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

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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.