749A Poster - 12. Physiology, metabolism and aging
Thursday April 07, 2:00 PM - 4:00 PM

Authors:
Helin Hocaoglu; Lei Wang; Mengye Yang; Sibiao Yue; Matthew Sieber

Affiliation: UT Southwestern Medical Center, Dallas, TX

Keywords:
b. metabolism; l. Insulin signaling/ insulin-like peptides

Maternal diet and metabolic stress have a profound effect on health and disease susceptibility of progeny. Previous studies have shown this transgenerational effect; however, the mechanisms remain unknown because of the challenges in obtaining pure populations of quiescent oocytes. To overcome this challenge, we utilized the Drosophila oogenesis system to isolate large quantities of staged oocytes to study how the quiescent nature of oocytes impacts the effect of maternal metabolic stress on progeny metabolism. Using biochemical and systems-based approaches, we found that in the late stages of oogenesis, oocytes acquire a unique redox state due to suppression of mitochondrial oxidative metabolism in a process called mitochondria respiratory quiescence (MRQ). We have found that maternal metabolic stress triggers MRQ prematurely and induces the reprogramming of progeny metabolism and life-long changes in glucose and triglyceride homeostasis. In addition, we have found that maternal metabolic stress causes a disruption in the unique redox state of oocytes by impairing NAD biosynthesis. We have shown that reducing the levels of NAD in the oocyte are sufficient to induce progeny reprogramming, moreover maternal NAD precursor supplementation can suppress the progeny phenotypes caused by maternal metabolic stress. Compromised NAD levels inherited from the oocyte causes impaired methionine cycle activity and a 50% decrease in the production of the methyl-donor S-adenosyl methionine (SAM). Lower levels of SAM lead to a global 30% reduction in H3K27-me3, a corresponding increase in H3K27-ac, and de-repression of 550 genes during embryogenesis. Interestingly, 1/3 of these genes are specifically expressed in the intestine and are involved in processes such as lipid digestion, uptake, storage, protein digestion, nutrient transport, and calcium signaling. As a result of this intestinal metabolic shift, reprogrammed progeny were able to develop better on a low nutrient diet but have a shorter adult life span compared to control progeny. Taken together we believe that progeny metabolic reprogramming is an adaptive tradeoff that tunes progeny metabolism to promote development in a poor nutrient environment, at the expense of a shorter lifespan.