Adipose tissue-derived immune factors, globally referred to as "adipokines," are chronically elevated in obesity and contribute to the development of adverse health outcomes including atherosclerosis and diabetes. Adipokines exert local effects on adipose tissue physiology and unfavorable systemic effects on liver, lung, muscle, and the vasculature. Zinc Finger Protein-36 (ZFP36) is an mRNA-binding protein that destabilizes adipokine mRNAs leading to reduced protein expression. ZFP36 also directly binds and represses the transcription factor nuclear factor-:B (NF:B), an important activator of inflammatory gene expression. The extent to which ZFP36 alters gene expression post-transcriptionally (via mRNA binding) vs. transcriptionally (via inhibition of NF:B) is unknown. Little is known about the function of ZFP36 in adipose depot macrophages and adipocytes or in macrophage foam cells of atherosclerotic lesions. No comprehensive description of ZFP36-bound mRNA targets exists for these cell types. The net effects of ZFP36 on adipose depot production of adipokines have not been studied although the protein is predicted to be anti-inflammatory. It is unknown whether up-regulating ZFP36 expression in the adipose depot or in macrophages of atherosclerotic lesions will reduce the development or progression of inflammatory disorders such as atherosclerosis or diabetes. We hypothesize that high ZFP36 expression will repress inflammatory adipokine expression in adipose depots and in atherosclerotic lesions. We will identify the molecular targets of ZFP36 and test the biological functions of ZFP36 in adipocytes and macrophages in vitro and in mice. We will distinguish gene expression changes that depend upon ZFP36:mRNA interactions from those that depend upon ZFP36-mediated inhibition of NF:B. Our mouse model systems will test the effects of high ZFP36 expression in diet-induced obese mice and in mice that develop atherosclerosis. We will test whether enhancing ZFP36 expression in adipocytes and macrophages can suppress local and systemic inflammation and mitigate the development of adverse metabolic and atherogenic outcomes in lean and obese mice. This proposal focuses on a new mechanism for regulating systemic inflammatory responses by targeting adipokine mRNA stability in fat and vascular tissues. Our work may identify ZFP36 as a new therapeutic target for important medical conditions exacerbated by obesity and inflammation including atherosclerosis and diabetes.
Roughly 66% of Americans are overweight and 33% are obese. Fat tissues secrete high levels of inflammatory substances called adipokines that contribute to important health disorders including heart attacks and diabetes. The goal of this research is to reduce the adipokine production in fat tissues using a new molecular approach that will form the basis for new therapies.
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