title: A novel JNK2/SREBP-1c pathway involved in insulin-induced fatty acid synthesis in human adipocytes.
abstract: Insulin plays important roles in apoptosis and lipid droplet (LD) formation, and it is one of the determinants involved in increasing fat mass. However, the mechanisms underlying insulin-induced enlargement of fat mass remain unclear. Our previous study suggested that insulin-induced increases in LDs are related to c-Jun N-terminal kinase (JNK)2-mediated upregulation of cell death-inducing DNA fragmentation factor-α-like effector (CIDE)C in human adipocytes. However, other genes involved in insulin/JNK2-induced LD formation are unknown. Here, we explored insulin/JNK2-regulated genes to clarify the mechanism of enlargement of LDs. Microarray analysis revealed that an insulin/JNK2 pathway mostly regulates expression of genes involved in lipid metabolism, including sterol regulatory element binding protein (SREBP)-1, a key transcription factor of lipogenesis. The JNK inhibitor SP600125 blocked insulin-induced upregulation of SREBP-1c expression. Small interfering RNA-mediated depletion of JNK2 suppressed insulin-induced nuclear accumulation of the active form of SREBP-1 protein and upregulation of SREBP-1c. Furthermore, depletion of JNK2 attenuated insulin-induced upregulation of SREBP-1c target lipogenic enzymes, leading to reduced de novo fatty acid synthesis. In addition, JNK2 coimmunoprecipitated with SREBP-1, reinforcing the correlation between JNK2 and SREBP-1. These results suggest that SREBP-1c is a novel insulin/JNK2-regulated gene and that the JNK2/SREBP-1c pathway mediates insulin-induced fatty acid synthesis, which may lead to enlargement of LDs in human adipocytes.
authors.affiliation: Discovery Research Laboratories, Kyorin Pharmaceutical Company Limited, Tochigi 329-0114, Japan.
authors.forename: Minoru
authors.initials: M
authors.lastname: Ito
authors.affiliation: Discovery Research Laboratories, Kyorin Pharmaceutical Company Limited, Tochigi 329-0114, Japan. Electronic address: michiaki.nagasawa@mb.kyorin-pharm.co.jp.
authors.forename: Michiaki
authors.initials: M
authors.lastname: Nagasawa
authors.affiliation: Discovery Research Laboratories, Kyorin Pharmaceutical Company Limited, Tochigi 329-0114, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Omae
authors.affiliation: Discovery Research Laboratories, Kyorin Pharmaceutical Company Limited, Tochigi 329-0114, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Tsunoda
authors.affiliation: Discovery Research Laboratories, Kyorin Pharmaceutical Company Limited, Tochigi 329-0114, Japan.
authors.forename: Junichi
authors.initials: J
authors.lastname: Ishiyama
authors.affiliation: Discovery Research Laboratories, Kyorin Pharmaceutical Company Limited, Tochigi 329-0114, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Ide
authors.affiliation: Discovery Research Laboratories, Kyorin Pharmaceutical Company Limited, Tochigi 329-0114, Japan.
authors.forename: Yunike
authors.initials: Y
authors.lastname: Akasaka
authors.affiliation: Discovery Research Laboratories, Kyorin Pharmaceutical Company Limited, Tochigi 329-0114, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Murakami
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000235:genetics; D017667:Adipocytes / Q000166:cytology / Q000378:metabolism*; D000328:Adult; D000873:Anthracenes / Q000494:pharmacology; D002467:Cell Nucleus / Q000378:metabolism*; D002478:Cells, Cultured; D005227:Fatty Acids / Q000096:biosynthesis* / Q000235:genetics; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D048056:Mitogen-Activated Protein Kinase 9 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D000873:Anthracenes; D005227:Fatty Acids; D007004:Hypoglycemic Agents; D007328:Insulin; C497387:SREBF1 protein, human; D051780:Sterol Regulatory Element Binding Protein 1; C432165:pyrazolanthrone; D048056:Mitogen-Activated Protein Kinase 9
keywords: c-Jun N-terminal kinase 2; cell death-inducing DNA fragmentation factor-α-like effector; de novo lipogenesis; microarray; small interfering RNA; sterol regulatory element-binding protein-1c