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Carl S. Thummel

Professor of Human Genetics

B.A. Colgate University

Ph.D. University of California, Berkeley

Research

References

carl.thummel@genetics.utah.edu

Carl Thummel's Lab Page

Carl Thummel's PubMed Literature Search

Research

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 clear 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 sugar, 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 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 several lines of study underway in the Thummel lab, including the transcriptional regulation of metabolism by nuclear receptors and 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 nuclear receptors known in any genetic model system. In spite of this small number, the fly nuclear receptors include orthologs of key 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, DHR96, and dERR. To date, we have defined the temporal expression patterns of all detectable nuclear receptors throughout the fly life cycle. By raising antibodies against the encoded proteins we can determine their patterns of expression in the animal. We analyze the phenotypes associated with both loss-of-function and gain-of-function mutations as a means of determining gene function. Transgenic expression of dsRNA for RNAi allows us to disrupt gene function in a precise temporal and spatial manner. We use microarrays to determine the effects of loss-of-function and gain-of-function mutations on gene expression, and classify these targets into functional groups by bioinformatics. In addition, we use metabolomic profiling to determine the effects of nuclear receptor mutations on specific metabolic pathways, linking these functions to key target genes identified in our microarray studies as well as developmental defects. The long-term goal of these studies is to exploit our ability to link Drosophila nuclear receptors with defined transcriptional cascades and specific biological responses as a means of furthering our understanding of how nuclear receptors control metabolic homeostasis and contribute to human disease.

Our lab is also studying the functions of key evolutionarily conserved mitochondrial proteins (MCPs) in close collaboration with Jared Rutter’s lab in the Biochemistry Department. 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 most 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-quarter of these proteins remain largely uncharacterized. These include many proteins that are highly conserved throughout eukarya, a strong indication that they perform a fundamentally important function. We are conducting detailed characterization of MCP function in Drosophila, building off key results obtained from analysis of the yeast homologs by the Rutter lab. Our studies include phenotypic studies of null mutant animals, studies of responses to dietary changes and stresses, and metabolomic profiling. 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.

References