Obesity currently affects over one-third of reproductive-age women in the United States leading to overall health and metabolic disorders, including reproductive function. Obese women experience subfertility and infertility at greater rates but more importantly, when they do get pregnant, their offspring suffer significant health consequences. Offspring of obese women are more likely than those born to normal-weight women to be obese at one year of age; to have metabolic syndrome, hypertension, and liver disease as young children; and to experience developmental delay, intellectual disabilities, and autism spectrum disorder. Given the severity and intractability of the obesity epidemic, we must identify effective means of intervention to prevent these detrimental effects of maternal obesity; this requires determination of the underlying mechanisms. In this proposal, we plan to determine how maternal diet-induced obesity affects offspring in the next generation via oocyte programming.
In Aim 1, we plan to examine if and how metabolic changes in TCA cycle components in the oocyte lead to mitophagic dysregulation. We will establish a timetable for this oocyte phenomenon and then determine how each of these steps manifests in the offspring. By triggering, inhibiting and replacing missing parts of mitophagy in the oocyte we hope to delineate the role of this pathway in normal and abnormal oocytes. Finally, using different mouse strains we will distinguish paternal from maternal mtDNA and determine if elimination of paternal mitochondrial is perturbed.
In Aim 2, we tackle the question of whether the transmission to offspring is nuclear or mitochondrial in origin. Using the unique expertise of two key Co- Investigators, we will discern if epigenetic modifications, nuclear or mitochondrial, are occurring. Also using the reciprocal techniques of ST and CT we will determine which cellular constituent is responsible for the phenotype. Finally, using the same dual strain experiments used in Aim 1, we will answer the important question of the origin of the offspring bad mitochondria-left over or newly made.
In Aim 3, we test the possibility that maternal interventions, specifically exercise and dietary changes, can reverse or rescue these events and offspring outcomes. If successful, these findings will greatly enhance our understanding of developmental origins of disease and will have implications for not only the timing, but also the nature, of effective therapeutic and behavioral recommendations for reproductive-age women.
Obesity is a global health problem, leading to increased risk for cardiovascular disease, diabetes, and reproductive dysfunction. Not only do obese women suffer from subfertility and infertility, but when they do conceive, their offspring experience significant health consequences, such as obesity, metabolic syndrome, hypertension, liver disease as well as developmental deficiencies as young children. Given the severity and intractability of the obesity epidemic, we must identify effective means of intervention to prevent these detrimental effects of maternal obesity; this requires determination of the underlying mechanisms. The objective of this proposal is to reveal these mechanisms so as to develop therapeutic or behavioral modifications to prevent the health consequences of maternal diet-induced obesity.
| Oestreich, Arin K; Moley, Kelle H (2017) Developmental and Transmittable Origins of Obesity-Associated Health Disorders. Trends Genet 33:399-407 |
| Boudoures, Anna L; Saben, Jessica; Drury, Andrea et al. (2017) Obesity-exposed oocytes accumulate and transmit damaged mitochondria due to an inability to activate mitophagy. Dev Biol 426:126-138 |
| Jaeger, Kathleen; Saben, Jessica L; Moley, Kelle H (2017) Transmission of Metabolic Dysfunction Across Generations. Physiology (Bethesda) 32:51-59 |
| Saben, Jessica L; Boudoures, Anna L; Asghar, Zeenat et al. (2016) Maternal Metabolic Syndrome Programs Mitochondrial Dysfunction via Germline Changes across Three Generations. Cell Rep 16:1-8 |
| Asghar, Zeenat A; Thompson, Alysha; Chi, Maggie et al. (2016) Maternal fructose drives placental uric acid production leading to adverse fetal outcomes. Sci Rep 6:25091 |
| Moley, Kelle H; Colditz, Graham A (2016) Effects of obesity on hormonally driven cancer in women. Sci Transl Med 8:323ps3 |
| Govero, Jennifer; Esakky, Prabagaran; Scheaffer, Suzanne M et al. (2016) Zika virus infection damages the testes in mice. Nature 540:438-442 |
| Boudoures, Anna L; Chi, Maggie; Thompson, Alysha et al. (2016) The effects of voluntary exercise on oocyte quality in a diet-induced obese murine model. Reproduction 151:261-70 |
