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

X. Xu, Peddinti Gopalacharyulu, Tuulikki Seppänen-Laakso, Anna-Liisa Ruskeepää, C. Cho Aye, A. Carson, S. Mora, Matej Orešič, A. A. Teleman (Corresponding Author)

Research output: Contribution to journalArticleScientificpeer-review

48 Citations (Scopus)

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.
Original languageEnglish
Article numbere1002478
Number of pages14
JournalPLoS Genetics
Volume8
Issue number1
DOIs
Publication statusPublished - 2012
MoE publication typeA1 Journal article-refereed

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catabolism
Coenzyme A
insulin
Fatty Acids
fatty acid
Insulin
fatty acids
metabolism
lipid
homeostasis
Ligases
Metabolic Networks and Pathways
ligases
acid activation
biochemical pathways
Triglycerides
Homeostasis
triacylglycerols
Lipids
beta oxidation

Cite this

Xu, X. ; Gopalacharyulu, Peddinti ; Seppänen-Laakso, Tuulikki ; Ruskeepää, Anna-Liisa ; Cho Aye, C. ; Carson, A. ; Mora, S. ; Orešič, Matej ; Teleman, A. A. / Insulin signaling regulates fatty acid catabolism at the level of CoA activation. In: PLoS Genetics. 2012 ; Vol. 8, No. 1.
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Xu, X, Gopalacharyulu, P, Seppänen-Laakso, T, Ruskeepää, A-L, Cho Aye, C, Carson, A, Mora, S, Orešič, M & Teleman, AA 2012, 'Insulin signaling regulates fatty acid catabolism at the level of CoA activation', PLoS Genetics, vol. 8, no. 1, e1002478. https://doi.org/10.1371/journal.pgen.1002478

Insulin signaling regulates fatty acid catabolism at the level of CoA activation. / Xu, X.; Gopalacharyulu, Peddinti; Seppänen-Laakso, Tuulikki; Ruskeepää, Anna-Liisa; Cho Aye, C.; Carson, A.; Mora, S.; Orešič, Matej; Teleman, A. A. (Corresponding Author).

In: PLoS Genetics, Vol. 8, No. 1, e1002478, 2012.

Research output: Contribution to journalArticleScientificpeer-review

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AU - Xu, X.

AU - Gopalacharyulu, Peddinti

AU - Seppänen-Laakso, Tuulikki

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AU - Cho Aye, C.

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AU - Orešič, Matej

AU - Teleman, A. A.

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AB - 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.

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