Date of Award

5-9-2016

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Neuroscience Institute

First Advisor

Dr. Bingzhong Xue

Second Advisor

Dr. Nancy G. Forger

Third Advisor

Dr. Anne Z. Murphy

Fourth Advisor

Dr. Aaron G. Roseberry

Abstract

Obesity is a grave disease that is increasing in global prevalence. Aberrant neuronal DNA methylation patterns have been implicated in the promotion of obesity development, but the role of neuronal DNA methyltransferases (Dnmts; enzymes that catalyze DNA methylation) in energy balance remains poorly understood. We investigated the role of neuronal Dnmt1 in normal energy regulation and obesity development using a novel Dnmt1 knockout mouse model, Dnmt1fl/fl Synapsin1Cre (ND1KO), which specifically deletes Dnmt1 in neurons. ND1KO and fl/fl control littermates were fedeither a standard chow diet or a high fat diet (HFD). We conducted a deep analysis to characterize both peripheral and central aspects of the ND1KO phenotype. We found that neuronal Dnmt1 deficiency reduced adiposity in chow-fed mice and attenuated obesity in HFD-fed male mice. ND1KO male mice had reduced food intake and increased energy expenditure on the HFD. Furthermore, these mice had improved insulin sensitivity as measured by an insulin tolerance test. HFD-fed ND1KO mice had smaller fat pads and an upregulation of thermogenic genes in brown adipose tissue. These data suggest that neuronal Dnmt1 deletion increased diet-induced thermogenesis, which may explain the lean phenotype in HFD-fed ND1KO mice. Interestingly, we found that ND1KO male mice had elevated estrogen receptor-α gene expression in the hypothalamus, which previously has been shown to control body weight. Immunohistochemistry experiments revealed that estrogen receptor-α (ERα) protein expression was upregulated in the dorsomedial region of the VMH (VMHdm), a region which may mediate the central effect of leptin. Finally, we tested whether ND1KO mice had reduced methylation of the ERα gene promoter, which might explain the ERα upregulation. Neuronal Dnmt1 deficiency decreased methylation at two CpG sites on Exon A in chow-fed mice. Collectively, these data suggest that neuronal Dnmt1 regulates energy homeostasis through pathways controlling food intake and energy expenditure, and that ERα in the VMHdm may mediate these effects.

Share

COinS