The Influence Of Tumor Necrosis Factor-alpha For The Wnt/β-catenin Signaling Pathway In Adipocyte Of Early Obesity

Obesity is an energy metabolic disease. It has been a worldwide health concern. It is the main basis of pathophysiology for diabetes, artherosclerosis and other related diseases. Usually, the disorders of lipid and glucose metabolic and the abnormal differentiation of adipocyte were considered the major induction for obesity. Now the control of adipocyte differentiation has been the focus in obesity research field. But the concrete pathogenesis of obesity is not clear. TNF-αis a pleiotropic cytokine which plays important role in cancer, inflammation and other diseases. TNF-αis produced by different kind of cells, including macrophages, T cells, smooth muscle cells and adipocytes. Some studies have reported that the concentration of plasma TNF-αis higher in obese individual, and the excessive expression of TNF-αis also detected in adipose tissue. TNF-αcan affect the lipid metabolism, glucose metabolism and the differentiation of adipocyte to control the obesity.To better understand the effects of TNF-αon the obesity, especially to definite whether it play its role through Wnt signaling pathway, Lepr^db/db/TNF-α^-/- double-gene mutant mice (OT) were established and used for studying the mechanisms of polygenetic dysfunction in obesity. The relationship between double-gene mutation and the disorders of lipid and glucose metabolic and the abnormal differentiation of adipocyte have been investigated. Study of its mechanisms can provide available preventive measures and clinical therapy strategies. The results showed that:At protein level, the expression of IL-6 was down-regulated at 3-week-old, however it was up-regulated at 6-, 9-week old in OT group vs. Lepr^db/db group (P<0.05). The expression of adiponectin in OT group was higher than Lepr^db/db mice at 3-, 9-week-old (P<0.01).At mRNA level, the expression of Wnt10b, IL-6 andβ-catenin was down-regulated and C/EBPβ, PPARγ2 and C/EBPαdisplayed significant increases in OT group vs. Lepr^db/db group (P<0.01). The mRNA level of LPL in OT mice was higher than Lepr^db/db mice at 3-, 6-week-old (P<0.01). Meanwhile, there was an obvious up regulation of adiponectin in OT mice compared with Lepr^db/db mice at 6-week-old (P<0.01). From 6-week-old, the expression of FAS and ACC1 were significantly increased in OT mice compared with Lepr^db/db mice (P<0.05).Serum levels of TC, LDL-C and HDL-C in OT mice were higher than Lepr^db/db mice at 9 week (P < 0.05); and the TG level was lower than Lepr^db/db mice (P<0.05). Compared to WT group, TC levels of other three groups raised from 6-week-old (P<0.05). LDL-C levels were significant higher at 9-week-old (P<0.05). HDL-C levels were higher, but there were no statistical difference in Lepr^db/db and TNF-α^-/- group. However, TG levels of each age point have no difference to WT mice.The absence of TNF-αcan cause the body weight of Lepr^db/db mice heavier; And also can increase the insulin sensitivity. The TNF-α^-/- mice remained euglycemic during the experimental period. At 6-, 9-week-old the glucose levels of Lepr^db/db and OT mice are all significant higher than TNF-α^-/- mice (P<0.01). And compared to Lepr^db/db mice, the plasma glucose concentration of OT mice was significantly increased at 9-week-old (P<0.05). Correspond with the glucose level, the Lepr^db/db mice displayed an highest pattern of plasma insulin level at each age point. And the insulin concentration of OT mice was minor compared with the Lepr^db/db mice, especially at 6-, 9-week-old (P<0.01). The lowest plasma insulin concentration among all genotypes however, was also observed in the TNF-α^-/- mice (P<0.01).In conclusion, these findings demonstrated that TNF-αplay a critical role through maintaining Wnt/β-catenin signaling in the regulation of its downstream transcription factors of adipocyte differentiation. Accordingly, the above analysis will help us further understanding the mechanism of the TNF-αon obesity...