Sex-specific hypothalamic axis disruption in the rNLS8 mouse model of amyotrophic lateral sclerosis (ALS)

Sex-related differences have gained increasing attention in recent years due to evidence of varying prevalence, pathophysiology, survival rates, and disease progression between males and females in amyotrophic lateral sclerosis (ALS). Differences in brain metabolism between sexes in ALS patients have also been reported; however, the specific molecular mechanisms remain poorly understood. As growing evidence supports a strong metabolic component in ALS, this study investigates alterations in leptin, one of the key regulators of metabolism, that is known to be altered during ALS progression in rNLS8 mice, a transgenic mouse model of ALS which closely recapitulates the TAR DNA-binding protein (TDP-43) pathology observed in most patients with ALS. We also examined changes in hypothalamic neuronal genes involved in metabolic regulation through food intake in rNLS8 mice. Additionally, pathological alterations in the spinal cord, a primary site of ALS pathology, were also assessed. Using molecular biology techniques we analysed the expression levels of leptin, its long receptor (Ob-Rb), and its downstream signaling pathways (Akt and STAT3) in rNLS8 mice compared to age- and sex-matched wild-type littermates. Our results revealed significant sex- and disease stage-dependent differences in leptin and Ob-Rb expression in white adipose tissue and the hypothalamus, along with increased activation of the Akt signaling pathway in the spinal cord of rNLS8 mice. These findings suggest that ALS progression differs by sex in rNLS8 mice, which may impact overall disease progression and the effectiveness of potential therapeutic interventions targeting metabolism, such as nutritional strategies that influence leptin levels.