Research Group Leader - CECAD Research Center
The Storelli lab is interested in a basic, but fundamental question: how do organisms function properly and maintain homeostasis despite constant internal and environmental perturbations? Among the mechanisms involved in these adaptations, we are particularly interested in the role for metabolism. Understanding how cellular metabolism is fine-tuned to maintain tissue physiology and to support systemic homeostasis will not only expand our knowledge of animal physiology – it could deliver mechanistic insights into the deleterious effects of aging, a complex biological process characterized by chronic activation of stress signaling pathways and metabolic dysfunction.
Our research: The Storelli lab uses the model organism Drosophila melanogaster to investigate the relationship between stress and metabolism. Drosophila are relevant to study this question: they have organs analog to all of the key metabolic tissues found in more complex organisms, and the basic mechanisms of metabolic control and intertissue communication are conserved between invertebrates and vertebrates. In addition, the powerful genetic resources available in Drosophila combined to their fast life cycle make them a prime model system to conduct large-scale approaches but also targeted studies in select tissues or cell types. Along these lines, the Storelli lab currently investigates how nutritionally-, chemically- or genetically-induced stress shapes cellular metabolism in several tissues, and how these metabolic responses support organ physiology and maitain organismal fitness. Our main goals are:
1) To characterize how stress signaling and metabolic pathways regulate each-other
2) To characterize the mechanisms by which specific metabolic pathways support physiology. In particular, we wish to understand how different tissues collaborate, at the metabolic level, to maintain homeostasis (Figure 1).
3) To draw the limits of these homeostatic roles for metabolism. For example, we wish to understand if aging, which is characterized by chronic activation of stress signaling pathways, promotes disease through metabolic dysfunction.
Our goals: Our long-term goal is to understand how discrete metabolic pathways act in specific cell types to support systemic homeostasis and health. The knowledge gained from these studies will provide us with insights into the relationship between conditions frequently associated to metabolic dysfunction (such as aging, diabetes, or inflammatory diseases) and the onset of disease (Figure 2).
Our successes: Dr. Storelli previously studied Metabo-Devo, or how animals adjust their metabolism to meet the needs associated with each stage in their life cycle.
Drosophila larvae (juveniles) are “eating machines”: they constantly feed to grow and metamorphose into an adult as fast as possible. Poor nutrition has a deleterious impact on larval growth and delays the onset of adulthood. In Dr. Leulier’s lab, Dr. Storelli demonstrated that Drosophila larvae set up a metabolic cooperation with their intestinal microbes to overcome malnutrition. Symbionts induce the expression of digestive enzymes in the Drosophila intestine, maximizing nutrient extraction from the poor diet and supporting growth despite malnutrition. In return, the intestine secretes “maintenance factors” which fuel bacterial metabolism and support symbiont persistence in the niche (Storelli et al., 2018).
While larvae live buried in their nutritive substrate, adults are highly motile: their primary mission is to mate and seed their progeny into new niches. In Pr. Dr. Thummel’s lab, Dr. Storelli discovered that a switch in lipid metabolism supports this fundamental change in lifestyle. The lipid stores generated during larval stages are converted within the first hours of adult life into hydrophobic hydrocarbons, which are required for cuticular and epidermal barrier function. Timely hydrocarbon production protects the young adult against desiccation, as it gets first exposed to an unpredictable environment. This switch in lipid metabolism also protect against diabetes, and we demonstrated a physiological link between defects in epidermal barrier function, chronic dehydration and the intolerance to dietary sugar (Storelli et al., 2019).
Our methods/techniques: The Storelli lab combines Drosophila genetics with transcriptomic and metabolomic approaches, as well as automated behavioral assays. We also use routine molecular biology, biochemistry and immunohistochemistry technics, as wells as assays to measure select metabolites. We aim at transposing our observations in more complex organisms, mostly through mammalian cell culture or through collaborations with mouse and human geneticists.
Figure 1: Inter-tissue metabolic cooperation.
Triglycerides (stained with a green fluorescent dye) are stored in adipocytes. Lipid-metabolizing cells called oenocytes are embedded in the fat tissue (arrowhead). After their mobilization in adipocytes (for example during starvation), lipid stores are metabolized in oenocytes. Tracheae (arrow) supply oxygen to this metabolic unit. (G.Storelli)
Figure 2: Genetic alteration of fatty acid metabolism in oenocyte causes lipid accumulation in this cell type and diabetes.
Oenocyte-specific alteration of fatty acid metabolism induces neutral lipid accumulation in this cell type (as visualized with a red dye, oenocytes are outlined with a blue dotted line). This manipulation also has systemic consequences, and triggers diabetes. (Figure adapted from (Storelli et al., 2019))