EFFECT OF OBESITY-INDUCED TUMOR NECROSIS FACTOR ALPHA ON ADIPOCYTE FUNCTION

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.