Abstract 13287: Sex Differences in the Impact of Parental Obesity on Offspring Cardiac SIRT3 Expression, Mitochondrial Efficiency and Diastolic Function Early in Life

Abstract

Introduction: Previous studies suggest that the perinatal environment can profoundly impact long-term metabolic health of the offspring. Hypothesis: We tested the hypothesis that parental (paternal + maternal) obesity impairs cardiac function in the offspring early in life. Methods: Within 1-3 days after weaning, offspring from obese rats fed a high fat diet (HFD-Offs) and age-matched offspring from lean rats (ND-Offs) were submitted to echocardiography and cardiac catheterization for assessment of pressure-volume relationships. Then, hearts were digested and isolated cardiomyocytes were used to determine contractile function, calcium transients, proteins related to calcium signaling, and mitochondrial bioenergetics. Results: Female and male HFD-Offs were heavier (72±2 and 61±4 vs 57±2 and 49 ±1 g), hyperglycemic (112±8 and 115±12 vs 92±10 and 96±8 mg/dL), with higher plasma insulin and leptin concentrations compared to female and male ND-Offs respectively. Compared to male ND-Offs controls, male HFD-Offs exhibited similar systolic function but impaired diastolic function as indicated by increased isovolumetric relaxation time (IVRT, 22±1 vs. 17±1 ms), the ratio of mitral peak velocity of early filling (E) to early diastolic mitral annular velocity (E’) (E/E’ ratio, 29±2 vs. 23±1) and Tau (5.7±0.2 vs. 4.8±0.2 ms). The impaired diastolic function was associated with reduced resting free Ca 2+ levels and phospholamban protein expression, increased activated matrix metalloproteinase 2 and reduced sirtuin 3 (SIRT3) protein expression, mitochondrial ATP reserve and ATP-linked respiration. We found no differences in diastolic function or SIRT3 expression levels in female HFD-Offs and ND-Offs. Conclusions: These results indicate that male and female offspring from obese parents have metabolic abnormalities early in life (1-3 days after weaning) and that male, but not female, Offs from obese parents have impaired diastolic dysfunction and reductions in cardiac SIRT3, resting free Ca +2 levels and mitochondrial bioenergetics. (R01 DK121411, NHLBI-PO1HL51971, NIGMS P20GM104357 and U54GM115428)