title: The Drosophila HNF4 nuclear receptor promotes glucose-stimulated insulin secretion and mitochondrial function in adults.
abstract: Although mutations in HNF4A were identified as the cause of Maturity Onset Diabetes of the Young 1 (MODY1) two decades ago, the mechanisms by which this nuclear receptor regulates glucose homeostasis remain unclear. Here we report that loss of Drosophila HNF4 recapitulates hallmark symptoms of MODY1, including adult-onset hyperglycemia, glucose intolerance and impaired glucose-stimulated insulin secretion (GSIS). These defects are linked to a role for dHNF4 in promoting mitochondrial function as well as the expression of Hex-C, a homolog of the MODY2 gene Glucokinase. dHNF4 is required in the fat body and insulin-producing cells to maintain glucose homeostasis by supporting a developmental switch toward oxidative phosphorylation and GSIS at the transition to adulthood. These findings establish an animal model for MODY1 and define a developmental reprogramming of metabolism to support the energetic needs of the mature animal.
authors.affiliation: Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, United States.
authors.forename: William E
authors.initials: WE
authors.lastname: Barry
authors.affiliation: Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, United States.
authors.forename: Carl S
authors.identifier: 0000-0001-8112-4643
authors.initials: CS
authors.lastname: Thummel
mesh_terms: D000818:Animals; D004330:Drosophila / Q000502:physiology*; D005947:Glucose / Q000378:metabolism*; D051557:Hepatocyte Nuclear Factor 4 / Q000378:metabolism*; D007004:Hypoglycemic Agents; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion
chemical_list: D051557:Hepatocyte Nuclear Factor 4; D007004:Hypoglycemic Agents; D007328:Insulin; D005947:Glucose
keywords: D. melanogaster; chromosomes; developmental biology; gene regulation; genes; insulin secretion; metabolism; mitochondria; nuclear receptors; stem cells; transcription