Metabolic homeostasis plays a central role in all aspects of life, allowing animals to balance their dietary intake with the energy needs required for day-to-day survival. Conversely, misregulation of metabolism can lead to obesity and type 2 diabetes, which are critical risk factors for human disease, including cardiovascular disorders and cancer. The goal of our research is to use the fruit fly, Drosophila melanogaster, as a simple model system to define the central regulatory pathways that control metabolism in all higher organisms, including humans. The molecular context for our studies is nuclear receptors (NRs) - ligand-regulated transcription factors that play a central role in sensing small lipophilic signals and maintaining metabolic homeostasis. Drosophila has 18 NR genes, significantly fewer than the 48 genes found in humans, spanning all vertebrate NR subclasses and encoding homologs of key human receptors, including HNF4 (dHNF4), LXR/FXR (DHR96), LRH-1 (DHR39), NR4A receptors (DHR38), and ERR (dERR). Our recent studies of dHNF4, DHR96, DHR38, and dERR, have shown, for the first time, that the basic regulation and metabolic functions of these NRs have been conserved through evolution. In addition, our use of genetics to dissect Drosophila NR signaling pathways has provided new insights into their mechanism of action and new directions for understanding their mammalian counterparts. In this renewal application, we propose further characterization of Drosophila NRs in metabolism, with a focus on lipid metabolic pathways. We will build off our initial studies of dHNF4 and DHR96 - NRs that control the starved and fed state, respectively. In addition, we will undertake an analysis of the Drosophila LRH-1 homolog, DHR39, with the goal of defining how it interacts with DHR96 to control triglyceride and cholesterol homeostasis. There are three specific aims to this proposal: (1) To define the metabolic functions of dHNF4 during development, (2) To define the mechanisms by which DHR96 coordinates lipid metabolism, and (3) To characterize the role of NR regulatory interactions in lipid metabolism. By combining metabolite measurements, metabolomic profiling, microarray studies, tissue- specific rescue, RNAi experiments, functional characterization of select target genes, promoter studies in transgenic animals, ligand regulation of the receptor, and ChIP-seq experiments, we will define the mechanisms of NR signaling at a level of detail that is difficult to achieve in more complex organisms. These experiments will provide insights into how the orthologous mammalian receptors, HNF4, LXR/FXR, and LRH-1 contribute to metabolic homeostasis through their regulation of specific downstream transcriptional programs. These studies also have direct implications for understanding how the orthologous human NRs contribute to critical diseases associated with NR dysfunction, including cardiovascular disease, diabetes, and obesity.

Public Health Relevance

Our studies use Drosophila as a simple model system to define the molecular mechanisms of nuclear receptor action that are conserved through evolution up to humans. This work will have an impact on our understanding of normal nuclear receptor signaling pathways and provide new directions for combating critical human diseases associated with nuclear receptor dysfunction, including cardiovascular disease, diabetes, and obesity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK075607-07
Application #
8293225
Study Section
Molecular and Cellular Endocrinology Study Section (MCE)
Program Officer
Margolis, Ronald N
Project Start
2006-07-01
Project End
2016-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
7
Fiscal Year
2012
Total Cost
$343,850
Indirect Cost
$113,850
Name
University of Utah
Department
Genetics
Type
Schools of Medicine
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Tennessen, Jason M; Bertagnolli, Nicolas M; Evans, Janelle et al. (2014) Coordinated metabolic transitions during Drosophila embryogenesis and the onset of aerobic glycolysis. G3 (Bethesda) 4:839-50
Tennessen, Jason M; Barry, William E; Cox, James et al. (2014) Methods for studying metabolism in Drosophila. Methods 68:105-15
Sieber, Matthew H; Thummel, Carl S (2012) Coordination of triacylglycerol and cholesterol homeostasis by DHR96 and the Drosophila LipA homolog magro. Cell Metab 15:122-7
Tennessen, Jason M; Thummel, Carl S (2011) Coordinating growth and maturation - insights from Drosophila. Curr Biol 21:R750-7
Tennessen, Jason M; Baker, Keith D; Lam, Geanette et al. (2011) The Drosophila estrogen-related receptor directs a metabolic switch that supports developmental growth. Cell Metab 13:139-48
Ruaud, Anne-Fran├žoise; Lam, Geanette; Thummel, Carl S (2011) The Drosophila NR4A nuclear receptor DHR38 regulates carbohydrate metabolism and glycogen storage. Mol Endocrinol 25:83-91
Kozlova, Tatiana; Lam, Geanette; Thummel, Carl S (2009) Drosophila DHR38 nuclear receptor is required for adult cuticle integrity at eclosion. Dev Dyn 238:701-7
Palanker, Laura; Tennessen, Jason M; Lam, Geanette et al. (2009) Drosophila HNF4 regulates lipid mobilization and beta-oxidation. Cell Metab 9:228-39
Sieber, Matthew H; Thummel, Carl S (2009) The DHR96 nuclear receptor controls triacylglycerol homeostasis in Drosophila. Cell Metab 10:481-90
Horner, Michael A; Pardee, Keith; Liu, Suya et al. (2009) The Drosophila DHR96 nuclear receptor binds cholesterol and regulates cholesterol homeostasis. Genes Dev 23:2711-6

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