Enomoto Takashi, Ohashi Koji, Shibata Rei, Kambara Takahiro, Uemura Yusuke, Yuasa Daisuke, Kataoka Yoshiyuki, Miyabe Megumi, Matsuo Kazuhiro, Joki Yusuke, Hayakawa Satoko, Hiramatsu-Ito Mizuho, Ito Masanori, Murohara Toyoaki, Ouchi Noriyuki
Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Department of Molecular Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
PLoS One. 2013 Dec 16;8(12):e83183. doi: 10.1371/journal.pone.0083183. eCollection 2013.
Obese states characterized by chronic inflammation are closely linked to the development of metabolic dysfunction. We identified adipolin/CTRP12 as an insulin-sensitizing and anti-inflammatory adipokine. Although obese conditions down-regulate adipolin expression, its molecular mechanism is largely unknown. Here we show that the transcriptional regulator Krüppel-like factor (KLF) 15 is involved in the regulation of adipolin expression in adipocytes. White adipose tissue from diet-induced obese (DIO) mice showed decreased expression of KLF9 and KLF15 among several KLFs, which was accompanied by reduced expression of adipolin. In cultured 3T3L1 adipocytes, treatment with TNFα significantly reduced the mRNA levels of KLF9, KLF15 and adipolin. Adenovirus-mediated overexpression of KLF15 but not KLF9 reversed TNFα-induced reduction of adipolin expression in adipocytes. Conversely, gene targeting ablation of KLF15 attenuated adipolin expression in adipocytes. Expression of KLF15 but not KLF9 enhanced the promoter activity of adipolin in HEK293 cells. Pretreatment of 3T3L1 adipocytes with the JNK inhibitor SP600125, but not p38 MAPK inhibitor SB203580 blocked the inhibitory effects of TNFα on adipolin and KLF15 expression. These data suggest that adipose inflammation under conditions of obesity suppresses adipolin expression via JNK-dependent down-regulation of KLF15 in adipocytes.
以慢性炎症为特征的肥胖状态与代谢功能障碍的发展密切相关。我们将脂联素/CTRP12鉴定为一种具有胰岛素增敏和抗炎作用的脂肪因子。尽管肥胖状态会下调脂联素的表达，但其分子机制在很大程度上尚不清楚。在此我们表明，转录调节因子Krüppel样因子（KLF）15参与脂肪细胞中脂联素表达的调控。饮食诱导肥胖（DIO）小鼠的白色脂肪组织在几种KLF中显示KLF9和KLF15的表达降低，这伴随着脂联素表达的减少。在培养的3T3L1脂肪细胞中，用TNFα处理显著降低了KLF9、KLF15和脂联素的mRNA水平。腺病毒介导的KLF15而非KLF9的过表达逆转了TNFα诱导的脂肪细胞中脂联素表达的降低。相反，靶向敲除KLF15基因减弱了脂肪细胞中脂联素的表达。KLF15而非KLF9的表达增强了HEK293细胞中脂联素的启动子活性。用JNK抑制剂SP600125预处理3T3L1脂肪细胞，但不用p38 MAPK抑制剂SB203580，可阻断TNFα对脂联素和KLF15表达的抑制作用。这些数据表明，肥胖条件下的脂肪炎症通过JNK依赖的脂肪细胞中KLF15的下调来抑制脂联素的表达。
