title: CoA protects against the deleterious effects of caloric overload in Drosophila.
abstract: We developed a Drosophila model of T2D in which high sugar (HS) feeding leads to insulin resistance. In this model, adipose TG storage is protective against fatty acid toxicity and diabetes. Initial biochemical and gene expression studies suggested that deficiency in CoA might underlie reduced TG synthesis in animals during chronic HS feeding. Focusing on the Drosophila fat body (FB), which is specialized for TG storage and lipolysis, we undertook a series of experiments to test the hypothesis that CoA could protect against the deleterious effects of caloric overload. Quantitative metabolomics revealed a reduction in substrate availability for CoA synthesis in the face of an HS diet. Further reducing CoA synthetic capacity by expressing FB-specific RNAi targeting pantothenate kinase (PK orfumble) or phosphopantothenoylcysteine synthase (PPCS) exacerbated HS-diet-induced accumulation of FFAs. Dietary supplementation with pantothenic acid (vitamin B5, a precursor of CoA) was able to ameliorate HS-diet-induced FFA accumulation and hyperglycemia while increasing TG synthesis. Taken together, our data support a model where free CoA is required to support fatty acid esterification and to protect against the toxicity of HS diets.
authors.affiliation: Division of Endocrinology, Metabolism, and Lipid Research, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110.
authors.forename: Laura
authors.initials: L
authors.lastname: Palanker Musselman
authors.affiliation: Division of Endocrinology, Metabolism, and Lipid Research, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110.
authors.forename: Jill L
authors.initials: JL
authors.lastname: Fink
authors.affiliation: Division of Endocrinology, Metabolism, and Lipid Research, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110 tbaransk@dom.wustl.edu.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Baranski
mesh_terms: D000818:Animals; D003065:Coenzyme A / Q000378:metabolism*; D004040:Dietary Carbohydrates / Q000009:adverse effects; D004331:Drosophila melanogaster / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D002149:Energy Intake / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D010641:Phenotype
chemical_list: D004040:Dietary Carbohydrates; D003065:Coenzyme A
keywords: coenzyme A; diabetes; fatty acid/metabolism; lipotoxicity; nutrition; obesity; triglycerides