Drosophila lipin interacts with insulin and TOR signaling pathways in the control of growth and lipid metabolism

Abstract

Lipin proteins have key functions in lipid metabolism, acting as both phosphatidate phosphatases (PAPs) and nuclear regulators of gene expression. We show that the insulin and TORC1 pathways independently control functions of Drosophila Lipin (dLipin). Reduced signaling through the insulin receptor strongly enhanced defects caused by dLipin deficiency in fat body development, whereas reduced signaling through TORC1 led to translocation of dLipin into the nucleus. Reduced expression of dLipin resulted in decreased signaling through the insulin-receptor-controlled PI3K-Akt pathway and increased hemolymph sugar levels. Consistent with this, downregulation of dLipin in fat body cell clones caused a strong growth defect. The PAP but not the nuclear activity of dLipin was required for normal insulin pathway activity. Reduction of other enzymes of the glycerol-3 phosphate pathway affected insulin pathway activity in a similar manner, suggesting an effect that is mediated by one or more metabolites associated with the pathway. Taken together, our data show that dLipin is subject to intricate control by the insulin and TORC1 pathways, and that the cellular status of dLipin impacts how fat body cells respond to signals relayed through the PI3K-Akt pathway.

Innate immune signaling inDrosophilashifts anabolic lipid metabolism from triglyceride storage to phospholipid synthesis in an ER stress-dependent manner

“…Knockdown of Lipin or midway in fat body or loss of midway in the whole animal decreased triglyceride storage ( Figures S2A-S2C), consistent with previous findings (Beller et al, 2010;Grillet et al, 2016;Schmitt et al, 2015;Ugrankar et al, 2011). Elevated fat body expression of Lipin or midway was not sufficient to drive triglyceride accumulation in otherwise wild type larvae ( Figures S2D-S2F).…”

“…Except where noted, experiments were performed using mid-to late-third instar larvae (96-108 h after egg lay). The UAS-Toll 10b (Hu et al, 2004), UAS-Dif (Yagi and Ip, 2005), UAS-Lipin (Schmitt et al, 2015), Clemmons et al, 2015), and Drs D7-17 (Kenmoku et al, 2017).…”

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.…”

“…Drosophila uses the flippase/flippase recognition target (Flp/FRT) recombination system to generate single homozygous mutant clones in otherwise heterozygous, chimeric fat bodies. Clonal analysis has been successfully employed to detect autonomous roles of Plin1 (Beller et al, 2010), dSeipin (Bi et al, 2014) and the lipogenesis enzyme encoded by the dLipin gene (Schmitt et al, 2015) in fat body lipid storage droplets. Given the role of the fat body as the central hub in inter-organ communication, in vivo monitoring of signaling pathway activities is particularly valuable.…”

mTORC1 signalling mediates PI3K-dependent large lipid droplet accumulation inDrosophilaovarian nurse cells

“…Lipolysis of LDs is controlled by lipases, including hormone-sensitive lipase, which is regulated positively and negatively by β-adrenergic and insulin signalling, respectively, via effects on cAMP levels in adipose tissue (Lampidonis et al, 2011). IIS and mTORC1 signalling also affect the activity of Lipin, which positively regulates enzymes involved in TAG synthesis (Schmitt et al, 2015). …”