Bisphenol S exacerbates high-fat diet-induced obesity and insulin resistance in offspring: insights from a multi-tissue systemic lipidomic and proteomic atlas.

Bisphenol S (BPS) is a widely used substitute for bisphenol A in food-contact materials; but its role in perinatal programming of obesity and insulin resistance remains unclear. Here, we constructed a multi-tissue lipidomic-proteomic atlas to examine the effects of perinatal BPS exposure in high-fat diet-fed offspring mice. Non-targeted lipidomics revealed extensive disturbances in lipid metabolism across the heart, liver, pancreas, white adipose tissue (WAT), and brown adipose tissue (BAT), identifying BAT as the primary target. Males displayed extensive lipidomic alterations, whereas females showed predominant proteomic disturbances. Integrative lipidomic-proteomic analysis uncovered coordinated dysregulation of phosphatidylglycerol/cardiolipin (PG/CL) metabolism and thermogenesis, fatty acid metabolism, and glucose metabolism and insulin signaling. Differential PG and CL patterns were evident between BAT and WAT, with PG, CL, and cardiolipin synthase (CRLS1) upregulated in BAT but attenuated in WAT, indicating tissue-specific divergence in mitochondrial lipid metabolism. Enhanced CL synthesis, a lipid feature linked to thermogenic fat activity and metabolic regulation, was accompanied by increased expression of UCP1 and mitochondrial respiratory components, including NDUFB6. Together with concurrent lipid accumulation and insulin resistance in WAT, these findings reveal disrupted inter-adipose metabolic balance, providing mechanistic insight into how early-life BPS exposure predisposes offspring to obesity and insulin resistance.