The leading cause of death in the US is heart disease, and the global problem of obesity is an important risk factor. Additionally, the offspring of overweight and obese women are more likely than those born to normal- weight women to develop cardiovascular disease as adults. This is especially distressing because over two- thirds of reproductive-age women are overweight or obese in the US. Work in mice has shown that maternal obesity programs mitochondrial dysfunction via germ-line changes and transmission of damaged oocyte mitochondria across three generations. The long-term goals of this applicant are to define the mechanisms by which maternal obesity impairs cardiac health in subsequent, non-obese generations and identify therapies to prevent adverse outcomes. The objective of this proposal is to develop a multigenerational model of cardiac deficiencies arising from maternal obesity. This model will then be used to test the central hypothesis that impaired cardiac function in offspring is due to a feed-forward loop in which offspring inherit damaged mitochondria that disrupt energy signaling, leading to further mitochondrial damage. This hypothesis is founded on preliminary and published work showing that when mice (F0) were fed a high-fat/high-sucrose diet from before conception and through weaning, they gained significant weight and developed peripheral insulin resistance; their F1 progeny developed heart disease as adults; and their F1, F2, and F3 descendants had misshapen and dysfunctional mitochondria in their skeletal muscle and oocytes, despite consuming a control diet. The central hypothesis will be tested by pursuing two aims.
Aim 1 will establish a multigenerational model of cardiac deficiencies arising from maternal obesity. Echocardiography will be used to measure cardiac function and high- resolution respirometry will be used to measure mitochondrial function in the F1 through F3 offspring of obese F0 dams.
Aim 2 will test the hypothesis that F1 through F3 offspring of obese dams have disturbed cardiac function due to defective cardiac mitochondria, disrupted autophagy, and increased lipid storage. Offspring will be treated with an activator of the low-energy state sensing protein AMP-activate protein kinase (AMPK). Activation of AMPK should enhance autophagy, and therefore result in diminished lipid droplet quantity and removal of dysfunctional/damaged mitochondria. Moreover, activation of AMPK should increase fatty acid oxidation and mitochondrial biogenesis, replenishing the pool of healthy mitochondria and restoring cardiac metabolic homeostasis, ultimately improving cardiovascular health. Completion of these aims will yield several basic science outcomes that are significant because they will add to our understanding of the relationship between maternal obesity and offspring cardiovascular health. The proposed studies support a postdoctoral training plan that includes interdisciplinary technical training, scientific meetings, and consultation with leaders in both cardiovascular and developmental biology fields, which will prepare the applicant to transition to independence as an investigator.
The proposed research is relevant to public health as it expands our understanding of the relationship between maternal obesity and offspring cardiovascular health through maternal transmission of dysfunctional/damaged mitochondria. Understanding this relationship is crucial to developing stronger diagnostic criteria and pharmaceutical treatments for cardiovascular disease in descendants of obese individuals. This research is relevant to the mission of NIH because we are pursuing knowledge on the mechanisms affecting cardiovascular health with the purpose of improving health in obese individuals and in their progeny.
