dMyc expression in the fat body affects DILP2 release and increases the expression of the fat desaturase Desat1 resulting in organismal growth

Abstract

Drosophila dMyc (dMyc) is known for its role in cell-autonomous regulation of growth. Here we address its role in the fat body (FB), a metabolic tissue that functions as a sensor of circulating nutrients to control the release of Drosophila Insulin-like peptides (Dilps) from the brain influencing growth and development. Our results show that expression of dMyc in the FB affects development and animal size. Expression of dMyc, but not of CycD/cdk4 or Rheb, in the FB diminishes the ability to retain Drosophila Insulin-like peptide-2 (DILP2) in the brain during starvation, suggesting that expression of dMyc mimics the signal that remotely controls the release of Dilps into the hemolymph. dMyc also affects glucose metabolism and increases the transcription of Glucose-transporter-1 mRNA, and of Hexokinase and Pyruvate-Kinase mRNAs, key regulators of glycolysis. These animals are able to counteract the increased levels of circulating trehalose induced by a high sugar diet leading to the conclusion that dMyc activity in the FB promotes glucose disposal. dMyc expression induces cell autonomous accumulation of triglycerides, which correlates with increased levels of Fatty Acid Synthase and Acetyl CoA Carboxylase mRNAs, enzymes responsible for lipid synthesis. We also found the expression of Stearoyl-CoA desaturase, Desat1 mRNA significantly higher in FB overexpressing dMyc. Desat1 is an enzyme that is necessary for monosaturation and production of fatty acids, and its reduction affects dMyc’s ability to induce fat storage and resistance to animal survival. In conclusion, here we present novel evidences for dMyc function in the Drosophila FB in controlling systemic growth. We discovered that dMyc expression triggers cell autonomous mechanisms that control glucose and lipid metabolism to favor the storage of nutrients (lipids and sugars). In addition, the regulation of Desat1 controls the synthesis of triglycerides in FB and this may affect the humoral signal that controls DILP2 release in the brain.

Drosophilaas a model to study obesity and metabolic disease

“…The conserved transcription factors sterol regulatory element-binding protein (SREBP) and carbohydrate-responsive element-binding protein (ChREBP; also called Mondo and Mio in the fly) promote the expression of lipogenic enzymes such as fatty acid synthase, stearoylCoA desaturase and diacylglycerol O-acyltransferase 1 (DGAT1; also called Midway in flies), which all increase triglyceride storage (Buszczak et al, 2002;Garrido et al, 2015;Havula et al, 2013;Kunte et al, 2006;Musselman et al, 2013;Sassu et al, 2012). Other genes required for lipogenesis in the fat body include those encoding the phosphatidate phosphatase dLipin (Schmitt et al, 2015;Ugrankar et al, 2011), pantothenate kinase and phosphopantothenoylcysteine synthase (Musselman et al, 2016) and Myc (Parisi et al, 2013). These represent potential targets for the development of anti-obesity therapeutic strategies, which can be modeled in the fly.…”

The Fruit Fly, Drosophila melanogaster: The Making of a Model (Part I)

“…Second, the fat body controls animal survival with the activation of autophagy, consuming the fats and sugars that accumulated during the feeding phase. Third, the fat body responds to reduced ecdysone signaling from the brain by restraining metabolism and protein synthesis cell-autonomously before each molt by controlling the expression of the growth regulator Myc [20], which was shown to also regulate growth and Dilp2 secretion [21] constituting a regulatory loop that controls animal growth. Insulin signaling is the foremost important growth signal that in flies controls both growth/development and metabolism, with a unique and conserved pathway [22].…”

The Systemic Control of Growth

“…The general activation of IIS that is observed upon adipose EcR inhibition suggests that there is an increase in circulating Dilp levels. Indeed, dMyc activity in the fat cells remotely controls Dilp release from the brain IPCs, although the molecular mechanism underlying this control remains unknown (Parisi et al 2013). Therefore, the activation of ecdysone production by IIS in the PG could be part of a feedback mechanism that permits the integration of nutritional and metabolic inputs from the fat body.…”