Insulin Signaling Regulates Fatty Acid Catabolism at the Level of CoA Activation

Abstract

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.

Mating activates the heme peroxidase HPX15 in the sperm storage organ to ensure fertility in Anopheles gambiae

“…This increase in glycolysis may be linked to a breakdown of lipids. Indeed, we detected the up-regulation of a predicted lipase that converts triglycerides to fatty acids and glycerol, and of three acyl-CoA ligases, whose orthologs in Drosophila are involved in the activation of longchain fatty acids (21,22). A glycerol-3-phosphate dehydrogenase was also identified, which may convert glycerol produced by triglyceride breakdown to dihydroxyacetone phosphate and feed it into glycolysis as a triose.…”

Lipid metabolism in <italic>Drosophila</italic>: development and disease

“…In fly and mouse models, knockdown of CDK8 or CycC increases the expression of lipogenic genes, such as FAS and acyl-CoA synthetase (ACS) [66]. In addition, in Drosophila and mammalian cells, insulin directly represses the expression of pudgy/ ACS, which is involved in fatty acid b-oxidation [67]. These discoveries of novel regulators/targets of insulin signaling might provide new therapeutic targets towards alleviating the defects in diabetes and other metabolic syndromes.…”

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