Lipoxins differentially modulate sex-specific adipose tissue transcriptional programs in diet-induced obesity

Background Biological sex is an important determinant of adipose tissue distribution, inflammation, and metabolic disease risk. Although females generally show greater protection from obesity-related metabolic dysfunction than males, the molecular mechanisms underlying these differences remain incompletely understood. The specialized pro-resolving lipid mediators lipoxin A 4 (LXA 4 ) and lipoxin B 4 (LXB 4 ) counter obesity-associated inflammation and promote metabolic homeostasis. However, their effects have been studied predominantly in male animals, leaving potential sex differences largely unexplored. Here, we investigated how biological sex shapes adipose tissue remodeling in response to high-fat diet (HFD) feeding and treatment with LXA 4 or LXB 4 . Methods We used a mouse model of diet-induced obesity to assess sex-dependent responses to HFD feeding and transcriptional/RNA-Seq and histological analyses of perigonadal white adipose tissue from female and male mice were performed to characterize changes in gene expression, adipocyte size, and collagen deposition. Results HFD induced pronounced transcriptional remodeling of adipose tissue, with substantial differences between males and females. Male mice exhibited stronger inflammatory transcriptional signatures, whereas females displayed gene expression patterns related to acyl-CoA and fatty acid metabolic processes. Lipoxins did not alter weight gain, but LXB 4 reduced HFD-induced adipocyte hypertrophy in female mice. Lipoxin signaling further modified adipose tissue gene expression in obesity, with LXB 4 eliciting greater transcriptome changes compared to LXA 4 . Intriguingly, pathway enrichment analysis suggests that LXB 4 administration in obesity resulted in increased expression of ribosomal subunits and cytoplasmic translation processes regardless of sex. Conclusions These findings demonstrate that adipose tissue transcriptomic responses to HFD are strongly influenced by biological sex, and that LXB 4 signaling modulates specific aspects of these responses in both a sex- dependent and sex-independent manner. Understanding how pro-resolving lipid mediator pathways interact with sex-dependent and sex-independent genetic adipose tissue programs may provide insight into mechanisms that may inform future therapeutic development for obesity-related metabolic disease.