Periodic Reporting for period 1 - SweetEggs (The impact of germline metabolic reprogramming on reproduction and physiology)
Reporting period: 2023-01-01 to 2025-06-30
Within multicellular organisms, different cell populations can have fundamentally different metabolic needs. Cells can undergo metabolic reprogramming, a process by which metabolism is rewired to react to specific metabolic challenges or for cells to acquire novel functions. The most well-described example is the rewiring of metabolism observed in tumor cells, known as the Warburg effect. Although most intensively studied in pathological conditions, metabolic reprogramming also occurs in physiological settings, being best appreciated in the context of development. However, we still know very little about the mechanisms that implement cellular metabolic programs and regulate their reprogramming in the context of a developing tissue and their importance in organ functions.
Metabolic challenges induced by changes in the environment such as dietary nutrient scarcity, induce the coordinated adjustment of multi-organ metabolic statuses. Although animals have mechanisms for adapting feeding behavior to match nutrient intake to their current needs, a challenging task faced by them is that tissue-specific metabolic requirements need to be coordinated at the whole-organism level. However, how animals satisfy the metabolic needs of different tissues and in turn how cell-specific metabolic programs modulate animal physiology remains largely unexplored.
Female fertility has emerged as a highly relevant paradigm to study the integration of inter-organ communication with cell metabolism, and dietary nutrient availability. Oocyte production requires a high and balanced nutrient provision and the concerted action of multiple organs acting on the ovaries, modulated by the action of hormones. Because of the complex nature of the regulatory processes underlying female fertility, dissecting the molecular mechanisms which compose them requires a highly tractable experimental system such as the fruit fly. The advantage of using Drosophila at this stage is that it will allow us to approach this multidimensional network from a systems biology perspective allowing for a fast screening of molecules acting at different levels of regulation.
Using this model system, we previously have uncovered a central role for carbohydrate metabolism, namely the specific branch of pentose phosphate pathway (PPP), as a novel integration node in the regulation of animal physiology and reproduction. 1. PPP as an integrator of dietary sugars and the germline function: during early oogenesis, the germline undergoes metabolic rewiring through the upregulation of the PPP. This process is critical for oogenesis, as knockdown of PPP enzymes in the germline leads to female infertility. Consistent with the fact that the PPP is fueled by glucose, dietary sugars are also required for oocyte production. 2. PPP as a new communication axis between the ovary and the adipose tissue: upregulation of the PPP in the germline defines a new axis of communication that is required for the transcriptional regulation of a satiety factor, fit in the fat body (FB), the fly’s adipose tissue. In turn, Fit acts on the central nervous system (CNS) to regulate the appetite for sugar-rich food, which fuels PPP in the germline.
Metabolic challenges induced by changes in the environment such as dietary nutrient scarcity, induce the coordinated adjustment of multi-organ metabolic statuses. Although animals have mechanisms for adapting feeding behavior to match nutrient intake to their current needs, a challenging task faced by them is that tissue-specific metabolic requirements need to be coordinated at the whole-organism level. However, how animals satisfy the metabolic needs of different tissues and in turn how cell-specific metabolic programs modulate animal physiology remains largely unexplored.
Female fertility has emerged as a highly relevant paradigm to study the integration of inter-organ communication with cell metabolism, and dietary nutrient availability. Oocyte production requires a high and balanced nutrient provision and the concerted action of multiple organs acting on the ovaries, modulated by the action of hormones. Because of the complex nature of the regulatory processes underlying female fertility, dissecting the molecular mechanisms which compose them requires a highly tractable experimental system such as the fruit fly. The advantage of using Drosophila at this stage is that it will allow us to approach this multidimensional network from a systems biology perspective allowing for a fast screening of molecules acting at different levels of regulation.
Using this model system, we previously have uncovered a central role for carbohydrate metabolism, namely the specific branch of pentose phosphate pathway (PPP), as a novel integration node in the regulation of animal physiology and reproduction. 1. PPP as an integrator of dietary sugars and the germline function: during early oogenesis, the germline undergoes metabolic rewiring through the upregulation of the PPP. This process is critical for oogenesis, as knockdown of PPP enzymes in the germline leads to female infertility. Consistent with the fact that the PPP is fueled by glucose, dietary sugars are also required for oocyte production. 2. PPP as a new communication axis between the ovary and the adipose tissue: upregulation of the PPP in the germline defines a new axis of communication that is required for the transcriptional regulation of a satiety factor, fit in the fat body (FB), the fly’s adipose tissue. In turn, Fit acts on the central nervous system (CNS) to regulate the appetite for sugar-rich food, which fuels PPP in the germline.
QUESTIONS and HYPOTHESES: Our previous findings create an exciting platform that we will use to uncover novel mechanisms allowing organisms to integrate cell-specific metabolic programs and dietary nutrients to mount cell-specific strategies which expand to the whole-animal, impacting physiology and reproduction.
Q1: Adjusting metabolic programs: How are germline metabolic programs transcriptionally implemented and how plastic are they? We will identify the transcription factors (TFs) required for the PPP implementation and regulation during oogenesis and adaptation to dietary sugar availability. The results of this aim will lead to a fundamental and broader understanding of how the environment modulates metabolism, processes which are transversal to most biological processes.
Q2: From metabolic programs to cellular and tissue functions: How do germline metabolic programs modulate cellular processes? We will identify the key PPP metabolites required for oogenesis and describe the germline cellular/tissue functions they support. Given the complexity of the cellular processes required for oogenesis, this aim will build on our understanding of how metabolism impacts other physiological and disease-related functions beyond reproduction.
Q3: Metabolites at the intersection of physiology, reproduction, and behavior: How do germline metabolic programs integrate and adjust ovary-FB communication to regulate whole-animal physiology and behavior? We will identify new secreted molecules regulating fit transcription in the FB and nutrient appetite. The complexity of functions masterfully coordinated by metabolism makes this a wonderful paradigm to reveal new fundamental pathways likely regulating other physiological functions, and new processes deregulated in disease contexts.
Q1: Adjusting metabolic programs: How are germline metabolic programs transcriptionally implemented and how plastic are they? We will identify the transcription factors (TFs) required for the PPP implementation and regulation during oogenesis and adaptation to dietary sugar availability. The results of this aim will lead to a fundamental and broader understanding of how the environment modulates metabolism, processes which are transversal to most biological processes.
Q2: From metabolic programs to cellular and tissue functions: How do germline metabolic programs modulate cellular processes? We will identify the key PPP metabolites required for oogenesis and describe the germline cellular/tissue functions they support. Given the complexity of the cellular processes required for oogenesis, this aim will build on our understanding of how metabolism impacts other physiological and disease-related functions beyond reproduction.
Q3: Metabolites at the intersection of physiology, reproduction, and behavior: How do germline metabolic programs integrate and adjust ovary-FB communication to regulate whole-animal physiology and behavior? We will identify new secreted molecules regulating fit transcription in the FB and nutrient appetite. The complexity of functions masterfully coordinated by metabolism makes this a wonderful paradigm to reveal new fundamental pathways likely regulating other physiological functions, and new processes deregulated in disease contexts.
Fundamental biological outcomes: This proposal will shed light on the cellular roles and regulation of PPP, a central metabolic pathway across species. Metabolic plasticity is at the core of a number of physiological responses and it is key for adaptation to environmental fluctuations. Understanding how environmental alterations are reflected in alterations in cellular metabolic changes and in turn how these control tissue cross-talk opens exciting possibilities for understanding general mechanisms integrating external and internal cellular cues to promote survival and reproduction of all living organisms.
Disease states: Metabolic dysfunctions are dramatically increasing in prevalence worldwide. Female infertility is strongly associated with metabolic dysfunctions including obesity and diabetes. This proposal will lay the foundation for follow-up studies using mammalian model systems, aiming at devising dietary interventions to improve reproductive outputs. Furthermore, these findings have a high potential to be relevant to other human conditions beyond infertility, including cancer, that are highly associated with processes of metabolic deregulation. This proposal will build upon our understanding of how tissues talk to each other, processes that are critical in several human diseases, including cachexia, the most common condition in cancer patients.
Disease states: Metabolic dysfunctions are dramatically increasing in prevalence worldwide. Female infertility is strongly associated with metabolic dysfunctions including obesity and diabetes. This proposal will lay the foundation for follow-up studies using mammalian model systems, aiming at devising dietary interventions to improve reproductive outputs. Furthermore, these findings have a high potential to be relevant to other human conditions beyond infertility, including cancer, that are highly associated with processes of metabolic deregulation. This proposal will build upon our understanding of how tissues talk to each other, processes that are critical in several human diseases, including cachexia, the most common condition in cancer patients.