Date of Award

2017

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Cell & Molecular Biology

First Advisor

Patrick Seale

Abstract

Brown and beige adipose tissues represent promising therapeutic targets for combating the rapidly growing obesity pandemic. The goal of this thesis work was to better understand the signaling pathways that affect brown and beige adipose function. First, we investigated pathways regulated by PRDM16, a critical transcription factor for brown and beige fat development. We found that PRDM16 represses type I Interferon (IFN) responses in both preadipocytes and mature adipocytes to promote thermogenic and mitochondrial function. Type I IFN signaling is a critical antiviral pathway, which was previously unexplored in the context of brown fat biology. We found that brown adipocyte character and mitochondrial function were disrupted by ectopic IFN signaling and that increased PRDM16 expression could reverse these negative effects. Additionally, we showed that PRDM16 is required to protect brown fat function from type I IFN signaling in vivo. Utilizing multiple transcriptional assays, we determined that PRDM16 blocks IFN regulatory factor 1 (IRF1)-mediated activation of ISGs by competitively binding ISG promoter regions. Adipose inflammation has been implicated in the progression of obesity and insulin resistance. Next, we aimed to determine the role of type I IFN in diet-induced obesity. We found that ISGs are activated in multiple tissues of mice early in the course of high-fat diet (HFD) feeding. Blocking IFN responses using an IFN alpha receptor knockout mouse led to protection from diet-induced obesity and insulin resistance. Additionally, HFD-induced type I IFN decreased energy expenditure, potentially due to mitochondrial dysfunction in the subcutaneous adipose depot. Together this work demonstrates for the first time the negative effects of type I IFN in adipose tissue that may contribute to obesity and insulin resistance.

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