Global Transcriptional Profiling of Adipose Tissue Uncovers Unique Sex-Dependent Mechanisms in Acute Obesity: Implications for Adipose-Heart Interorgan Crosstalk

Metabolic syndrome, accounting for over 30% of the adult population in the USA, consists of conditions such as obesity, insulin resistance, dyslipidemia, and inflammation among others. These lead to increased risk of coronary heart disease, heart failure, type 2 diabetes mellitus and stroke. Limited therapeutic interventions for obesity include lifestyle modifications such as diet and exercise, prolonged use of appetite lowering drugs, with morbidly obese subjects needing bariatric surgery. Thus, there is not only a clinically unmet need for lowering pre-existing obesity, but also to limit the progression of obesity. Several investigations over the past decade have elucidated previously unknown mechanisms of this debilitating clinical problem affecting patients of both biological sexes. However, there is still a gap in our understanding of the pathophysiological mechanisms underlying the differential onset of obesity between the two sexes. In the present study, we hypothesized that acute overload of dietary fats can elicit divergent responses of adipose tissue (AT) microenvironment in both males and females, with ramifications for cardiovascular diseases. To investigate this using a pre-clinical model of acute onset of diet-induced obesity (DIO), age-matched male and female mice were randomly assigned to receive a sucrose-matched high-fat diet (HFD) or low-fat diet for a week. Males showed increased adiposity represented by a significant increase in white adipose tissue (WAT) mass, despite similar food consumption as females. In contrast, HFD-fed female mice exhibited better glucose tolerance than males. Adipose tissue fibrosis is a hallmark of chronic overnutrition. Intriguingly, we observed a significant upregulation of genes involved in extracellular matrix synthesis in both sexes within a duration of one week suggesting that triggers for tissue remodeling occur early on in DIO. Further analysis of the WAT transcriptome demonstrated a downregulation of fatty acid biosynthesis and pyruvate metabolism pathways. Quite interestingly, cell cycle and PPAR signaling pathways were up- and downregulated respectively in female mice, but not in males, potentially suggestive of increased adipocyte turnover and reduced inflammation in DIO onset. These findings indicate an improved adaptive response of the WAT microenvironment to acute excess of dietary fats in females. To test the translatability of our findings from the pre-clinical murine model of DIO, we derived adipocytes from human mesenchymal stem cells of both sexes. Human adipocytes were treated with a cocktail of fatty acids that mimics a well-established model of physiological HFD in vitro. HFD-treated adipocytes from female donor exhibited lower lipid accumulation compared to their male counterparts and recapitulated the protective gene signature observed in our murine model. Human iPSC-derived cardiac cells exposed to adipocyte-conditioned medium demonstrated reduced lipid accumulation and remodeling genes in females compared to males, suggesting cardioprotective mechanisms may, at least in part, be contributed by AT microenvironment responses to metabolic stressors. Overall, our findings demonstrate that acute caloric excess differentially regulates the adipose tissue microenvironment between males and females and therefore signaling factors that alter other metabolically active organs such as the heart. Further studies investigating the sex-dependent molecular mechanisms underlying the deregulation of AT metabolism is critical for development of highly effective and personalized therapeutic strategies to combat the development of DIO and cardiometabolic diseases. This work was supported by UAMS/ABI Faculty Start-up funds, NHLBI-supported summer research program, and the American Heart Association Career Development Award to RAB. This abstract was presented at the American Physiology Summit 2025 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.