The Influence Of Tumor Necrosis Factor-alpha For The Molecular Mechanism Of Wnt/β-catenin Signaling Pathway And Obesity

In recent years, the obesity rate has significantly increased. Obesity is a state of excessaccumulation of fat tissue in the body, thus causing changes in human pathological andphysiological state. Obesity can result in a variety of diseases and have an adverse effect onhealth. Therefore it is very important to study the occurrence and development of obesity.Tumor necrosis factor-α (tumor necrosis factor-alpha, TNF-α) is an important adipokines,which has high expression in adipose tissue of obese individuals. Studies have shown that TNF-αcan inhibit differentiation of preadipocytes in vitro. And Wnt/β-catenin signaling pathway palysan significant role in the differentiation of preadipocytes in vitro. Most of the previous studiesfocused on3T3-L1preadipocytes or mouse, human primary preadipocytes, and has made a lot ofprogress. But in vivo the mechanism of TNF-α for the Wnt/β-catenin signaling pathway andearly obesity is not entirely clear. Therefore, we established the OT mouse model (db/TNF-αdouble-gene mutant mice), detected the changes of body weight, fat cells size, and the expressionof obesity-related factor, by weighting, HE staining, quantitative real-time PCR andWestern-Blot. And then we explore the mechanism of TNF-α in Wnt/β-catenin signaling pathwayand early obesity. The results showed that:1. In contrast to WT mice, the rate of db/db mice weight gaining increased significantly(P<0.05); adipose tissue volume and adipocyte size is larger. In the process of obesity, theexpression of Wnt10b and β-catenin is inhibited (P<0.05), the expression of PPARγ, C/EBPαand Adiponectin is activated (P<0.05), which promote lipogenic process and contribute to theoccurrence of obesity. And there is correlation between Wnt/β-catenin signaling pathway andlipogenic factor (such as PPARγ, C/EBPα).2. In contrast to db/db mice, the weight of OT mice has significantly increased (P<0.05);adipose tissue volume and adipocyte size has obviously differences at6-week-old. Quantitativereal-time results show that compared to db/db mice, the mRNA expression of C/EBPβ, PPARγ,C/EBPα, adiponectin, ACC1, FAS is significantly raised (P<0.05), while the mRNA expression of β-catenin and Wnt10b is significantly down regulated (P<0.05) at6-week-old of OT mice.Western-Blot analysis also found that the protein level of PPARγ, adiponectin, Wnt10b,β-catenin is the same with those mRNAlevel.3. In the experiment of exploring LiCl intervention concentration, both100mg/kg and200mg/kg can reduce the growth rate of body weight, increase β-catenin protein level (P<0.05), andreduce PPARγ protein level (P<0.05). Accounting the effect and medicine saving, we choose100mg/kg.4. Using LiCl, the agonist of Wnt/β-catenin signaling pathway, the weight growth rate andfat cells size of both db/db mice and OT mice decreased. Quantitative real-time results show that,the mRNA expression of β-catenin is significantly raised (P<0.05), while the mRNA expressionof PPARγ, C/EBPα, adiponectin, ACC1, FAS and Wnt10b is down regulated (P<0.05) in bothmice. Western-Blot analysis also found that the protein level of PPARγ, adiponectin, Wnt10b,β-catenin is the same with those mRNA level.After injecting LiCl, the expression ofWnt/β-catenin signaling pathway associated factor (Wnt10b, β-catenin) and lipogenic processkey factor (PPARγ, C/EBPα, Adiponectin, etc.) of OT mice is larger than that of db/db mice.In conclusion, the findings show that, TNF-α plays an important role for Wnt/β-cateninsignaling pathway and early obesity. TNF-α affect the process of early obesity by Wnt/β-cateninsignaling pathway through the key factor β-catenin, which is similar to the effect of LiCl. TNF-αmay compete with LiCl by antagonistic mechanisms to play their respective roles. TNF-α and theWnt/β-catenin signaling pathway co-regulate early obesity. Accordingly, the above analysisprovide further insights into the mechanism of TNF-α and Wnt/β-catenin signaling pathway inearly obesity.