A high-fat diet rescues muscle atrophy by restoring adiponectin and attenuating systemic inflammation in cachectic mice

Cancer cachexia is a multifactorial syndrome characterized by progressive muscle and fat loss, driven by systemic inflammation and metabolic dysfunction. The role of adipose tissue in modulating muscle wasting through endocrine signaling remains underexplored. This study investigates the therapeutic potential of a high-fat diet (HFD) in mitigating muscle atrophy in cancer cachexia through adiponectin signaling. Lewis lung carcinoma (LLC) cells (1.5 × 10⁶ cells per mouse) were subcutaneously implanted in C57BL/6J mice to induce cachexia. Mice were randomized to receive either a standard diet (CD) or an HFD (65% energy from fat) for 21 days post-tumor implantation. Serum and tissue samples were analyzed for inflammatory markers, muscle mass, adiponectin expression, and muscle function using enzyme-linked immunosorbent assay (ELISA), quantitative real-time PCR (qRT-PCR), hematoxylin-eosin (H&E) staining, and functional assays. The HFD did not affect tumor size or energy intake but reduced hepatosplenomegaly (liver: P = 0.0282, spleen: P < 0.0001) and circulating inflammatory factor levels (tumor necrosis factor alpha (TNFα): 22.9%, interleukin 6 (IL6): 30.4%, interleukin 1 beta (IL1β): 33.6%, compared to LLC+CD) in cachectic mice. The HFD attenuated the loss of muscle mass (P = 0.0115), functional decline, reduction in myofiber cross-sectional area, and the expression of atrophy-related genes. It also mitigated weight loss (inguinal white adipose tissue (iWAT) mass loss: 54% in CD vs. 12% in HFD; epididymal white adipose tissue (eWAT) mass loss: 49% in CD vs. 19% in HFD) and adipocyte atrophy in both iWAT and eWAT, concurrently reducing adipose browning and inflammatory factor expression. Mechanistically, transcriptome analysis of muscle and iWAT implicated adiponectin-related pathways. The HFD enhanced adiponectin expression in iWAT, partially restored circulating adiponectin levels (9.6%, P = 0.0220, compared to LLC+CD), and upregulated AdipoR1 expression in muscle. This increased adiponectin expression in adipose tissue appeared to be mediated by peroxisome proliferator-activated receptor gamma (PPARγ) and CCAAT/enhancer-binding protein alpha (C/EBPα). Consequently, gene expression associated with mitochondrial biogenesis, muscle cell regeneration, and fatty acid utilization was activated in muscle tissue. An HFD mitigates fat loss and muscle atrophy in cancer cachexia. It restores adiponectin secretion in adipose tissue and attenuates systemic inflammation. These findings underscore the therapeutic potential of dietary modulation in cachexia and highlight the fat-to-muscle axis as a promising target for future interventions.