Maternal High Fat, High Sucrose Diet-induced Cardiac Mitochondrial Abnormalities in the Offspring are Transmitted via the Oocyte Nucleus

Introduction: Maternal obesity correlates with higher cardiovascular disease risk in human offspring. We found high fat, high sucrose (HF/HS) diet results in accretion of abnormal mitochondria in mouse oocytes, and chow-fed offspring of HF/HS-fed dams exhibit transgenerational transmission of abnormal cardiac mitochondria through male and female germlines. Nuclear or mitochondrial inheritance can occur via the female germline, whereas male germline inheritance implicates nuclear epigenetic changes. However, recent reports indicate sperm mitochondria transmission is possible. Whether the mechanism is via effects on the nucleus or germ cell mitochondria is unknown. Hypothesis: Maternal HF/HS-feeding results in cardiac mitochondrial dysfunction in offspring due to effects on the oocyte nucleus. Methods: C57BL/6 female mice were chow- or HF/HS-fed, and mated to chow-fed C57BL/6 males. Female pronuclei were exchanged between embryos obtained from chow- and HF/HS-fed dams. Embryos without pronuclear transfer were additional controls. All embryos were transferred into chow-fed ICR dams. Cardiac mitochondrial structure (transmission electron microscopy) and function (high-resolution respirometry) were evaluated in 12-week-old offspring. Results: Adult offspring born of embryos having maternal pronuclei from chow-fed dams and ooplasm from chow- or HF/HS-fed dams had mitochondrial structure or oxygen consumption levels comparable to offspring born of control chow-fed dam embryos. In contrast, offspring born from embryos with maternal pronuclei from HF/HS-fed dams and ooplasm from chow-fed dams had abnormal cardiac mitochondrial structure (round shape, cristal rarefaction) and reduced oxygen consumption (~40%), comparable to embryo transfer offspring of HF/HS-fed dams. Conclusion: Shown for the first time, abnormal cardiac mitochondria in obese dam offspring result from HF/HS diet effects on the oocyte nucleus (likely epigenetic changes during oogenesis). Elucidating diet/obesity-induced oocyte epigenetic changes, and the mechanisms for induction and transgenerational transmission, could enable therapies to target inheritable heart disease risk in humans.