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14th Annual Patton lecture

Carl Thrummel, University of Utah on  2nd March 2016 at 12:15 p.m. in 2123 Comstock Hall.  The title of Professor Thrummel’s presentation is: Developmental Regulation of Metabolic Transitions by Drosophila Nuclear Receptors.  Dr Thrummel will be leading a linked Patton Symposium on Hemiptera on 3rd March


Developmental Regulation of Metabolic Transitions by Drosophila Nuclear Receptors
William Barry, Jason Tennessen, Keith Baker, Janelle Evans, Geanette Lam, and Carl Thummel
Department of Human Genetics, University of Utah School of Medicine, 15 N 2030 E Room 2100, Salt Lake City, UT 84112-5330 USA

The Drosophila genome encodes 18 nuclear receptors, providing an ideal model system for studying the roles of these ligand-regulated transcription factors in growth, development, and metabolism. Our studies of two nuclear receptors, dERR and dHNF4, have shown that they direct widespread metabolic switches during development that establish the metabolic state of larvae and adults, respectively. dERR directly activates a transcriptional program during mid-embryogenesis, up-regulating the genes that encode enzymes in glycolysis, the pentose phosphate pathway, and lactate production. Combined with metabolomic analysis, this work indicates that dERR establishes a metabolic state related to the Warburg effect, which is normally associated with proliferating cancer cells. This dERR-regulated mid-embryonic transition anticipates the metabolic needs of the next stage in development, establishing an aerobic glycolytic state that supports the remarkable 200-fold increase in mass that normally occurs during larval development.

Interestingly, our functional studies of dHNF4 have revealed a subsequent nuclear receptor-regulated metabolic transition that establishes a different metabolic state in the adult fly. Through a series of studies we have shown that dHNF4 mutants display adult-onset hyperglycemia, glucose intolerance, and defects in glucose-stimulated insulin (DILP2) secretion. These phenotypes mirror those of MODY1 patients, who carry mutations in the human ortholog of dHNF4, HNF4α, providing an animal model to study this disorder. dHNF4 is required in both the fat body and insulin-producing cells to maintain glucose homeostasis by supporting a developmental switch toward oxidative metabolism and glucose-stimulated insulin secretion at the transition to adulthood, supporting the energetic needs of the mature animal. 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 regulate metabolism and contribute to human disease.