# A Drosophila Model for the Regulation of Aerobic Glycolysis

> **NIH NIH R35** · TRUSTEES OF INDIANA UNIVERSITY · 2022 · $442,947

## Abstract

Project Summary
The Tennessen Lab uses the fruit fly, Drosophila melanogaster, as a model to understand how carbohydrate
metabolism supports the biosynthetic and energetic demands of animal growth and development. Our ongoing
studies focus on a metabolic program known as the Warburg effect (aerobic glycolysis). This metabolic program
allows growing and proliferating cells to metabolize large quantities of glucose in order to generate biomass and
synthesize pro-growth signaling molecules. While aerobic glycolysis is most commonly associated with tumors,
where it promotes the growth and survival of cancer cells, healthy animal cells, such as stem cells and activated
T cells, also use this metabolic program to drive biosynthesis and regulate cell fate decisions. Therefore, basic
studies of aerobic glycolysis have the potential to not only identify metabolic mechanisms that could be targeted
to inhibit tumor growth but also to reveal how healthy cells manipulate glycolytic metabolism as a means of
supporting normal developmental growth. I have discovered that the fruit fly Drosophila melanogaster also uses
aerobic glycolysis to promote growth and have established the fly as a model system for studying the genetic
mechanisms that regulate this metabolic program. My initial efforts using this model have proven successful, as
I have determined that the Drosophila Estrogen-Related Receptor (dERR) is a master regulator of aerobic
glycolysis. My lab will now expand upon these initial observations to identify the molecular mechanisms that both
activate and repress aerobic glycolysis in vivo. Furthermore, we have determined that Drosophila larvae use
aerobic glycolysis to synthesize the oncometabolite L-2-hydroxyglutarate (L-2HG). This compound is almost
exclusively studied in the context of cancer metabolism and endogenous L-2HG function remains largely
unexplored. We will determine how L-2HG synthesis is controlled in vivo and explore how this oncometabolite
controls normal animal growth. Finally, we will use a combination of genetics, genomics, and metabolomics to
determine how the disruption of key reactions in aerobic glycolysis affects growth and physiology. Many of these
enzymes represent potential therapuetic targets and our innovative approach provides a rare opportunity to
systematically evaluate the effects of inhibiting individual glycolytic enzymes in a whole animal system.
Moreover, our studies also explore the compensatory metabolic pathways that are activated in response to
decreased glycolytic flux, which in a clinical setting, could render tumors insenstive to drug treatments. Finally,
we have uncovered an unexpected correlation between the repression of aerobic glycolysis, increased levels of
fatty acid oxidation, and pyrimidine metabolism. My lab will use this unexpected discovery as a foundation to
explore the poorly understood role of fatty acid beta-oxidation in nucleotide production. Our studies will allow, for
the first time, a genet...

## Key facts

- **NIH application ID:** 10415963
- **Project number:** 5R35GM119557-07
- **Recipient organization:** TRUSTEES OF INDIANA UNIVERSITY
- **Principal Investigator:** Jason Michael Tennessen
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $442,947
- **Award type:** 5
- **Project period:** 2016-08-01 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10415963

## Citation

> US National Institutes of Health, RePORTER application 10415963, A Drosophila Model for the Regulation of Aerobic Glycolysis (5R35GM119557-07). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10415963. Licensed CC0.

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