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|Title:||REGULATION OF HYPOTHALAMIC POMC EXPRESSION BY MECP2 AND ITS CONTRIBUTION TO LEPTIN RESISTANCE||Authors:||WANG XIAORUI||Keywords:||POMC, MeCP2, Leptin resistance||Issue Date:||17-Jan-2013||Citation:||WANG XIAORUI (2013-01-17). REGULATION OF HYPOTHALAMIC POMC EXPRESSION BY MECP2 AND ITS CONTRIBUTION TO LEPTIN RESISTANCE. ScholarBank@NUS Repository.||Abstract:||Pro-opiomelanocortin (POMC) neuron is a key neuron in the hypothalamus to regulate energy homeostasis by reducing food intake and promoting energy expenditure. POMC neuron is activated by leptin to promote pomc transcription. High level of leptin that fails to regulate energy homeostasis is termed as leptin resistance. Pomc expression is closely related to DNA methylation on POMC promoter. Maternal or perinatal programming causes epigenetic changes on POMC promoter, including DNA methylation, which may cause leptin resistance in the future. Methyl-CpG-binding protein 2 (MeCP2) is recruited to methylated or unmethylated DNA to regulate gene expression. The aim of this study is to examine the regulation of hypothalamic pomc expression by MeCP2; and whether and how epigenetic regulation of POMC promoter, especially DNA methylation, contributes to leptin resistance. We generated a mouse line with MeCP2 specifically deleted in POMC neurons and analyzed their metabolic phenotypes. The knockout (KO) mice had higher body weight with increased adiposity and they displayed leptin resistance. DNA methylation on hypothalamic POMC promoter was increased, whereas hypothalamic pomc mRNA level was downregulated in the KO mice. Hypermethylation on POMC promoter reduced POMC promoter activity, while MeCP2 and CREB1 worked synergistically on POMC promoter to promote its activity in vitro. It was also found that high fat diet (HFD) treatment also caused hypermethylation on hypothalamic POMC promoter and reduced hypothalamic pomc expression in wild type (WT) mice. The results from this study demonstrate that MeCP2 is a positive regulator of pomc expression in the hypothalamus. Absence of MeCP2 in POMC neurons and HFD treatment leads to increased DNA methylation on POMC promoter as well as reduced pomc expression in the hypothalamus that contributes to leptin resistance.||URI:||http://scholarbank.nus.edu.sg/handle/10635/37874|
|Appears in Collections:||Ph.D Theses (Open)|
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