The Coordination of Lipid Synthesis and Breakdown in Metabolism and Aging

项目名称：代谢与衰老过程中脂质合成与降解的协调

Project Title: The coordination of lipid synthesis and degradation in metabolism and aging ABSTRACT/SUMMARY Lipid imbalances are characteristic of obesity and a feature of many age-related ailments and reproductive pathologies in humans. Yet, the relationship between lipid metabolism, aging and reproduction remains poorly studied. We propose to use the nematode C. elegans to characterize this relationship. In particular, we propose to investigate how the balance between lipid synthesis and breakdown influences an organism's rate of aging and health. In C. elegans, eliminating the germline extends lifespan. Besides fertility loss, germline removal is a major challenge to lipid metabolism because the animal needs to stop fat deposition into eggs and reorganize its lipid profile. Thus, germline-less worms provide a unique platform to understand how lipid balance is established in the cells and tissues of complex multicellular animals that are facing major physiological changes. We have discovered that fat production and degradation appear to be increased simultaneously in response to germline loss in worms. We recently demonstrated that in germline-less adults a conserved transcription factor, NHR-49, upregulate fatty-acid β-oxidation and desaturation- processes that contribute to lipid breakdown and build-up, respectively. Independently, we have also discovered that these two, and many other processes involved in lipid synthesis and degradation, are elevated in response to germline removal by the conserved transcription factors, DAF-16 and TCER-1. These data have led us to hypothesize that the coordinated enhancement of lipid synthesis and breakdown facilitates the adaptation to germline loss by ensuring lipid homeostasis. We propose to test this hypothesis by using molecular genetics, microscopy and biochemical approaches. The knowledge obtained from these studies is likely to reveal fundamental insights into the relationship of lipid metabolism, reproduction and aging. These studies are of relevance to human health and disease because they address major public health issues such as aging and obesity. The discoveries made through these experiments can lead to the discovery of therapeutic interventions targeting age-related ailments and metabolic diseases.