PPARγ Deacetylation: A Novel Approach to Managing Cardiovascular Dysfunction in Postmenopausal Mice

Background: As middle-aged women reach post-menopause, a natural life transition marked by estrogen decline induced by loss of ovarian function, they face significantly higher risks of developing cardiovascular disease due to the onset of risk factors such as weight gain and increased arterial stiffness. Despite this, post-menopause and its underlying mechanisms that lead to cardiometabolic dysfunction remain inadequately understood. Recent studies shed light on the regulatory role of estrogen in modulating PPARγ, a master regulator of adipose tissue and vascular function. Our group demonstrated that PPARγ deacetylation confers robust vasculoprotective effects. Based on these findings, we hypothesize that PPARγ deacetylation mitigates postmenopause-induced weight gain and arterial stiffness, both early markers of metabolic and vascular dysfunction. Methods: Ovariectomy (OVX), a well-established surgical procedure for ovary removal, was employed to create our murine model of post-menopause. Female C57Bl/6 (WT) and 2KR mice, a genetically engineered knock-in model designed to mimic PPARγ deacetylation (K268R, K293R), were randomly assigned to receive a sham (WT-SHAM and 2KR-SHAM) or OVX procedure. Body weight (BW) measurements were obtained weekly throughout the 24-week study period. Advanced ultrahigh-resolution ultrasound (Vevo3100) was utilized to measure intracarotid pulse wave velocity (icPWV), the gold standard for assessing arterial stiffness. At the terminal experiments, gonadal white adipose tissue (gWAT) and uterine weights were obtained. Results: Significantly reduced uterine weight in the postmenopausal groups (WT: p < 0.0001; 2KR: p < 0.0001) validated the effectiveness of our murine model. As expected, WT postmenopausal mice exhibited a significant increase in BW (27.71 ± 0.70 g vs. 24.22 ± 0.41 g WT-SHAM; p = 0.0035) and gWAT (p < 0.0001). Remarkably, these effects were abolished in the 2KR postmenopausal mice (BW: 22.89 ± 0.41 g vs. 22.10 ± 1.08 g 2KR-SHAM; p = 0.6998, and gWAT: p = 0.9780), indicating that PPARγ deacetylation protects against BW and gWAT gain during postmenopause. icPWV results revealed that WT postmenopausal mice developed arterial stiffness starting at week 12 through 24 (3.915 ± 0.702 m/s vs. 1.626 ± 0.184 m/s WT-SHAM; p= 0.0427), an effect not observed in 2KR postmenopausal mice (2.692 ± 0.936 m/s vs. 2.848 ± 0.420 m/s 2KR-SHAM; p = 0.9027). Conclusion: PPARγ deacetylation protects against the development of postmenopause-induced cardiovascular risk factors, including weight gain and arterial stiffness. These findings highlight PPARγ deacetylation as a promising target for mitigating cardiometabolic dysfunction in postmenopausal populations. NIH-NHLBI 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.