title: Differential regulation of CIDEA and CIDEC expression by insulin via Akt1/2- and JNK2-dependent pathways in human adipocytes.
abstract: Both insulin and the cell death-inducing DNA fragmentation factor-α-like effector (CIDE) family play important roles in apoptosis and lipid droplet formation. Previously, we reported that CIDEA and CIDEC are differentially regulated by insulin and contribute separately to insulin-induced anti-apoptosis and lipid droplet formation in human adipocytes. However, the upstream signals of CIDE proteins remain unclear. Here, we investigated the signaling molecules involved in insulin regulation of CIDEA and CIDEC expression. The phosphatidylinositol 3-kinase (PI3K) inhibitors wortmannin and PI-103 blocked both insulin-induced downregulation of CIDEA and upregulation of CIDEC. The Akt inhibitor API-2 and the c-Jun N-terminal kinase (JNK) inhibitor SP600125 selectively inhibited insulin regulation of CIDEA and CIDEC expression, respectively, whereas the MAPK/ERK kinase inhibitor U0126 and the p38 inhibitor SB203580 did not. Small interfering RNA-mediated depletion of Akt1/2 prevented insulin-induced downregulation of CIDEA and inhibition of apoptosis. Depletion of JNK2, but not JNK1, inhibited insulin-induced upregulation of CIDEC and lipid droplet enlargement. Furthermore, insulin increased both Akt and JNK phosphorylation, which was abrogated by the PI3K inhibitors. These results suggest that insulin regulates CIDEA and CIDEC expression via PI3K, and it regulates expression of each protein via Akt1/2- and JNK2-dependent pathways, respectively, in human adipocytes.
authors.affiliation: Discovery Research Laboratories, Kyorin Pharmaceutical Co. Ltd., Tochigi 329-0114, Japan.
authors.forename: Minoru
authors.initials: M
authors.lastname: Ito
authors.forename: Michiaki
authors.initials: M
authors.lastname: Nagasawa
authors.forename: Naoki
authors.initials: N
authors.lastname: Omae
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Ide
authors.forename: Yunike
authors.initials: Y
authors.lastname: Akasaka
authors.forename: Koji
authors.initials: K
authors.lastname: Murakami
mesh_terms: D017667:Adipocytes / Q000166:cytology / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D002747:Chlorpropamide / Q000031:analogs & derivatives / Q000494:pharmacology; D053938:DNA Fragmentation / Q000187:drug effects; D015536:Down-Regulation; D005260:Female; D005663:Furans / Q000494:pharmacology; D005786:Gene Expression Regulation; D020868:Gene Silencing / Q000187:drug effects; D006801:Humans; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology; D048056:Mitogen-Activated Protein Kinase 9 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009765:Obesity / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000494:pharmacology; D015398:Signal Transduction; D015854:Up-Regulation; D000096926:Benzenesulfonamides
chemical_list: D051017:Apoptosis Regulatory Proteins; D002747:Chlorpropamide; D005663:Furans; D007328:Insulin; D048056:Mitogen-Activated Protein Kinase 9; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011506:Proteins; D051057:Proto-Oncogene Proteins c-akt; D011725:Pyridines; D011743:Pyrimidines; D034741:RNA, Small Interfering; C111224:API 2; D000096926:Benzenesulfonamides; C502539:CIDEA protein, human; C472088:CIDEC protein, human; C522973:PI103