Protecting the heart in obesity: pparγ deacetylation preserves coronary microvascular function

Introduction: Obesity, a major risk factor for cardiometabolic diseases, remains one of the most significant public health challenges in the United States, affecting nearly half of the population. Despite its strong association with adverse cardiovascular outcomes, the mechanisms by which obesity contributes to coronary microvascular impairment and cardiac problems remain poorly understood. Hypothesis: Building on our previous findings that PPARγ deacetylation confers macrovascular protection, we hypothesized that PPARγ deacetylation would preserve coronary microvascular blood flow and mitigate chronic obesity–induced cardiac dysfunction. Methods and Results: To test our hypothesis in the context of chronic obesity, adult male C57BL/6 (wild-type, WT) and 2KR mice, a genetically engineered knock-in model designed to mimic PPARγ deacetylation, were randomly assigned to either a Control Group (WT-Control and 2KR-Control) fed a low-fat diet (4% fat, 70% carbohydrate 58% starch) or Obese Group (WT-Obese and 2KR-Obese) fed a western diet (20% fat, 50% carbohydrate 35% sucrose) for 7 months. Obesity in the WT-Obese Group was confirmed by increased body weight (43.35 ± 2.87 vs 30.90 ± 1.34 g, p=0.0159) and by greater fat mass, both in grams (10.97 ± 0.71 vs. 7.41 ± 0.76 g, p=0.008) and as a percentage of body weight (25.27 ± 0.64 vs. 21.13 ± 1.16%, p=0.010), as determined by Dual-Energy X-ray Absorptiometry. As expected, the WT-Obese Group also exhibited a marked decrease in coronary peak blood flow velocity (318.0 ± 49.7 vs. 601.9 ± 93.5 mm/s, p=0.025), accessed in the left coronary artery by using color doppler high-resolution ultrasound. Interestingly, the Obese 2KR Group gained weight (35.44 ± 3.00 vs 29.58 ± 0.57 g 2KR-Control, p=0.2541), but they did not exhibit significant gains in fat mass in grams (7.15 ± 0.76 vs 5.76 ± 0.23 g 2KR-Control, p=0.4185) or percentage of body weight (21.22 ± 1.03 vs 18.42 ± 0.43% 2KR-Control, p=0.0855). Strikingly, although the 2KR mice gained weight, they were protected against changes in coronary peak blood flow velocity (583.9 ± 97.73 vs 416.1 ± 70.34 mm/s 2KR-Control, p=0.118). Regarding cardiac function, our echocardiogram data revealed a reduction of cardiac output in both strains with chronic obesity; however, the delta reduction was significantly smaller in the 2KR mice (6.92 ± 1.80 mL/min, p=0.004) in comparison to the WT mice (9.91 ± 2.18 mL/min, p=0.001). Conclusion: These findings reveal that PPARγ deacetylation protects against obesity-induced coronary microvascular dysfunction, further protecting the heart during chronic obesity. Funding Sources: R15HL165328-01A1 to MACS 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.