Journal Article

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

Ceperuelo-Mallafré, Victòria, Fernández-Veledo, Sonia, Vendrell, Joan, Repollés-de-Dalmau, Maria, Marsal-Beltran, Anna, Núñez-Roa, Catalina

2026

Overview

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. Highlights Females develop more early severe liver damage, accompanied by pronounced intestinal alterations and impaired gut barrier integrity under a choline-deficient, methionine-restricted high-fat diet (CDAHFD). Males show early body weight loss, improved glucose tolerance, and reduced liver gene expression modifications in response to CDAHFD. CDAHFD elicits sex-specific central and peripheral adaptations, including altered hypothalamic neuroimmune signaling and adipose tissue transcriptional remodeling. Findings reveal that sex differences in MASLD appear early and progress along distinct biological pathways. Plain english summary Metabolic dysfunction-associated steatotic liver disease (MASLD) is a common liver disorder where fat builds up in the liver and disrupts overall metabolism. It is known that men and women experience this disease differently, but the reasons for these differences are still unclear. To explore this, researchers studied male and female mice that were fed a special diet designed to cause early liver stress. Surprisingly, the female mice showed more severe liver changes than the males, even though females are often thought to be protected against such damage. The females also showed signs of intestinal changes and a weakened gut barrier, suggesting their bodies were under higher stress. In contrast, male mice lost weight, had better blood sugar control, and showed reduced changes in the liver, which suggested that their bodies were adapting to the diet rather than being harmed by it. These differences were also linked to changes in the brain areas that control appetite, energy use, and inflammation. Overall, this study shows that sex differences in MASLD appear very early and follow different paths. Females respond with stronger stress and intestinal reactions, while males seem to trigger protective mechanisms. Understanding these early sex-specific patterns could help guide the development of better treatments for both men and women with liver disease.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Adipose tissue / Adipose Tissue - metabolism / Animals / Biomedical and Life Sciences / Biomedicine / Body weight loss / Carbohydrates / CDAHFD / Cholesterol / Choline / Colon / Complications and side effects / Demographic aspects / Development and progression / Diet / Diet, High-Fat / Digestive system / Endocrinology / Energy balance / Experiments / Fatty liver / Fatty Liver - metabolism / Female / Females / Food / Gastrointestinal tract / Gender differences / Gene expression / Glucose / Glucose tolerance / Gut / High density lipoprotein / High fat diet / Homeostasis / Human Physiology / Hypothalamus / Inflammation / Insulin / Intestine / Lipids / Lipoproteins / Liver / Liver - metabolism / Liver - pathology / Liver diseases / Male / Males / Metabolic diseases / Metabolism / Methionine / Mice / Mice, Inbred C57BL / Neuromodulation / Non-alcoholic Fatty Liver Disease - metabolism / Nutrient deficiency / Phenotypes / Plasma / Proteins / Risk factors / Sex Characteristics / Sex differences / Sex factors in disease / Sexual dimorphism / Signal transduction / Steatohepatitis / Stress response / Transcription