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ORCID
N/A
Access Type
Open Access Thesis
Document Type
thesis
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
DOI
https://doi.org/10.7275/8435854
First Advisor
Young-Cheul Kim
Recommended Citation
Yu, Seok-Yeong, "Effect of Obesity-Induced Tumor Necrosis Factor Alpha on Adipocyte Function" (2016). Masters Theses. 389.
https://doi.org/10.7275/8435854
https://scholarworks.umass.edu/masters_theses_2/389