Abstract P637: Absence Of Estrogen Receptor Alpha In T Regulatory Cells Results In Decreased Cardiac Glucose Uptake And Improves Diastolic Function In Western Diet-fed Female Mice

Abstract

Diabetic women are at greater risk of developing cardiovascular disease than diabetic men. Our group has shown that insulin resistant female mice are more prone to develop diastolic dysfunction than male mice when fed a high fat/high fructose (western diet - WD). T regulatory cells (Tregs) suppress inflammation and insulin resistance, and estrogen receptor alpha (ERα) signaling has been postulated to modulate their function. Consequently, using a novel rodent model lacking ERα in Treg cells (TregERαKO) we tested the hypothesis that in conditions of WD-feeding, abrogation of ERα signaling in Tregs in female mice results in worsened whole-body and cardiac-specific insulin sensitivity, as well as diastolic function. Female TregERαKO mice and ERαFloxed (ERα Fl2 ) littermate controls were fed a WD for 16 weeks. WD consisted of high fat (46%) and high carbohydrate as sucrose (17.5%) and high fructose corn syrup (17.5%). At the end of the intervention, rodents underwent hyperinsulinemic-euglycemic clamps (n=7-9 per group) and, in a separate cohort, cardiac MRI (n=4 per group). Although TregERα deletion did not significantly impact whole-body insulin sensitivity (glucose infusion rate at steady state: 20 ± 2 vs. 17 ± 2 mg/Kg/min, TregERαKO vs. ERαFl 2 respectively, p=0.22), cardiac glucose uptake was significantly lower in the TregERαKO cohort (214.0±7.5 vs.167.3±19.6 μmol/min/100g tissue, TregERαKO and ERαFl 2 respectively p<0.05) indicating cardiac insulin resistance. MRI analysis revealed no differences in systolic function between the cohorts. The initial filling rate (a marker of diastolic function) was greater in the WD-fed TregERαKO cohort (0.29±0.08 vs. 0.53±0.09 μL/ms, TregERαKO vs. ERαFl 2 respectively, p<0.05) pointing toward enhanced diastolic function. Conclusions: In female mice fed a WD, lack of ERα signaling in Tregs results in cardiac-specific insulin resistance. However, the decreased cardiac glucose uptake did not translate into deterioration of diastolic function. Further studies are needed to evaluate the differential effects of TregERα deletion on glucose uptake and diastolic function. Acknowledgments: We acknowledge Vanderbilt MMPC for performing the clamps. MMPC is supported in part by grant U24 DK059637.