Mio acts in the Drosophila brain to control nutrient storage and feeding

Abstract

Animals recognize the availability of nutrients and regulate the intake and storage of these nutrients accordingly. However, the molecular mechanisms underlying nutrient sensing and subsequent changes in behavior and metabolism are not fully understood. Mlx interactor (Mio), the Drosophila homolog of carbohydrate response element binding protein (ChREBP), functions as a transcription factor in the fat body of the fly to control triglyceride storage as well as feeding, suggesting that Mio may act in a nutrient-sensing pathway to coordinate food consumption and metabolism. Here, we show that Mio functions in neurons in Drosophila to regulate feeding and nutrient storage. Pan-neuronal disruption of Mio function leads to increased triglyceride and glycogen storage, and this phenotype is not due to increased food consumption. Interestingly, targeted disruption of Mio specifically in the insulin-producing cells (IPCs) has little effect on nutrient storage, but increases food consumption suggesting that Mio acts in these neurons to control feeding behavior. Since Mio is a transcription factor, one possible way Mio may act in the IPCs to control feeding is through regulating the expression of Drosophila insulin-like peptides (dilps) or drosulfakinin (dsk), neuropeptides produced in the IPCs. Consistent with this hypothesis, IPC-specific knockdown of Mio leads to an increase in dilp3 expression, while not affecting dilp2, 5 or dsk levels. Together, this study indicates a new function for Mio in the Drosophila brain and specifically in the IPCs, controlling neuropeptide gene expression, feeding and metabolism in accordance with nutrient availability.

Drosophilaas a model to study obesity and metabolic disease

“…Reduction of the fly adiponectin receptor in IPCs also led to increased TAG content, consistent with a role for these cells in the control of obesity (Kwak et al, 2013). IPC expression of RNAi targeting the lipogenic transcription factor ChREBP increased the feeding rate, although there was no effect observed on obesity (Docherty et al, 2015). Little is known about whether IPCs produce other peptides, which makes ablation studies difficult to interpret.…”

Using Drosophila to discover mechanisms underlying type 2 diabetes

“…The glucose-sensing transcription factor Mlx interactor (Mio) is an ortholog of the mammalian factor carbohydrate response element binding protein (ChREBP) and is expressed in IPCs. Although Mio is an appealing candidate for coordinating ILP expression and nutritional status, only Ilp3 is affected by Mio knockdown in Drosophila IPCs ( Docherty et al, 2015 ). An important challenge in understanding transcriptional regulation of ILPs is that manipulations that cause ILP deficiency result in organism-wide defects in metabolic homeostasis, likely mobilizing multiple compensatory pathways.…”

Modeling dietary influences on offspring metabolic programming in Drosophila melanogaster

“…Recently it has been reported that, in the brain, Mio can also regulate nutrient storage and feeding and that control of food consumption occurs in the IPCs likely via the Mio-driven down regulation of dILP3 mRNA (Docherty et al , 2015). …”