Publications

Biological sex significantly influences the prevalence, incidence, and severity of numerous human diseases, yet it remains an underappreciated variable in biomedical research. Although sexually dimorphic genes contribute to sex-specific traits and disease manifestations, their regulation under metabolic stress is poorly understood. To explore sex-specific metabolic adaptations, we analyzed responses to high-fat diet (HFD)-induced obesity in male and female mice, focusing on the regulation of sex-biased genes. Despite similar adiposity, HFD-fed males displayed more severe metabolic impairments than females, highlighting divergent metabolic outcomes. To investigate the basis for these sex-specific differences, we performed whole transcriptomic profiling of liver and white adipose tissue (WAT) at early (2 wk) and late (12 wk) stages of HFD exposure. Our analysis revealed marked sex-specific gene expression changes across multiple categories, particularly pronounced in male WAT after prolonged HFD feeding. Strikingly, genes exhibiting sexual dimorphism under normal conditions were preferentially modulated in both sexes, comprising up to 46% of all HFD-regulated genes. This led to a substantial loss of sex-biased gene expression in both liver and WAT after HFD exposure, correlating with metabolic dysfunction. Male-biased genes associated with cilia function and estrogen response were among the most affected, showing significant downregulation in male WAT under HFD. Our findings provide a novel perspective on how obesity disrupts sex-specific gene expression in key metabolic tissues, particularly targeting sex-biased genes. By revealing that a considerable proportion of sex-biased genes exhibit HFD-regulated modulation, our study highlights the critical role of these genes in maintaining metabolic health. NEW & NOTEWORTHY Biological sex shapes metabolic tissue physiology, largely through sex-biased gene regulation. Our comprehensive transcriptomic analysis reveals that sex-biased genes in liver and white adipose tissue undergo the most significant regulation during obesity-driven metabolic dysfunction, resulting in a loss of their bias. This disruption highlights a previously unrecognized role of sex-biased genes in maintaining metabolic health in both males and females.

JTD Keywords: Er-alpha, Estrogen-receptor, Female, Gender-differences, High-fat-diet, Insulin resistance, Insulin-resistance, Mitochondrial-function, Obesity, Oxidative-metabolism, Sex differences, Sex-differences, Transcriptomics, Type 2 diabetes, White adipose-tissue

Several pathogenic Escherichia coli strains cause diarrhea. Enteroaggregative E. coli (EAEC) strains are one of the diarrheagenic pathotypes. EAEC cells form a "stacked-brick" arrangement over the intestinal epithelial cells. EAEC isolates express, among other virulence determinants, the AggR transcriptional activator and the aggregative adherence fimbriae (AAF). Overexpression of the aggR gene results in increased expression of virulence factors such as the aff genes, as well as several genes involved in specific metabolic pathways such as fatty acid degradation (fad) and arginine degradation (ast). To support the hypothesis that induction of the expression of some of these pathways may play a role in EAEC virulence, in this study we used a murine infection model to evaluate the impact of the expression of these pathways on infection parameters. Mice infected with a mutant derivative of the EAEC strain 042, characterized by overexpression of the aggR gene, showed increased disease symptoms compared to those exhibited by mice infected with the wild type (wt) strain 042. Several of these symptoms were not increased when the infecting mutant, which overexpressed aggR, lacked the fad and ast pathways. Therefore, our results support the hypothesis that different metabolic pathways contribute to EAEC virulence.

JTD Keywords: Adherence, Aggr, Burde, Chain fatty-acids, Children, Enteroaggregative e. coli, Escherichia-coli, Etiology, Infection, Mice, Microbiota, Persistent diarrhea, Protein, Scfa, Sex-differences

Sex differences in immune-mediated diseases are linked to the activity of estrogens on innate immunity cells, including macrophages. Tamoxifen (TAM) is a selective estrogen receptor modulator (SERM) used in estrogen receptor-alpha (ER alpha)-dependent breast cancers and off-target indications such as infections, although the immune activity of TAM and its active metabolite, 4-OH tamoxifen (4HT), is poorly characterized. Here, we aimed at investigating the endocrine and immune activity of these SERMs in macrophages. Using primary cultures of female mouse macrophages, we analyzed the expression of immune mediators and activation of effector functions in competition experiments with SERMs and 17 beta-estradiol (E2) or the bacterial endotoxin LPS. We observed that 4HT and TAM induce estrogen antagonist effects when used at nanomolar concentrations, while pharmacological concentrations that are reached by TAM in clinical settings regulate the expression of VEGF alpha and other immune activation genes by ER alpha- and G protein-coupled receptor 1 (GPER1)-independent mechanisms that involve NRF2 through PI3K/Akt-dependent mechanisms. Importantly, we observed that SERMs potentiate cell phagocytosis and modify the effects of LPS on the expression of inflammatory cytokines, such as TNF alpha and IL1 beta, with an overall increase in cell inflammatory phenotype, further sustained by potentiation of IL1 beta secretion through caspase-1 activation.

JTD Keywords: drug repurposing, inflammation, macrophage, nrf2, Afimoxifene, Animals, Apoptosis, Breast-cancer, Cells, cultured, Drug repurposing, Esr1 protein, mouse, Estrogen receptor alpha, Expression, Female, Gper1 protein, mouse, Immunomodulating agents, Inflammation, Inflammation mediators, Lipopolysaccharide, escherichia coli o111 b4, Lipopolysaccharides, Macrophage, Macrophages, peritoneal, Mice, Mice, inbred c57bl, Mice, knockout, Nf-e2-related factor 2, Nfe2l2 protein, mouse, Nrf2, Phagocytosis, Phenotype, Receptors, estrogen, Receptors, g-protein-coupled, Resistance, Selective estrogen receptor modulators, Sex-differences, Signal transduction, Tamoxifen, Tumor-associated macrophages