Sex differences in the lipid profiles of visceral adipose tissue with obesity and gonadectomy

In obesity, adipose tissue (AT) expansion is accompanied by chronic inflammation. Altered lipid composition in the visceral or gonadal white AT (GWAT) directly drive AT macrophage accumulation and activation to a proinflammatory phenotype. Sex steroid hormones modulate visceral versus subcutaneous lipid accumulation that correlates with metabolic syndrome, especially in men and postmenopausal women who are more prone to abdominal obesity. Prior studies demonstrated sex differences in GWAT lipid species in HFD-fed mice, but the role of sex hormones is still unclear. We hypothesized that sex hormone alterations with gonadectomy (GX) would further impact lipid composition in the obese GWAT. Untargeted lipidomics of obese GWAT identified sex differences in phospholipids, sphingolipids, sterols, fatty acyls, saccharolipids and prenol lipids. Males had significantly more precursor fatty acids (palmitic, oleic, linoleic, and arachidonic acid) than females and GX mice. Targeted lipidomics for fatty acids and oxylipins in the HFD-fed male and female GWAT stromal vascular fraction identified higher omega-6 to omega-3 free fatty acid profile in males and differences in PUFAs-derived prostaglandins, thromboxanes, and leukotrienes. Both obese male and female GWAT stromal vascular fraction showed increased levels of arachidonic acid-derived oxylipins compared to their lean counterparts. Bulk RNA-seq of sorted GWAT AT macrophages highlighted sex and diet differences in PUFA and oxylipin metabolism genes. These findings of sexual dimorphism in both stored lipid species and PUFA-derived mediators with diet and GX emphasize sex differences in lipid metabolism pathways that drive inflammation responses and metabolic disease risk in obesity.