WHITE ADIPOSE TISSUE UNDERGOES PATHOLOGICAL DYSFUNCTION IN THE TDP‑43<SUP>A315T </SUP>MOUSE MODEL OF AMYOTROPHIC LATERAL SCLEROSIS (ALS)

White adipose tissue (WAT) is a major regulator of systemic energy homeostasis and growing evidence indicates that adipokine imbalance may contribute to the metabolic disturbances observed in amyotrophic lateral sclerosis (ALS). However, the direct involvement of WAT in ALS pathophysiology remains poorly understood. The aim of this study was to determine whether WAT dysfunction emerges during ALS progression and contributes to disease-associated metabolic abnormalities. Using the TDP-43^A315T mouse model of ALS, we examined WAT at asymptomatic, onset and end-stage of the disease through histological analyses, proteomic profiling, and molecular approaches. We demonstrate, for the first time, that WAT undergoes marked structural and molecular alterations prior to the onset of motor symptoms, including adipocyte remodeling and changes in proteins involved in lipid metabolism and inflammatory signaling. These early alterations indicate that WAT pathology precedes neuromuscular degeneration and may actively contribute to disease progression. Given that WAT is the primary source of circulating leptin, we assessed the translational relevance of these findings by measuring plasma leptin levels in ALS patients at diagnosis. We found significantly reduced leptin concentrations in overweight and obese men with rapidly progressive ALS, supporting a link between altered adipokine signaling, disease severity, and sex-specific metabolic regulation. In conclusion, our study identifies WAT as an early and previously unrecognized target tissue in ALS and provides evidence that adipose tissue dysfunction contributes to ALS pathophysiology. These findings underscore the importance of integrating systemic and sex-specific metabolic factors into ALS research and therapeutic strategies.