle mass and improve metabolic health in a mouse model. Our findings revealed that nobiletin significantly upregulated CYP7A1 expression in the liver, promoting bile acid synthesis and modulating bile acid composition in the ileum and feces, potentially through microbiota-mediated mechanisms. Furthermore, nobiletin supplementation suppressed muscle atrophy-related proteins, including p-4EBP1, TRIM63, and FBXO32, while promoting the phosphorylation of mTOR/AKT/p70S6K and FOXO3a in skeletal muscle. The FGF15/FGFR4/ERK signaling pathway was notably activated in the skeletal muscle tissues of nobiletin-supplemented mice, suggesting a protective effect against muscle atrophy despite the pathway’s inhibition in the liver to promote bile acid synthesis. These results indicate that nobiletin not only mitigates muscle atrophy in the context of obesity but also enhances glucose homeostasis, likely through improved skeletal muscle function. Overall, our study highlights the potential of nobiletin as a therapeutic agent for preventing obesity-related complications, regulating bile acid metabolism, and promoting skeletal muscle health.