title: 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.
authors.affiliation: Molecular Membrane Neuroscience, Brain Science Institute, RIKEN, Wako-shi, Saitama 351-0198, Japan.
authors.forename: Ayako
authors.initials: A
authors.lastname: Kohyama-Koganeya
authors.forename: Takuji
authors.initials: T
authors.lastname: Nabetani
authors.forename: Masayuki
authors.initials: M
authors.lastname: Miura
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Hirabayashi
mesh_terms: D051698:Activating Transcription Factor 2 / Q000378:metabolism; D000818:Animals; D004331:Drosophila melanogaster / Q000166:cytology / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D004734:Energy Metabolism / Q000235:genetics; D005216:Fat Body / Q000201:enzymology* / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D005963:Glucosylceramides / Q000378:metabolism; D005964:Glucosyltransferases / Q000378:metabolism*; D008297:Male; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D051698:Activating Transcription Factor 2; D005963:Glucosylceramides; D005964:Glucosyltransferases; C023246:ceramide glucosyltransferase; D048051:p38 Mitogen-Activated Protein Kinases