Abstract Body: Background: Cardiometabolic disease involves metabolic and inflammatory dysregulation. Circulating cardiac signals regulating peripheral tissues are poorly defined. In a cardiac-specific transgenic (Tg) mouse model of high-fat diet (HFD)-induced cardiometabolic disease, females (F) show maladaptive cardiac remodeling and impaired brown adipose tissue (BAT) activation, while males (M) have cardioprotection and metabolic flexibility. Fat therefore serves as a readout of cardiac signaling. Sex- and Tg-dependent shifts in circulating metabolites are enriched in inflammatory and metabolic pathways, supporting systemic reprogramming.

Research Question: Does cardiac stress drive sex- and genotype-dependent circulating proteins and lipids that may reprogram peripheral metabolism?

Goal: Define cardiac-derived mediators of cardiometabolic disease conserved in humans.

Methods: LC-MS was performed on serum and tissues from M and F Tg and control mice on HFD and human serum from CAD ± type 2 diabetes (T2D) patients. Inflammatory lipid mediators and polyunsaturated fatty acid (PUFA) precursors were quantified in mice and indices calculated. Serum proteomics were integrated with metabolomics and analyzed by gene ontology enrichment (ShinyGo).

Results: F Tg mice showed upregulated serum proteins of central metabolism and consistent with stress responsive secretion. In human serum, F’s had reduced abundance of proteins in immune regulation, proteolysis, and glycolytic metabolism independent of T2D, notably α-enolase (M/F fold change = 7.5, p = 0.042). Enriched pathways overlapped across species. Inflammatory lipids displayed tissue- and sex-specific remodeling: cardiac 12-HETE decreased early in Tg M versus controls (351.6 vs 955.6 ng/g; p = 0.011) but increased later in Tg F (849.7 vs 301.9 ng/g; p = 0.046). Linoleic acid metabolism resolved earlier in males (4 weeks) than females (16 weeks).

Conclusion: Cardiac stress drives sex-dependent remodeling of circulating proteins and cardiac derived lipid mediators, suggesting divergent metabolic trajectories of peripheral fuel utilization and thermogenic regulation, highlighting potential sex-informed cardiac signaling pathways as targets in cardiometabolic disease and obesity.