Increased intake of saturated fatty acids during adolescence impacts the endoplasmic reticulum to induce insulin resistance and compromised bone mineral density ameliorated by Withaferin A

Excessive intake of saturated fatty acids, particularly during adolescence, a critical growth period, disrupts metabolic processes in the body. GeneCards has linked palmitic acid (PA), a major saturated fatty acid, to lipotoxicity. We demonstrated that PA intake impairs the function of bone-forming cells by suppressing cellular defense against oxidative markers, leading to apoptosis and increased ER stress. Excess PA dysregulates glucose homeostasis by altering GLUT4 (insulin-regulated glucose transporter) and compromising skeletal health. In contrast, Withaferin A (WFA), an electrophilic steroidal lactone containing an α,β-unsaturated carbonyl moiety, counteracts palmitic acid–induced oxidative stress by limiting excessive reactive oxygen species generation, restoring redox potential, improving insulin signalling, and secondarily reactivating the Wnt/β-catenin mediated osteogenesis. Lipotoxic conditions were emulated in in vivo growing (adolescent) C57BL/6J mice after palmitic acid (PA) administration for 15 days. Subsequent GC-MS analysis of the serum revealed significant alterations in the metabolic profiles of fatty acids. PA results in compromised bone volume/tissue volume due to a deteriorated bone microarchitecture. This reduces bone mineral density (BMD) and impairs mechanical properties, indicating weakened bones. These data were corroborated by a significant decrease in the levels of serum biomarkers, such as P1NP, osteocalcin, and insulin. Our findings highlight the detrimental effects of PA overload during the window of rapid skeletal growth, leading to lipid accumulation and negatively impacting bone modeling.

Withaferin A; Palmitic acid; Adolescent Bone Health; Lipotoxicity; Insulin Resistance; Osteoblast dysfunction; Bone modeling.