Hu Yang, Hai Jinghan, Ti Yun, Kong Binghui, Yao Guoqing, Zhao Yuan, Zhang Chen, Zheng Xuehui, Zhang Chunmei, Ma Xiangping, Yu Huaitao, Qin Xiaoning, Kovarik Pavel, Zhang Cheng, Liu Shaozhuang, Zhang Wencheng, Li Jingyuan, Bu Peili
State Key Laboratory for Innovation and Transformation of Luobing Theory, Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China.
State Key Laboratory for Innovation and Transformation of Luobing Theory, Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China; Department of Geriatric Medicine, Qilu Hospital of Shandong University, 250012 Jinan, Shandong, China.
Metabolism. 2025 Mar;164:156131. doi: 10.1016/j.metabol.2024.156131. Epub 2025 Jan 4.
Obesity, as a worldwide healthcare problem, has become more prevalent. ZFP36 is a well-known RNA-binding protein and involved in the posttranscriptional regulation of many physiological processes. Whether the adipose ZFP36 plays a role in obesity and insulin resistance remains unclear.
The expression levels of ZFP36 were analyzed in adipose tissues of obese patients, diet-induced obese mice, ob/ob mice and db/db mice. To determine whether adipose ZFP36 protects against the diet-induced obesity, we generated adipose-specific ZFP36 knockout (ZFP36) mice, which were subjected to high-fat-diet (HFD) for 16 weeks. To explore the specific molecular mechanisms of ZFP36 regulating metabolic disorders, we used gene array assay of control and ZFP36-deficient adipose tissue, and assessed the pathways in vitro and vivo.
Western blotting and RT-PCR were performed to determine the downregulating level of ZFP36 in adipose tissues of obese patients, diet-induced obese mice, ob/ob mice and db/db mice. Relative to control mice, ZFP36 mice were more susceptible to HFD-induced obesity, along with insulin resistance, glucose tolerance, and increased metabolic disorders. The obesity of ZFP36 mice was attributed to hypertrophy of adipocytes in white adipose tissue via decreased expression of Perilipin1 (PLIN1), adipose triglyceride lipase (ATGL), and hormone-sensitive lipase (HSL). We discovered that ZFP36 oppositely regulated RNF128 expression by repressing the mRNA stability and translation of RNF128, a negative regulator of Sirt1 expression.
This study suggests that ZFP36 in adipose tissue plays an important role in diet-induced obesity, and identifies a novel molecular signaling pathway of ZFP36/RNF128/Sirt1 involved in obesity.
肥胖作为一个全球性的医疗保健问题，已变得越来越普遍。ZFP36是一种著名的RNA结合蛋白，参与许多生理过程的转录后调控。脂肪组织中的ZFP36是否在肥胖和胰岛素抵抗中发挥作用仍不清楚。
分析肥胖患者、饮食诱导肥胖小鼠、ob/ob小鼠和db/db小鼠脂肪组织中ZFP36的表达水平。为了确定脂肪组织中的ZFP36是否能预防饮食诱导的肥胖，我们构建了脂肪特异性ZFP36基因敲除（ZFP36）小鼠，并使其接受16周的高脂饮食（HFD）。为了探究ZFP36调节代谢紊乱的具体分子机制，我们对对照和ZFP36缺陷脂肪组织进行了基因芯片分析，并在体外和体内评估了相关通路。
通过蛋白质免疫印迹法和逆转录-聚合酶链反应（RT-PCR）检测肥胖患者、饮食诱导肥胖小鼠、ob/ob小鼠和db/db小鼠脂肪组织中ZFP36的下调水平。相对于对照小鼠，ZFP36基因敲除小鼠更容易受到HFD诱导的肥胖影响，同时伴有胰岛素抵抗、葡萄糖耐量降低和代谢紊乱加剧。ZFP36基因敲除小鼠的肥胖归因于白色脂肪组织中脂肪细胞肥大，这是由于 perilipin1（PLIN1）、脂肪甘油三酯脂肪酶（ATGL）和激素敏感性脂肪酶（HSL）的表达降低所致。我们发现ZFP通过抑制RNF128（Sirt1表达的负调节因子）的mRNA稳定性和翻译，对RNF128的表达起反向调节作用。
本研究表明脂肪组织中的ZFP36在饮食诱导的肥胖中起重要作用，并确定了一条涉及肥胖的ZFP36/RNF128/Sirt1新分子信号通路。
