Submitted on October 9, 2008
Revised on January 6, 2009
Accepted on January 6, 2009
Dual suppression of adipogenesis by cigarette smoke through activation of the aryl hydrocarbon receptor and induction of endoplasmic reticulum stress
Tsuyoshi Shimada1, Nobuhiko Hiramatsu1, Kunihiro Hayakawa1, Shuhei Takahashi1, Ayumi Kasai1, Yasuhiro Tagawa1, Mai Mukai1, Jian Yao1, Yoshiaki Fujii-Kuriyama2, and Masanori Kitamura1*
1 Yamanashi University
2 University of Tsukuba
* To whom correspondence should be addressed. E-mail: masanori{at}yamanashi.ac.jp.
Cigarette smoking decreases body weight, whereas molecular mechanisms underlying this phenomenon have not been elucidated. In this report, we investigated regulation of adipogenesis by cigarette smoke and involvement of aryl hydrocarbon receptor (AhR) and endoplasmic reticulum (ER) stress. We found that cigarette smoke extract (CSE) inhibited differentiation of preadipocytes into adipocytes dose dependently. It was associated with a decrease in lipid accumulation, blunted expression of adipocyte markers (adiponectin, PPAR
and C/EBP
) and sustained expression of a preadipocyte marker MCP-1. CSE markedly induced activation of AhR, and AhR agonists (2,3,7,8-tetrachlorodibenzo-p-dioxin, benzo[]pyrene and 3-methylcholanthrene) reproduced the inhibitory effect of CSE on adipocyte differentiation. Furthermore, knockout of the AhR gene or blockade of AhR by a dominant-negative mutant attenuated the suppressive effects of CSE on adipocyte differentiation. We also found that CSE induced ER stress in preadipocytes, and ER stress inducers (thapsigargin, tunicamycin and A23187) reproduced the suppressive effect of CSE on the differentiation of preadipocytes. Interestingly, AhR agonists did not cause ER stress, and ER stress inducers did not activate AhR. These results suggested that cigarette smoke has the potential to inhibit adipocyte differentiation via dual, independent mechanisms; i.e., through activation of the AhR pathway and induction of the unfolded protein response.
