Date of Award

Spring 5-2-2022

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biology

Abstract

Obesity results from a net energy influx due to energy intake exceeding expenditure. Brown fat thermogenesis, an integral part of overall energy expenditure, represents a promising target for the treatment of obesity. Obesity is a risk factor for the development of a panel of metabolic diseases including nonalcoholic fatty liver disease (NAFLD). Epigenetic mechanisms including DNA methylation have emerged as a key regulator of energy metabolism and metabolic pathways. DNA methylation status is maintained through dynamic biochemical pathways involving DNA methylation and demethylation. DNA methylation is handled by the enzymes DNA methyltransferases (DNMTs) that catalyze the addition of methyl groups to deoxycytidines, while DNA demethylation is processed by the enzymes, ten-eleven translocation dioxygenases (TETs) that catalyze the hydroxylation of 5-methylcytosine and convert them into unmodified cytosines. Here we first aimed to investigate the role of DNMT3b in brown fat thermogenesis and energy metabolism. The deletion of DNMT3b in brown fat-skeletal lineage precursor cells protects against diet-induced obesity. Interestingly, we found that myocyte enhancer factor 2c (MEF2c) is a mediator for the myogenic remodeling in Dnmt3b-deficient brown fat by decreased methylation at its promoter, resulting in impaired thermogenic function. Our data demonstrate DNMT3b as a key regulator for brown fat thermogenesis and obesity development. We next determined the role of DNA methylation in the regulation of hepatic lipid metabolism during the development of NAFLD. Inhibiting DNA methylation via specific deletion of DNMT1 or 3a in liver ameliorated high fat diet (HFD)-induced hepatic steatosis while increasing DNA methylation by liver-specific deletion of TET2 did the opposite. By a modified CRISPR/RNA-guided approach, we found that down-regulation of DNMTs by HFD may result in hypermethylation of the beta-klotho (Klb) promoter and subsequent down-regulation of Klb expression, thereby impairing the fibroblast growth factor 21 (FGF21) pathway; this in turn contributes to the development of fatty liver in obesity. Thus, this dissertation demonstrates that epigenetic regulation of brown fat thermogenesis and hepatic lipid metabolism by DNA methylation play a key role in the regulation of metabolic pathways and that deregulated epigenetic pathways by HFD may contribute to the development of obesity and its related metabolic disorders.

DOI

https://doi.org/10.57709/28914167

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