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Glucosylceramide synthase in the fat body controls energy metabolism in Drosophila.

ABSTRACT: Glucosylceramide synthase (GlcT-1) catalyzes the synthesis of glucosylceramide (GlcCer), the core structure of major glycosphingolipids (GSLs). Obesity is a metabolic disorder caused by an imbalance between energy uptake and expenditure, resulting in excess stored body fat. Recent studies have shown that GSL levels are increased in obese rodents and that pharmacologically reducing GSL levels by inhibiting GlcCer synthesis improves adipocyte function. However, the molecular mechanism underlying these processes is still not clearly understood. Using Drosophila as a model animal, we report that GlcT-1 expression in the fat body, which is equivalent to mammalian adipose tissue, regulates energy metabolism. Overexpression of GlcT-1 increases stored nutrition (triacylglycerol and carbohydrate) levels. Conversely, reduced expression of GlcT-1 in the fat body causes a reduction of fat storage. This regulation occurs, at least in part, through the activation of p38-ATF2 signaling. Furthermore, we found that GlcCer is the sole GSL of the fat body, indicating that regulation of GlcCer synthesis by GlcT-1 in the fat body is responsible for regulating energy homeostasis. Both GlcT-1 and p38-ATF2 signaling are evolutionarily conserved, leading us to propose an evolutionary perspective in which GlcT-1 appears to be one of the key factors that control fat metabolism.

SUBMITTER: Kohyama-Koganeya A

PROVIDER: S-EPMC3122912 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundObesity and phenotypic traits associated with this condition exhibit significant heritability in natural populations of most organisms. While a number of genes and genetic pathways have been implicated to play a role in obesity associated traits, the genetic architecture that underlies the natural variation in these traits is largely unknown. Here, we used 40 wild-derived inbred lines of Drosophila melanogaster to quantify genetic variation in body weight, the content of three major metabolites (glycogen, triacylglycerol, and glycerol) associated with obesity, and metabolic rate in young flies. We chose these lines because they were previously screened for variation in whole-genome transcript abundance and in several adult life-history traits, including longevity, resistance to starvation stress, chill-coma recovery, mating behavior, and competitive fitness. This enabled us not only to identify candidate genes and transcriptional networks that might explain variation for energy metabolism traits, but also to investigate the genetic interrelationships among energy metabolism, behavioral, and life-history traits that have evolved in natural populations.ResultsWe found significant genetically based variation in all traits. Using a genome-wide association screen for single feature polymorphisms and quantitative trait transcripts, we identified 337, 211, 237, 553, and 152 novel candidate genes associated with body weight, glycogen content, triacylglycerol storage, glycerol levels, and metabolic rate, respectively. Weighted gene co-expression analyses grouped transcripts associated with each trait in significant modules of co-expressed genes and we interpreted these modules in terms of their gene enrichment based on Gene Ontology analysis. Comparison of gene co-expression modules for traits in this study with previously determined modules for life-history traits identified significant modular pleiotropy between glycogen content, body weight, competitive fitness, and starvation resistance.ConclusionsCombining a large phenotypic dataset with information on variation in genome wide transcriptional profiles has provided insight into the complex genetic architecture underlying natural variation in traits that have been associated with obesity. Our findings suggest that understanding the maintenance of genetic variation in metabolic traits in natural populations may require that we understand more fully the degree to which these traits are genetically correlated with other traits, especially those directly affecting fitness.

Project description:Simple Summary To date, it is rare to study the effects of environmental toxicants (e.g., abamectin, a widely used pesticide) on mitochondrial energy metabolism in vitro from a subcellular level in insects, especially from an omics perspective (e.g., metabolomics) due to insufficient samples of mitochondria. The fat body of the German cockroach (Blattella germanica) plays an important role for detoxification, with responses of critical subcellular components (e.g., mitochondria) to abamectin. When B. germanica were fed abamectin, their in vitro mitochondrial morphology was affected, with changes in activity of key enzymes involved in energy metabolism. Furthermore, metabonomic analysis of in vitro mitochondria of B. germanica uncovered a set of metabolites and their pathways related to mitochondrial energy metabolism in response to abamectin feeding/stress. These molecules and pathways were primarily involved in ATP production and energy consumption including oxidative phosphorylation, TCA cycle, and pentose phosphate pathway. The current work is a good example of investigations on subcellular toxicology from multiple perspectives (morphology, physiology, and metabolomics). Abstract Mitochondria are the leading organelle for energy metabolism. The toxic effects of environmental toxicants on mitochondrial morphology, energy metabolism, and their determination of cell fate have already been broadly studied. However, minimal research exists on effects of environmental toxicants such as pesticides on mitochondrial energy metabolism at in vitro subcellular level, particularly from an omics perspectives (e.g., metabolomics). Here, German cockroach (Blattella germanica) was fed diets with (0.01 and 0.001 mg/mL) and without abamectin, and highly purified fat body mitochondria were isolated. Swelling measurement confirmed abnormal mitochondrial swelling caused by abamectin stress. The activity of two key mitochondrial energy metabolism-related enzymes, namely succinic dehydrogenase and isocitrate dehydrogenase, was significantly affected. The metabolomic responses of the isolated mitochondria to abamectin were analyzed via untargeted liquid chromatography/mass spectrometry metabolomics technology. Fifty-two differential metabolites (DMs) were identified in the mitochondria between the 0.001 mg/mL abamectin-fed and the control groups. Many of these DMs were significantly enriched in pathways involved in ATP production and energy consumption (e.g., oxidative phosphorylation, TCA cycle, and pentose phosphate pathway). Nineteen of the DMs were typically related to energy metabolism. This study is valuable for further understanding mitochondrial toxicology under environmental toxicants, particularly its subcellular level.

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Glucosylceramide synthase in the fat body controls energy metabolism in Drosophila.

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