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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.

SUBMITTER: Barry WE

PROVIDER: S-EPMC4869932 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Drosophila HNF4 promotes glucose-stimulated insulin secretion and increased mitochondrial function in adults

Project description:This SuperSeries is composed of the SubSeries listed below.

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Drosophila HNF4 promotes glucose-stimulated insulin secretion and increased mitochondrial function in adults [ChIP-seq]

Project description:Although mutations in the nuclear receptor HNF4A were identified as the cause of Maturity Onset Diabetes of the Young 1 (MODY1) nearly two decades ago, the mechanisms by which HNF4A 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 an unexpected role for dHNF4 within mitochondria to directly regulate mtDNA transcription, while also promoting the expression of nuclear genes involved in oxidative phosphorylation (OXPHOS) and 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 OXPHOS 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.

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Mitochondrial metabolism of pyruvate is essential for regulating glucose-stimulated insulin secretion.

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