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.

DOI: http://dx.doi.org/10.7554/eLife.11183.001

eLife digest

Diabetes is a complex disease that is caused by a combination of factors, including the person’s habits and environment, as well as their genetic make-up. However, there are some rare forms of diabetes that are caused simply by mutations in single genes and are directly inherited. For example, it has been known for twenty years that a type of diabetes called “Maturity Onset Diabetes of the Young type 1” (or MODY1 for short) occurs when a gene called HNF4 is mutated or deleted. The symptoms of MODY1 usually appear during early adulthood and include abnormally high levels of sugar in the blood, as well as the pancreas not being able to release the hormone insulin properly in response to these sugars.

Previous studies in mice have tried to understand how losing the HNF4 gene leads to MODY1. However, these mouse models did not fully recreate the symptoms of this disorder and the precise role of HNF4 in preventing diabetes remains unclear. Barry and Thummel have now used the fruit fly, because it is a model organism with simple genetics, to help shed light on this question. Furthermore, flies and mammals use many of the same pathways to control metabolism, making the fly a good model for the disease in humans.

Barry and Thummel deleted the HNF4 gene in fruit flies and observed that the flies had all the symptoms that are typical in people with MODY1. These symptoms included high sugar levels and decreased production of insulin-like hormones. The experiments also showed that HNF4 normally supports the proper expression of another gene called Hex-C; this gene encodes a protein that senses how much sugar is available and helps to keep the amount of sugar circulating the body within normal levels. Barry and Thummel went on to discover that the HNF4 gene is required for the expression of some genes in structures called mitochondria, which provide most of the energy used by animal cells. Lastly, the HNF4 gene became more active as the flies matured, and appeared to help the metabolism of a developing fruit fly transition towards that of an adult.

Together these findings show that HNF4 protects against MODY1 by influencing several components of sugar metabolism in fruit flies. In the future, more studies are needed to understand how exactly HNF4 acts in mitochondria and to explore if similar results are seen in mammals.

DOI: http://dx.doi.org/10.7554/eLife.11183.002