The anti-inflammatory mRNA-binding protein ZFP36 in Obesity and Metabolism

描述（由申请人提供）：肥胖产生与不良健康结果相关的全身性炎症状态。脂肪源性脂肪因子在肥胖中长期升高，导致动脉粥样硬化、糖尿病和某些癌症的发生。脂肪因子对脂肪组织生理产生局部影响，对肝脏、肺、肌肉和脉管系统产生不利的全身影响。目前尚不清楚脂肪因子是否会引起生殖组织的炎症反应，或者这种反应是否会导致肥胖个体生育能力下降、流产增加和其他不良生殖结果。利用饮食引起的肥胖小鼠模型，我们将检验肥胖在生殖组织中产生免疫缺陷从而导致不良生殖结果的假设。许多脂肪因子mrna的半衰期很短，它们的表达受mrna结合蛋白的调节，从而影响它们的稳定性。锌指蛋白-36 （ZFP36）是一种mRNA结合蛋白，可破坏靶mRNA的稳定性，导致信息破坏和蛋白表达减少。已知ZFP36可抑制肿瘤坏死因子(TNF)-1、单核细胞趋化蛋白(MCP)-1、白细胞介素(IL)-6和血管内皮生长因子（VEGF）等重要因子的表达。在脂肪细胞中很少有ZFP36的mRNA靶点被描述。我们假设：1)与肥胖相关的慢性炎症对子宫内膜和卵巢组织有直接影响，促进局部炎症反应，损害生育能力，并导致不良妊娠结局；2)脂肪细胞表达的ZFP36抑制脂肪库中的炎症。我们的目的是确定ZFP36的分子靶点，并在体外脂肪细胞和饮食性肥胖小鼠模型中测试ZFP36的生物学功能。通过靶向基因敲低和靶向过表达方法，我们的模型系统将被用于更好地了解脂肪组织的炎症环境及其对生殖组织的内分泌/旁分泌作用。我们将测试提高脂肪细胞中ZFP36的表达是否可以抑制局部和全身炎症，并减轻肥胖小鼠不良生殖结局的发生。本研究的重点是通过脂肪细胞中脂肪因子mRNA的稳定性来调节全身炎症反应的新机制。我们的工作可能会确定ZFP36作为一种新的治疗靶点，用于治疗由肥胖和炎症调节的重要疾病，包括动脉粥样硬化、糖尿病和危害母亲和婴儿的不良生殖结果。

DESCRIPTION (provided by applicant): Obesity produces a systemic inflammatory state associated with adverse health outcomes. Fat-derived adipokines are chronically elevated in obesity and contribute to the development of atherosclerosis, diabetes, and some cancers. Adipokines exert local effects on adipose tissue physiology and unfavorable systemic effects on liver, lung, muscle, and the vasculature. It is not known whether adipokines provoke an inflammatory response in reproductive tissues or if such a response contributes to decreased fertility, increased miscarriages, and other adverse reproductive outcomes in obese individuals. Using a mouse model of diet- induced obesity, we will test the hypothesis that obesity produces immune defects in reproductive tissues that lead to adverse reproductive outcomes. Many adipokine mRNAs have a short half-life and their expression is modulated by mRNA-binding proteins that influence their stability. Zinc Finger Protein-36 (ZFP36) is an mRNA- binding protein that destabilizes target mRNAs leading to message destruction and diminished protein expression. ZFP36 is known to repress expression of important factors including Tumor Necrosis Factor (TNF)-1, Monocyte Chemotactic Protein (MCP)-1, Interleukin (IL)-6, and Vascular Endothelial Growth Factor (VEGF). Few mRNA targets of ZFP36 have been described in adipocytes. We hypothesize that: 1) the chronic inflammation associated with obesity has direct effects on endometrial and ovarian tissues, promotes local inflammatory responses, impairs fertility, and causes adverse pregnancy outcomes, and 2) that adipocyte-expressed ZFP36 represses inflammation in fat depots. We aim to identify the molecular targets of ZFP36 and to test the biological functions of ZFP36 in adipocytes in vitro and in a mouse model of diet-induced obesity. Using targeted gene knockdown and targeted over-expression approaches, our model systems will be employed to better understand the inflammatory environment of fat tissue and its endocrine/paracrine effects on reproductive tissues. We will test whether enhancing ZFP36 expression in adipocytes can suppress local and systemic inflammation and mitigate against the development of adverse reproductive outcomes in obese mice. This proposal focuses on a new mechanism for regulating systemic inflammatory responses by targeting adipokine mRNA stability in fat cells. Our work may identify ZFP36 as a novel therapeutic target for important medical conditions modulated by obesity and inflammation including atherosclerosis, diabetes, and adverse reproductive outcomes which harm mothers and babies.