Sex-specific dynamics of MASLD reveal early hepatic and extrahepatic metabolic deterioration in females despite long-term protection

Abstract Background Metabolic dysfunction-associated steatotic liver disease (MASLD) is a chronic condition characterized by hepatic fat accumulation and systemic metabolic dysfunction. MASLD exhibits clear sex differences, yet the mechanisms underlying these disparities remain poorly defined. Methods To investigate the early temporal dynamics of MASLD, male and female mice were fed a choline-deficient, methionine-restricted (0.1%) high-fat (61%) diet (CDAHFD; characterized by impaired hepatic lipid export and enhanced lipotoxic stress) for two weeks, enabling assessment of initial metabolic responses. Results Despite their presumed protection, females developed an exacerbated hepatic phenotype accompanied by intestinal remodeling and compromised barrier integrity. In contrast, males displayed early weight loss and improved glucose tolerance, alongside reduced hepatic transcriptional changes indicative of adaptive metabolism. Additionally, sex-specific hypothalamic responses were observed, with males showing reduced expression of microglial homeostatic markers, increased inflammation, and alterations in energy balance-related signaling, consistent with neuroimmune modulation. These responses were paralleled by sex-dependent alterations in adipose tissue, including early adipocyte remodeling and distinct transcriptional changes, which were predominantly consistent with baseline sex differences and therefore suggest a limited contribution of this tissue to the early diet-induced metabolic divergence. Importantly, these early sex-dependent adaptations were not sustained over time, as prolonged CDAHFD (14 weeks) resulted in a shift towards a more sever inflammatory and fibrotic hepatic phenotype in males, while females exhibited relative preservation of hepatic metabolic function and attenuation of intestinal alterations. Conclusions These findings demonstrate that sexual dimorphism in MASLD arises early and evolves dynamically, with females mounting an acute metabolic and intestinal stress response, whereas males activate compensatory pathways that preserve metabolic homeostasis. These results highlight sex-specific trajectory in MASLD progression and emphasize the need for integrative approaches to unravel its pathophysiology.