Date of Award

8-7-2018

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biology

First Advisor

Bingzhong Xue

Second Advisor

Hang Shi

Third Advisor

Ming-Hui Zou

Abstract

Diet-induced obesity and its related metabolic diseases including type 2 diabetes are public health concern. While the major function of white adipose tissue (WAT) is to store excess energy as fat, that of brown adipose tissue (BAT) is to dissipate extra energy as heat, suggesting that activating BAT function may be an effective therapy for treating obesity and its related metabolic diseases. Epigenetic modification including histone methylation, histone acetylation and DNA methylation is associated with energy homeostasis. However, the epigenetic modification contributing to BAT reprogramming in high fat diet (HFD)-induced obesity is not known. Here, we found that histone deacetylase 1 (HDAC1) negatively regulated thermogenic program in brown adipocytes through regulation of histone H3 lysine 27 deacetylation and methylation. In addition, we found that HFD induced the reprogramming of brown adipocyte by down-regulating BAT-specific, whereas up-regulating skeletal muscle-specific gene expression program. Remarkably, we found that knockdown of histone demethylase UTX or DNA methyltransferase DNMT1 mimics HFD-induced brown fat remodeling, leading to BAT dysfunction. In addition, mice with brown fat specific deletion of UTX or DNMT1 displayed obesity and insulin resistance. Mechanistically, we found that UTX promoted brown fat thermogenic gene expression including PRDM16, which then recruited DNA methyltransferase DNMT1 to the promoter of Myod1, an important transcriptional factor for skeletal muscle cell development. DNMT1 increased methylation levels of Myod1 and inhibited its gene transcription in brown adipose tissue. Thus, this pathway is important in maintaining brown adipocyte function; disrupting this pathway in HFD results in reprogramming of brown adipocytes into skeletal muscle-like cells, which contributes to HFD-induced obesity.

Available for download on Saturday, July 13, 2019

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