TY - JOUR
T1 - Insulin signaling regulates fatty acid catabolism at the level of CoA activation
AU - Xu, Xiaojun
AU - Gopalacharyulu, Peddinti
AU - Seppänen-Laakso, Tuulikki
AU - Ruskeepää, Anna Liisa
AU - Aye, Cho Cho
AU - Carson, Brian P.
AU - Mora, Silvia
AU - Orešič, Matej
AU - Teleman, Aurelio A.
PY - 2012/1
Y1 - 2012/1
N2 - 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.
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.
UR - http://www.scopus.com/inward/record.url?scp=84857473501&partnerID=8YFLogxK
U2 - 10.1371/journal.pgen.1002478
DO - 10.1371/journal.pgen.1002478
M3 - Article
C2 - 22275878
AN - SCOPUS:84857473501
SN - 1553-7390
VL - 8
SP - e1002478
JO - PLoS Genetics
JF - PLoS Genetics
IS - 1
M1 - e1002478
ER -