Carl S. Thummel

Our lab is studying the regulation of metabolism using the fruit fly, Drosophila melanogaster, as a model system. Remarkably, in spite of its small size and differences from mammals, many of the basic metabolic pathways are conserved through evolution from flies to humans. Flies have analogs of the basic tissues that control metabolism, including the equivalents of a liver, intestine, adipose tissue, pancreas, and kidneys. Many of the basic metabolic regulatory circuits are intact. Thus, for example, flies secrete insulin in response to elevated levels of circulating nutrients, and mobilize stored energy in response to a hormone related to glucagon. Flies are also subject to similar metabolic disorders as people, and thus can acquire type 2 diabetes if exposed to a high sugar diet, or can more than double their fat content and acquire heart disease when subjected to a high fat diet. They are also responsive to drugs used to treat metabolic disorders, such as the weight loss drug Alli (Orlistat). Our lab is studying the basic molecular mechanisms by which energy metabolism is controlled using the wide range of genetic tools available in Drosophila. We seek to uncover fundamental aspects of metabolic regulation that are conserved through evolution, with the aim of preventing and curing human disease. There are two major lines of study underway in the Thummel lab: (1) the transcriptional regulation of metabolism by nuclear receptors and (2) functions for evolutionarily conserved mitochondrial proteins.

Nuclear receptors are a family of ligand-regulated transcription factors that bind small lipophilic compounds, such as fatty acids, sterols and bile acids. In response to these signals, nuclear receptors regulate the expression of genes in specific metabolic pathways. The Drosophila genome encodes 18 nuclear receptors, compared to 48 in humans and 284 in C. elegans, providing the smallest complete set of these factors in any genetic model system. In spite of this small number, the fly nuclear receptors represent all major subclasses of human receptors, providing a good model for studying nuclear receptor regulation and function. Our current research in this area is focused on three nuclear receptors that play central roles in metabolism: dHNF4, E78, and dERR. Our goal is to extend our understanding of nuclear receptor signaling in new directions by using Drosophila as a genetic tool to define receptor regulation and function in the context of an intact animal, with an emphasis on characterizing those pathways that are held in common with their mammalian homologs. We anticipate that, as with past studies in Drosophila, discoveries stemming from our work will improve our design of mouse models for future functional studies and provide new directions for combating critical human diseases associated with nuclear receptor dysfunction, including cardiovascular disease, diabetes, and obesity.

Mitochondria are dynamic and complex organelles that play a central role in all aspects of biology, including energy production, intermediary metabolism, and apoptosis. In addition, mitochondrial dysfunction is associated with a wide range of diseases, including cancer, type 2 diabetes, and neurodegenerative disorders. As a result of these critical activities, many efforts have focused on defining the mitochondrial proteome, with over 1,000 proteins identified to date in mammals. Remarkably, however, one-fifth of these proteins remain largely uncharacterized. Our lab is studying the functions of key evolutionarily conserved mitochondrial proteins (MCPs) in close collaboration with Jared Rutter’s lab in the Biochemistry Department. We are conducting detailed characterization of MCP function in Drosophila, building off results obtained from analysis of the yeast homologs by the Rutter lab. Our goal in this research is to use Drosophila to provide new insights into the biological and physiological functions of these MCPs that can guide our understanding of how these proteins impact human health and disease.