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. 2012 Sep 14;426(1):43-8.
doi: 10.1016/j.bbrc.2012.08.028. Epub 2012 Aug 12.

Mio/dChREBP coordinately increases fat mass by regulating lipid synthesis and feeding behavior in Drosophila

Eric D Sassu  1 , Jacqueline E McDermott, Brendan J Keys, Melody Esmaeili, Alex C Keene, Morris J Birnbaum, Justin R DiAngelo
Affiliations

Mio/dChREBP coordinately increases fat mass by regulating lipid synthesis and feeding behavior in Drosophila

Eric D Sassu et al. Biochem Biophys Res Commun. .

Abstract

During nutrient excess, triglycerides are synthesized and stored to provide energy during times of famine. The presence of high glucose leads to the activation of carbohydrate response element binding protein (ChREBP), a transcription factor that induces the expression of a number of glycolytic and lipogenic enzymes. ChREBP is expressed in major metabolic tissues and while we have a basic understanding of ChREBP function in liver, in vivo genetic systems to study the function of ChREBP in other tissues are lacking. In this study, we characterized the role of the Drosophila homolog of ChREBP, Mlx interactor (Mio), in controlling fat accumulation in larvae and adult flies. In Mio mutants, high sugar-induced lipogenic enzyme mRNA expression is blunted and lowering Mio levels specifically in the fat body using RNA interference leads to a lean phenotype. A lean phenotype is also observed when the gene bigmax, the fly homolog of ChREBP's binding partner Mlx, is decreased in the larval fat body. Interestingly, depleting Mio in the fat body results in decreased feeding providing a potential cause of the lowered triglycerides observed in these animals. However, Mio does not seem to function as a general regulator of hunger-induced behaviors as decreasing fat body Mio levels has no effect on sleep under fed or starved conditions. Together, these data implicate a role for Mio in controlling fat accumulation in Drosophila and suggests that it may act as a nutrient sensor in the fat body to coordinate feeding behavior with nutrient availability.

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Figures

Figure 1
Figure 1. Mio is necessary for proper expression of lipogenic enzymes under high sugar conditions
Heterozygous (Miok05106/+) and homozygous (Miok05106/Miok05106) Mio mutant larvae 40–43 hr AED were fed yeast paste (control) or 20% sucrose (high sugar) for 4 hr. Larvae were collected, total RNA isolation was performed followed by quantitative RT-PCR for the following genes: (A) Fatty acid synthase (dFAS), (B) Acetyl-CoA carboxylase (dACC), and (C) ATP citrate lyase (dATPCL) genes. mRNA levels of flies fed yeast were set to 1.0 and mRNA levels of flies fed 20% sucrose were then normalized to their appropriate yeast control for each genotype. Each experiment was performed at least three times and the values represent means ± SEM. *, P <0.05 by unpaired Student’s t test comparing 20% sucrose to the yeast control within each genotype.
Figure 2
Figure 2. Mio expression in the fat body is necessary for normal triglyceride storage in Drosophila larvae and adults
(A) Normalized triglyceride/protein ratios in Cg-Gal4>MiodsRNA, Cg-Gal4>Mio-IR, and Cg-Gal4>bigmax-IR wandering instar larvae compared to Cg-Gal4>GFP controls. (B) Normalized triglyceride/protein ratios in yolk-Gal4>MiodsRNA, yolk-Gal4>Mio-IR, and yolk-Gal4>bigmax-IR 5–8 day old females compared to yolk-Gal4>GFP controls. (C) Normalized triglyceride/protein ratios in to-Gal4>MiodsRNA, to-Gal4>Mio-IR, and to-Gal4>bigmax-IR 5–8 day old males compared to to-Gal4>GFP controls. Each experiment was performed at least three times and the values represent means ± SEM. *, P <0.05 by unpaired Student’s t test comparing each experimental genotype to its appropriate GFP control.
Figure 3
Figure 3. Mio regulates the amount of fat stored in each cell of the adult fat body
(A) Total DNA content of fat bodies dissected from 4- to 7-day-old adult yolk-Gal4>MiodsRNA females or yolk-Gal4>GFP controls. (B) Triglyceride/protein, triglyceride/DNA, and protein/DNA ratios of fat bodies dissected from yolk-Gal4>MiodsRNA females or yolk-Gal4>GFP controls. Each experiment was performed at least three times and the values represent means ± SEM. *, P <0.05 by unpaired Student’s t test.
Figure 4
Figure 4. Mio acts in the fat body to promote feeding
(A) Total food consumption was measured in the CAFE assay over 24 hrs in yolk-Gal4>GFP, yolk-Gal4>MiodsRNA, and yolk-Gal4>Mio-IR 5–8 day old females. Mio knockdown in the fat body significantly reduced feeding compared to GFP controls. (B) Flies were tested for sleep 24 hr on food and 24 hr on agar. Flies expressing Mio-IR and MiodsRNA using yolk-Gal4 significantly reduced sleep during starvation similarly to yolk-Gal4, UAS-Mio-IR and UAS-MiodsRNA controls. (C) Analysis of starvation-induced sleep suppression revealed no significant differences between Mio knockdown flies (yolk-Gal4>Mio-IR and yolk-Gal4>MiodsRNA) and yolk-Gal4, UAS-Mio-IR and UAS-MiodsRNA controls. (D, E) yolk-Gal4, UAS-Mio-IR, UAS-MiodsRNA, yolk-Gal4>Mio-IR, and yolk-Gal4>MiodsRNA all displayed significantly reduced bout number (D), and no changes in average bout length (E), indicating that Mio does not alter sleep architecture in fed or starved flies. Each experiment was performed at least two times and the values represent means ± SEM. *, P <0.05, ** P <0.01 by unpaired Student’s t test.
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