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The impact of germline metabolic reprogramming on reproduction and physiology

Objective

Animals are composed of multiple tissues with different metabolic needs. During differentiation, the establishment of specific metabolic programs allows cells to acquire specialized functions. The nutrients that fuel these cell-specific metabolic pathways are obtained via the diet. In order to secure proper nutrient supply to these tissues, the central nervous system accesses their metabolic states, allowing the animal to mount behavioral strategies to adapt nutrient appetite. Our understanding of how cell-specific metabolic programs regulate animal physiology and behavior has been hindered by the lack of tractable experimental systems. Using Drosophila melanogaster I uncovered that the germline undergoes metabolic reprogramming, upregulating a specific carbohydrate metabolism branch, the pentose phosphate pathway (PPP) and that oogenesis progression requires the supply of dietary sugars, fueling this pathway. I further showed that the germline communicates its metabolic status to the fat body (FB), regulating the transcription of a satiety factor that acts on the brain to regulate sugar appetite. These findings represent a unique experimental platform, which I will use to study how cell-specific metabolic programs and nutrition regulate whole-animal animal physiology and fertility. I will: 1) identify the transcriptional factors regulating metabolic reprogramming in the germline; 2) test the requirement of specific PPP metabolites in germline cell functions and fertility; and 3) identify the molecules mediating the ovary-FB signaling axis and characterize their impact on FB transcriptional regulation, nutrient appetite, and fertility. Metabolic dysfunctions are known to result in many human conditions. This proposal will not only contribute to our understanding of how metabolism ensures reproduction, but will also help developing dietary interventions to tackle impactful human disorders including infertility.

Coordinator

INSTITUTO DE MEDICINA MOLECULAR JOAO LOBO ANTUNES
Net EU contribution
€ 1 481 513,00
Address
Avenida Prof Egas Moniz
1649 028 Lisboa
Portugal

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Region
Continente Área Metropolitana de Lisboa Área Metropolitana de Lisboa
Activity type
Research Organisations
Non-EU contribution
€ 0,00