Ku Hui-Chen, Chan Tsai-Yun, Chung Jia-Fang, Kao Yung-Hsi, Cheng Ching-Feng
Department of Pediatrics, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City 23142, Taiwan.
Department of Life Sciences, National Central University, Taoyuan 320, Taiwan.
Biomed Pharmacother. 2022 Jan;145:112440. doi: 10.1016/j.biopha.2021.112440. Epub 2021 Nov 25.
In this study, we investigated whether the activating transcription factor 3 (ATF3) inducer ST32db, a synthetic compound with a chemical structure similar to that of native Danshen compounds, exerts an anti-obesity effect in 3T3-L1 white preadipocytes, D16 beige cells, and mice with obesity induced by a high-fat diet (HFD). The results showed that ST32db inhibited 3T3-L1 preadipocyte differentiation by inhibiting adipogenesis/lipogenesis-related gene (and protein levels) and enhancing lipolysis-related gene (and protein levels) via the activation of β3-adrenoceptor (β3-AR)/PKA/p38, AMPK, and ERK pathways. Furthermore, ST32db inhibited triacylglycerol accumulation in D16 adipocytes by suppressing adipogenesis/lipogenesis-related gene (and protein levels) and upregulating browning gene expression by suppressing the β3-AR/PKA/p38, and AMPK pathways. Intraperitoneally injected ST32db (1 mg kg twice weekly) inhibited body weight gain and reduced the weight of inguinal white adipose tissue (iWAT), epididymal WAT (eWAT), and mesenteric WAT, with no effects on food intake by the obese mice. The adipocyte diameter and area of iWAT and eWAT were decreased in obese mice injected with ST32db compared with those administered only HFD. In addition, ST32db significantly suppressed adipogenesis and activated lipolysis, browning, mitochondrial oxidative phosphorylation, and β-oxidation-related pathways by suppressing the p38 pathway in the iWAT of the obese mice. These results indicated that the ATF3 inducer ST32db has therapeutic potential for reducing obesity.
在本研究中，我们探究了激活转录因子3（ATF3）诱导剂ST32db（一种化学结构与天然丹参化合物相似的合成化合物）对3T3-L1白色前脂肪细胞、D16米色细胞以及高脂饮食（HFD）诱导的肥胖小鼠是否具有抗肥胖作用。结果显示，ST32db通过激活β3-肾上腺素能受体（β3-AR）/蛋白激酶A（PKA）/p38、腺苷酸活化蛋白激酶（AMPK）和细胞外信号调节激酶（ERK）信号通路，抑制脂肪生成/脂质生成相关基因（及蛋白水平）并增强脂肪分解相关基因（及蛋白水平），从而抑制3T3-L1前脂肪细胞分化。此外，ST32db通过抑制脂肪生成/脂质生成相关基因（及蛋白水平）并通过抑制β3-AR/PKA/p38和AMPK信号通路上调褐变基因表达，抑制D16脂肪细胞中三酰甘油的积累。腹腔注射ST32db（每周两次，每次1 mg/kg）可抑制体重增加，并减轻腹股沟白色脂肪组织（iWAT）、附睾白色脂肪组织（eWAT）和肠系膜白色脂肪组织的重量，对肥胖小鼠的食物摄入量无影响。与仅给予高脂饮食的肥胖小鼠相比，注射ST32db的肥胖小鼠iWAT和eWAT的脂肪细胞直径和面积减小。此外，ST32db通过抑制肥胖小鼠iWAT中的p38信号通路，显著抑制脂肪生成并激活脂肪分解、褐变、线粒体氧化磷酸化和β-氧化相关信号通路。这些结果表明，ATF3诱导剂ST32db具有减轻肥胖的治疗潜力。
