Sex-specific white adipose tissue dysfunction in the TDP-43 A315T mice model of amyotrophic lateral sclerosis (ALS)

Abstract Sex differences in the metabolic regulation of energy homeostasis are increasingly recognized as modifiers of amyotrophic lateral sclerosis (ALS) progression; however, their impact on adipose tissue pathology remains insufficiently characterized. White adipose tissue (WAT), beyond its role in triglyceride storage, functions as an endocrine organ and is the primary source of leptin, a key adipokine regulating neuroendocrine and metabolic pathways. In ALS, circulating leptin levels are altered in both patients and animal models and correlate with adiposity and disease progression. In parallel, leptin signaling pathways are disrupted in ALS mouse models. Whether these alterations, particularly in a sex-dependent manner, reflect a primary dysfunction of WAT during disease progression remains unclear. Here, we characterize WAT remodeling in female TDP-43 A315T mice across disease stages using histological and molecular analyses combined with plasma leptin measurements. Female TDP-43 A315T mice exhibited progressive WAT impairments, including adipocyte atrophy, structural disorganization, and altered circulating leptin levels. These changes were associated with transcriptional alterations in key genes regulating adipocyte differentiation, thermogenesis, and TDP-43 homeostasis, consistent with impaired adipose tissue plasticity. Notably, WAT alterations emerged later than previously reported in males, indicating sex-specific temporal dynamics. In parallel, hypothalamic gene expression analyses revealed increased orexigenic signaling despite relatively preserved circulating leptin levels, suggesting early central leptin dysregulation. Together, these findings support the existence of sex-dependent mechanisms affecting both peripheral adipose tissue remodeling and central metabolic regulation in ALS. This study identifies WAT as a relevant peripheral contributor to metabolic dysfunction and highlights leptin-related pathways as potential targets for sex-specific therapeutic strategies.