Reduction of nucleolar NOC1 leads to the accumulation of pre-rRNAs and induces Xrp1, affecting growth and resulting in cell competition.

NOC1 is a nucleolar protein necessary in yeast for both transport and maturation of ribosomal subunits. Here, we show that Drosophila NOC1 (annotated CG7839) is necessary for rRNAs maturation and for a correct animal development. Its ubiquitous downregulation results in a dramatic decrease in polysome level and of protein synthesis. NOC1 expression in multiple organs, such as the prothoracic gland and the fat body, is necessary for their proper functioning. Reduction of NOC1 in epithelial cells from the imaginal discs results in clones that die by apoptosis, an event that is partially rescued in a Minute/+ background, suggesting that reduction of NOC1 induces the cells to become less fit and to acquire a 'loser' state. NOC1 downregulation activates the pro-apoptotic Eiger-JNK pathway and leads to an increase of Xrp1, which results in the upregulation of DILP8, a member of the insulin/relaxin-like family known to coordinate organ growth with animal development. Our data underline NOC1 as an essential gene in ribosome biogenesis and highlight its novel functions in the control of growth and cell competition.

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

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.

A Novel Drosophila Model to Investigate Adipose Tissue Macrophage Infiltration (ATM) and Obesity highlights the Therapeutic Potential of Attenuating Eiger/TNFα Signaling to Ameliorate Insulin Resistance and ATM.

Obesity is a global health concern associated with various metabolic disorders including insulin resistance and adipose tissue inflammation characterized by adipose tissue macrophage (ATM) infiltration. In this study, we present a novel Drosophila model to investigate the mechanisms underlying ATM infiltration and its association with obesity-related pathologies. Furthermore, we demonstrate the therapeutic potential of attenuating Eiger/TNFα signaling to ameliorate insulin resistance and ATM. To study ATM infiltration and its consequences, we established a novel Drosophila model (OBL) that mimics key aspects of human adipose tissue and allows for investigating ATM infiltration and other related metabolic disorders in a controlled experimental system. We employed genetic manipulation to reduce ecdysone levels to prolong the larval stage. These animals are hyperphagic, and exhibit features resembling obesity in mammals, including increased lipid storage, adipocyte hypertrophy, and high levels of circulating glucose. Moreover, we observed a significant infiltration of immune cells (hemocytes) in the fat bodies accompanied by insulin resistance and systemic metabolic dysregulation. Furthermore, we found that attenuation of Eiger/TNFα signaling and using metformin and anti-oxidant bio-products like anthocyanins led to a reduction in ATM infiltration and improved insulin sensitivity. Our data suggest that the key mechanisms that trigger immune cell infiltration into adipose tissue are evolutionarily conserved and may provide the opportunity to develop Drosophila models to better understand pathways critical for immune cell recruitment into adipose tissue, in relation to the development of insulin resistance in metabolic diseases such as obesity and type 2 diabetes, and non-alcoholic fatty liver disease (NAFLD). We believe that our OBL model can also be a valuable tool and provide a platform either to perform genetic screens or to test the efficacy and safety of novel therapeutic interventions for these diseases.

A Drosophila model targets Eiger/TNFα to alleviate obesity-related insulin resistance and macrophage infiltration.

Obesity is associated with various metabolic disorders, such as insulin resistance and adipose tissue inflammation (ATM), characterized by macrophage infiltration into adipose cells. This study presents a new Drosophila model to investigate the mechanisms underlying these obesity-related pathologies. We employed genetic manipulation to reduce ecdysone levels to prolong the larval stage. These animals are hyperphagic and exhibit features resembling obesity in mammals, including increased lipid storage, adipocyte hypertrophy and high circulating glucose levels. Moreover, we observed significant infiltration of immune cells (hemocytes) into the fat bodies, accompanied by insulin resistance. We found that attenuation of Eiger/TNFα signaling reduced ATM and improved insulin sensitivity. Furthermore, using metformin and the antioxidants anthocyanins, we ameliorated both phenotypes. Our data highlight evolutionarily conserved mechanisms allowing the development of Drosophila models for discovering therapeutic pathways in adipose tissue immune cell infiltration and insulin resistance. Our model can also provide a platform to perform genetic screens or test the efficacy of therapeutic interventions for diseases such as obesity, type 2 diabetes and non-alcoholic fatty liver disease.

The Stearoyl-CoA Desaturase-1 (Desat1) in Drosophila cooperated with Myc to Induce Autophagy and Growth, a Potential New Link to Tumor Survival.

Lipids are an important energy supply in our cells and can be stored or used to produce macromolecules during lipogenesis when cells experience nutrient starvation. Our proteomic analysis reveals that the Drosophila homologue of human Stearoyl-CoA desaturase-1 Desat1) is an indirect target of Myc in fat cells. Stearoyl-CoA desaturases are key enzymes in the synthesis of monounsaturated fatty acids critical for the formation of complex lipids such as triglycerides and phospholipids. Their function is fundamental for cellular physiology, however in tumors, overexpression of SCD-1 and SCD-5 has been found frequently associated with a poor prognosis. Another gene that is often upregulated in tumors is the proto-oncogene c-myc, where its overexpression or increased protein stability, favor cellular growth. Here, we report a potential link between Myc and Desat1 to control autophagy and growth. Using Drosophila, we found that expression of Desat1, in metabolic tissues like the fat body, in the gut and in epithelial cells, is necessary for Myc function to induce autophagy a cell eating mechanism important for energy production. In addition, we observed that reduction of Desat1 affects Myc ability to induce growth in epithelial cells. Our data also identify, in prostatic tumor cells, a significant correlation between the expression of Myc and SCD-1 proteins, suggesting the existence of a potential functional relationship between the activities of these proteins in sustaining tumor progression.