5,7-Dimethoxyflavone Attenuates Sarcopenic Obesity by Enhancing PGC-1α–Mediated Mitochondrial Function in High-Fat-Diet-Induced Obese Mice

<b>Background/Objectives</b>: Sarcopenic obesity, defined by the coexistence of excessive fat accumulation and progressive muscle loss, is associated with an increased risk of metabolic dysfunction and physical disability. While 5,7-dimethoxyflavone (DMF), a bioactive flavone derived from <i>Kaempferia parviflora</i>, has demonstrated anti-obesity and muscle-preserving properties, its effects on sarcopenic obesity remain unclear. <b>Methods</b>: Four-week-old male C57BL/6J mice were fed a high-fat diet (HFD) for 6 weeks to induce sarcopenic obesity, followed by 8 weeks of continued HFD with the oral administration of DMF. Muscle function was assessed through grip strength and treadmill running tests, while muscle and fat volumes were measured using micro-CT. Mechanistic analyses were performed using gene expression and Western blot analysis. <b>Results</b>: DMF significantly reduced body weight, fat mass, and adipocyte size while enhancing grip strength, endurance, skeletal muscle mass, and the muscle fiber cross-sectional area. In the gastrocnemius muscle, DMF increased the gene expression of <i>peroxisome proliferator-activated receptor gamma coactivator-1α</i> (<i>Ppargc1a</i>) and its isoform <i>Ppargc1a4</i>, thereby promoting mitochondrial biogenesis. It also improved protein turnover by modulating protein synthesis and degradation via the phosphatidylinositol 3-kinase/protein kinase B/mechanistic target of rapamycin signaling pathway. In subcutaneous and brown adipose tissues, DMF increased mitochondrial DNA content and the expression of thermogenic and beige adipocyte-related genes. These findings suggest that DMF alleviates sarcopenic obesity by improving mitochondrial function and regulating energy metabolism in both skeletal muscle and adipose tissues via PGC-1α-mediated pathways. Thus, DMF represents a promising therapeutic candidate for the integrated management of sarcopenic obesity.