Maternal obesity is correlated with cardiovascular disease in offspring, with a 1.3-fold increase in events observed in offspring of obese women. We have observed that obesity-exposed oocytes demonstrate impaired mitophagy and transmit damaged mitochondria to the offspring. Accordingly, we hypothesized that maternal obesity induces cardiac mitochondrial dysfunction in the offspring via transgenerational inheritance of abnormal oocyte mitochondria. We mated female mice fed a high-fat/high-sucrose (HFS) diet (or chow) with chow-fed males and assessed cardiac structure and function in their descendants that were chow fed in each generation. All F1 to F3 descendants bred via the female in each generation were nonobese and demonstrated cardiac mitochondrial abnormalities with crystal rarefaction and reduced oxygen consumption pointing to a transgenerational effect, while obese F0 dams’ hearts were unaffected. Furthermore, male offspring from F1 to F3 generations and female F1 and F2 offspring developed increased left ventricular (LV) mass (vs. chow-fed controls). Increased LV mass was also observed in offspring generated by in vitro fertilization of obesity-exposed oocytes and gestation in nonobese surrogates, ruling out a gestational environment effect. Contrary to our hypothesis, male F1 also transmitted these effects to their offspring, ruling out maternal mitochondria as the primary mode of transmission. We conclude that transmission of obesity-induced effects in the oocyte nucleus rather than abnormal mitochondria underlie transgenerational inheritance of cardiac mitochondrial defects in descendants of obese females. These findings will spur exploration of epigenetic alterations in the oocyte genome as potential mechanisms whereby a family history of maternal obesity predisposes to cardiovascular disease in humans.
|Journal||American Journal of Physiology - Heart and Circulatory Physiology|
|State||Published - May 2019|
- Developmental origins of health and disease
- Maternal obesity
- Mitochondria dysfunction
- Transgenerational inheritance