Obesity is now considered as an epidemic problem, which is associated with a panel of metabolic disorders, including insulin resistance/type 2 diabetes, dyslipidemia and cardiovascular diseases. While white adipose tissue (WAT) is involved in energy storage, that of brown adipose tissue (BAT) is to dissipate energy as heat due to the unique expression of uncoupling protein 1 (UCP1). In rodents, there exist two types of brown adipocytes. Traditional brown adipocytes are located in discrete areas; whereas inducible beige adipocytes are dispersed in WAT, and can be induced by cold exposure or ?3-adrenergic receptor activation. Activation of brown/beige adipocyte thermogenic function alleviates obesity and its associated metabolic diseases. Recent discovery of functional brown and beige adipocytes in humans suggest that increasing brown/beige cell function may be a novel approach in treating obesity. Epigenetic mechanisms play an important role in the regulation of complex diseases, including obesity. Suppressor of variegation 4-20 homolog 2 (Drosophila) (SUV420H2) is a histone methyltransferase that is important for the tri-methylation at histone H4 lysine 20 (H4K20). Our preliminary data suggest that SUV420H2 is important in the regulation of brown and beige adipocyte development. SUV420H2 expression parallels that of UCP1 expression in brown and beige adipocytes; knocking down of SUV420H2 significantly reduces, whereas overexpressing SUV420H2 significantly increases UCP1 levels. Therefore, we hypothesize that the histone H4K20 methyltransferase SUV420H2 is important in the regulation of brown and beige adipocyte development, and further regulates energy homeostasis in animal models. We will use brown/beige adipocyte specific SUV420H2 deficient mice and adipocyte-specific SUV420H2 transgenic mice to address the following specific aims.
In Aim 1, we will test the importance of adipocyte SUV420H2 in the regulation of cold- and diet-induced brown and beige adipocyte thermogenesis. We will test: 1) whether brown/beige adipocyte-deletion of SUV420H2 impairs, whereas adipocyte-specific overexpression of SUV420H2 enhances brown and beige adipocyte thermogenesis during cold exposure; and 2) whether mice with brown/beige adipocyte-deletion of SUV420H2 are prone to; whereas mice with adipocyte-specific overexpression of SUV420H2 are resistant to high fat diet-induced obesity.
In Aim 2, we will test the importance of SUV420H2-mediated H4K20 trimethylation at 4E-BP1 promoter in the regulation of PGC1? protein translation and SUV420H2-regulated brown/beige adipocyte thermogenesis.
In Aim 3, we will test SUV420H2/H4K20me3-targeted cellular and molecular pathways in brown/beige adipocytes during cold exposure and in diet-induced thermogenesis using a combination of H4K20me3 ChIP-Seq and RNA-Seq approaches.
The goal of this grant is to understand the histone methyltransferase SUV420H2-mediated H4K20 trimethylation in the regulation of brown/beige adipocyte function during cold- and diet-induced thermogenesis and energy homeostasis, and identify SUV420H2/H4K20me3 as a novel therapeutic target in obesity by regulating brown/beige adipocyte thermogenesis and energy expenditure.
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