Sex-Specific Adipose Transcriptomic Reprogramming Drives Early Inter-Organ Remodeling in Heart and Liver Under Nutrient Excess

Once viewed primarily as an energy store, adipose tissue (AT) is now recognized as an active endocrine organ that communicates with both the heart and liver to coordinate systemic metabolism. Under conditions of nutrient overload, maladaptive AT signaling can propagate dysfunction across these organs, yet the extent to which these pathways diverge between males and females is still poorly characterized. As obesity rates continue to rise worldwide, uncovering the earliest transcriptional and physiological disturbances initiated by AT is essential for understanding the onset of cardiometabolic disease. We hypothesized that acute dietary fat overload elicits sexually divergent AT transcriptional responses that subsequently shape tissue-specific remodeling in the heart and liver. Using a pre-clinical model of diet-induced obesity (DIO), age-matched male and female mice were fed sucrose-matched high-fat or low-fat diets for one week. Despite comparable caloric intake, males exhibited increased adiposity and rapid expansion of white adipose tissue (WAT), whereas females maintained superior glucose tolerance. Early induction of extracellular matrix remodeling genes in both sexes indicated that fibrotic cues arise within days of nutrient excess. Integrative transcriptomic profiling across AT, heart, and liver revealed coordinated yet sex-divergent metabolic reprogramming. In WAT, both sexes showed suppression of fatty acid biosynthesis and pyruvate metabolism, but females uniquely upregulated cell cycle pathways and downregulated PPAR signaling, suggesting increased adipocyte turnover and reduced inflammatory activation. Cross-tissue correlation analysis demonstrated that these early AT programs paralleled organ-specific signatures in the heart and liver. Heart RNA-seq revealed that female mice were protected from the strong induction of stress–remodeling genes and inflammatory mediators observed in males, while liver transcriptomics showed robust male-biased upregulation of lipogenic, inflammatory, and hepatokine pathways, consistent with their greater adiposity and lipolytic drive. Gene-level concordance highlighted distinct clusters of sex-specific heart–liver crosstalk, including male-biased induction of acute-phase response factors and female-biased preservation of metabolic resilience. To translate these findings, human iPSC-derived cardiac cells were exposed to conditioned medium from fatty acid–loaded adipocytes generated from male and female human mesenchymal stem cells. Female adipocytes displayed reduced lipid accumulation and recapitulated the adaptive transcriptomic signatures identified in murine AT. Cardiac cells exposed to female adipocyte conditioned medium showed diminished lipid loading and attenuated expression of remodeling and stress-response genes, reinforcing a cardioprotective effect of the female AT secretome. Together, these murine and human data identify a sexually dimorphic, multi-organ transcriptional network that emerges within days of dietary fat exposure. Females mount a more adaptive AT response that confers downstream protection against hepatic steatosis and cardiac metabolic remodeling. This study provides, to our knowledge, the first integrated transcriptomic analysis of the AT–heart–liver triad during the acute onset of diet-induced cardiometabolic disease, highlighting the essential role of sex as a biological variable. Targeting early inter-organ communication may offer new therapeutic avenues to mitigate metabolic dysfunction in obesity. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.