Document Type

Open Access Thesis

Embargo Period

4-6-2016

Degree Program

Nutrition

Degree Type

Master of Science (M.S.)

Year Degree Awarded

2016

Month Degree Awarded

May

Abstract

Obesity-induced inflammation has been linked to the onset of insulin

resistance (IR), which is a strong risk factor for the development of T2DM. Recent

studies have indicated that tumor necrosis factor alpha (TNFα) plays a causative role

in obesity-mediated IR via its overexpression in adipose tissue. Moreover, TNFα has

been shown to induce the IR and the alteration of lipid and glucose metabolism in

adipose tissue at various levels including normal adipocyte differentiation and mature

adipocyte function. However, the mechanisms linking TNFα-induced adipocyte

dysfunction in chronic obesity to the IR and T2DM are largely unknown. Herein we

report that TNFα inhibited the mRNA expression of PPARγ, which is a key nuclear

transcriptional factor for driving preadipocyte differentiation and maintaining normal

function of mature adipocyte. TNFα treatment suppressed preadipocyte differentiation

by downregulating mRNAs for FAS, perilipin, GLUT4, adiponectin, PGC-1α and

C/EBPα and also altered adipocyte function by inhibiting mRNAs for perilipin,

GLUT4, CPT-1 and PGC-1α, while increasing the expression of IL-6 and MCP1

mRNAs. In palmitic acid (PA)-induced in vitro hypertrophic adipocytes, we found

that mRNA expression of inflammatory cytokines (TNFα and IL-6) was significantly

elevated, while the expression of mRNAs for PPARγ, perilipin and adiponectin was

markedly reduced, suggesting that TNFα may induce dysfunctional adipocyte

phenotypes by targeting PPARγ and its target genes. In in vivo study, mice fed high

fat diet (HFD) for 16 weeks had adipose tissue dysfunction as reflected by significant

reduction of protein expression for PPARγ, perilipin, FAS and FABP4, consistent

with the results observed in in vitro hypertrophic adipocytes. Interestingly, this was

reversed by the loss of TNFα in TNFα knockout mice, indicating that TNFα may

induce adipocyte dysfunction via the inhibition of PPARγ and its target genes. In the

liver, HFD significantly increased hepatic triglyceride (TG) contents, while

decreasing de novo lipogenesis (SCD1 and FAS), whereas TNFα deficiency

decreased TG content and de novo lipogenesis compared to HFD-fed wild-type (WT)

mice, suggesting that TNFα-induced adipocyte dysfunction is associated with hepatic

lipid deposition in chronic obesity. Taken together, the current findings provide new

insights into the role of TNFα in obesity-induced inflammation and also suggest the

TNFα as a mediator for obesity-induced IR & T2DM

First Advisor

Young-Cheul Kim

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