Unexpected blockade of adipocyte differentiation by K-7174: implication for endoplasmic reticulum stress.
Preadipocytes constitutively express GATA-2 and GATA-3 that are required to halt the cells at the undifferentiated stage. However, we unexpectedly found that K-7174, a GATA-specific inhibitor, did not induce but rather inhibited differentiation of 3T3-L1 preadipocytes. It was associated with lack of lipid accumulation, blunted expression of adipocyte markers including adiponectin and peroxisome proliferator-activated receptor gamma (PPARgamma), and sustained expression of a preadipocyte marker monocyte chemoattractant protein 1 (MCP-1). Subsequent experiments revealed that K-7174 had the potential to induce endoplasmic reticulum (ER) stress evidenced by induction of GRP78 and CHOP. Other inducers of ER stress completely reproduced the effects of K-7174 including suppression of lipid accumulation, blockade of induction of adiponection and PPARgamma and maintenance of MCP-1 expression. These results indicated a possibility that ER stress suppresses adipocyte differentiation and that GATA inhibitor K-7174 has the potential for interfering with adipogenesis through induction of ER stress.
Shimada
Tsuyoshi
T
Department of Molecular Signaling, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Shimokato 1110, Chuo, Yamanashi 409-3898, Japan.
Hiramatsu
Nobuhiko
N
Okamura
Maro
M
Hayakawa
Kunihiro
K
Kasai
Ayumi
A
Yao
Jian
J
Kitamura
Masanori
M
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D000840:Anisoles / Q000008:administration & dosage*; D001381:Azepines / Q000008:administration & dosage*; D002454:Cell Differentiation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure*; D000091342:Endoplasmic Reticulum Chaperone BiP; D050980:GATA Transcription Factors / Q000378:metabolism*; D051379:Mice; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*
D000840:Anisoles; D001381:Azepines; D000091342:Endoplasmic Reticulum Chaperone BiP; D050980:GATA Transcription Factors; C000717248:Hspa5 protein, mouse; C410337:K 7174