In addition to the widely studied type 1 and type 2 diabetes, there are a number of monogenic inherited forms of this disorder, including Maturity-Onset Diabetes of the Young (MODY). The genetic basis for the first MODY subtype was discovered 20 years ago through its association with mutations in the HNF4A nuclear receptor. This link with a transcription factor focused efforts on defining the central roles of Hnf4A in the key tissues where it controls metabolism: the liver, intestine, and pancreas. Genetic studies in mouse models, however, did not recapitulate the full range of symptoms associated with MODY1 ? in particular, the sustained hypoinsulinemic hyperglycemia seen in the clinic. We discovered that the expression pattern of HNF4A is conserved through evolution, from flies to mammals, and that mutants for the Drosophila ortholog of Hnf4A (dHNF4) display a range of phenotypes that resemble those of MODY1 patients. These include adult-onset hyperglycemia, impaired glucose-stimulated insulin secretion, glucose intolerance, and reduced peripheral insulin signaling. In addition, our RNA-seq transcriptional profiling identified several functional groups of dHNF4-regulated genes that act in the tissues where the receptor is expressed in flies and humans. This includes widespread effects on inflammatory response pathways, similar to the role of Hnf4A in the mammalian intestine, as well as key genes involved in glucose-stimulated insulin secretion. Unexpectedly, we also discovered that mitochondrial-encoded gene expression is significantly reduced in the mutant, and that dHNF4 protein localizes to mitochondria and binds specifically to the control region of the mitochondrial genome. dHNF4 also directly regulates nuclear genes that encode mitochondrial proteins, demonstrating a central role in mitochondrial physiology. Given that only a few nuclear transcription factors have been identified in mitochondria, and their roles are poorly understood, we propose to undertake a detailed analysis of the mitochondrial functions of dHNF4 and link these to key downstream roles of the receptor. In addition, we will use Drosophila genetics to elucidate the interactions between mitochondrial dysfunction, inflammation, and metabolic defects in the context of diabetes. Although these pathways are often associated in metabolic syndrome, their cause and effect relationships remain unclear. Our overall hypothesis is that dHNF4 acts in multiple tissues to maintain mitochondrial function and to suppress inflammation and diabetes. We propose three specific aims to (1) determine the tissue-specific functions of dHNF4, (2) determine the physiological functions of dHNF4-regulated pathways and target genes, and (3) characterize the evolutionary conservation of dHNF4 functions, from flies to mammals. Taken together, this research will provide a simple genetic system to dissect the interplay between mitochondrial dysfunction, inflammation, and diabetes, as well as an animal model for MODY1. Our results, in turn, can be used to guide future studies in mouse models as well as devise new potential therapeutic approaches for preventing and treating diabetes in humans.

Public Health Relevance

Our studies use Drosophila as a simple model system to define the molecular mechanisms of glucose-stimulated insulin secretion and the regulation of glucose homeostasis in an intact developing animal. This work will provide insights into normal metabolism as well as provide new directions for combating diabetes and reducing its devastating impact on human health.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK108941-03
Application #
9529639
Study Section
Cellular Aspects of Diabetes and Obesity Study Section (CADO)
Program Officer
Silva, Corinne M
Project Start
2016-09-30
Project End
2020-07-31
Budget Start
2018-08-01
Budget End
2019-07-31
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Utah
Department
Genetics
Type
Schools of Medicine
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Storelli, Gilles; Nam, Hyuck-Jin; Simcox, Judith et al. (2018) Drosophila HNF4 Directs a Switch in Lipid Metabolism that Supports the Transition to Adulthood. Dev Cell :
Cox, James E; Thummel, Carl S; Tennessen, Jason M (2017) Metabolomic Studies in Drosophila. Genetics 206:1169-1185
Praggastis, Sophia A; Thummel, Carl S (2017) Right time, right place: the temporal regulation of developmental gene expression. Genes Dev 31:847-848