Insulin signaling regulates fatty acid catabolism at the level of CoA activation

• Published in: PLoS genetics Vol. 8; no. 1; p. e1002478
• Main Authors: Xu, Xiaojun, Gopalacharyulu, Peddinti, Seppänen-Laakso, Tuulikki, Ruskeepää, Anna-Liisa, Aye, Cho Cho, Carson, Brian P, Mora, Silvia, Orešič, Matej, Teleman, Aurelio A
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.01.2012; Public Library of Science (PLoS)
• Subjects: 3T3 Cells; Acyl Coenzyme A - metabolism; Animals; Biology; Cellular signal transduction; Coenzyme A Ligases - genetics; Coenzyme A Ligases - metabolism; Drosophila melanogaster - genetics; Drosophila melanogaster - metabolism; Drosophila Proteins - genetics; Drosophila Proteins - metabolism; Enzymes; Fatty acid metabolism; Fatty acids; Fatty Acids - metabolism; Forkhead Transcription Factors - genetics; Forkhead Transcription Factors - metabolism; Gene Expression Regulation; Genetic aspects; HEK293 Cells; Humans; Hyperglycemia; Insulin - genetics; Insulin - metabolism; Insulin resistance; Ligases; Lipid Metabolism; Lipids; Male; Metabolism; Mice; Physiological aspects; Proteins; Signal Transduction; Transcriptional Activation; Triglycerides - metabolism; United Kingdom
• ISSN: 1553-7404; 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1002478

The insulin/IGF signaling pathway is a highly conserved regulator of metabolism in flies and mammals, regulating multiple physiological functions including lipid metabolism. Although insulin signaling is known to regulate the activity of a number of enzymes in metabolic pathways, a comprehensive understanding of how the insulin signaling pathway regulates metabolic pathways is still lacking. Accepted knowledge suggests the key regulated step in triglyceride (TAG) catabolism is the release of fatty acids from TAG via the action of lipases. We show here that an additional, important regulated step is the activation of fatty acids for beta-oxidation via Acyl Co-A synthetases (ACS). We identify pudgy as an ACS that is transcriptionally regulated by direct FOXO action in Drosophila. Increasing or reducing pudgy expression in vivo causes a decrease or increase in organismal TAG levels respectively, indicating that pudgy expression levels are important for proper lipid homeostasis. We show that multiple ACSs are also transcriptionally regulated by insulin signaling in mammalian cells. In sum, we identify fatty acid activation onto CoA as an important, regulated step in triglyceride catabolism, and we identify a mechanistic link through which insulin regulates lipid homeostasis.