Genetic Ablation of TNF‐α Attenuates High Fat Diet‐induced Obesity Potentially via Diminishing Wnt‐signaling and Determinant Genes of Adipogenesis

Abstract

Recent decades have seen a rapid increase in obesity, which is associated with increased risk of multiple medical complications including diabetes, cardiovascular disease, and some cancers. As obesity has reached an epidemic level and no decrease is projected in the near future, new prevention and medication strategies are needed for obesity and related disorders. Tumor necrosis factor alpha (TNF‐α), a critical pro‐inflammatory cytokine, is elevated in adipose tissue and its expression level correlates with the degree of obesity. Impressive evidence shows that diets or drugs, which are used to reduce inflammation, can ameliorate obesity. The objective of the study was to investigate the role of TNF‐α in high‐fat diet‐induced obesity and thereby to examine the potential implication of targeting TNF‐α in obesity and obesity‐related complications. Fifty‐two wildtype and 52 TNF‐α knockout mice (male and female evenly) with the same C57BL6 genetic background were randomly divided into two groups receiving either a high‐fat diet (HFD, 60% fat) or a low fat diet (LFD, 10% fat) for 16 weeks. Body weight were monitored weekly and body composition were determined by Magnetic Resonance Imaging (MRI), The expression of pro‐inflammatory cytokines, key components within Wnt pathway and determinants of adipogenesis in the visceral adipose tissue were also measured. The results shows that, while there are no significant differences among the LFD groups (p > 0.05), wildtype HFD group has significantly higher body weight and fat composition compared to TNF‐α knockout HFD group. In addition to TNF‐α itself, the expressions of IL‐6 and IFNγ, as measured by chemiluminescent immunoassay, were also significantly lower in the HFD‐induced obese animals with TNF‐α knockout when comparing to the wildtype HFD group (p < 0.05). In the obese state, the genetic ablation of TNF‐α significantly reduced Wnt‐signaling, as indicated by decreased phospho‐GSK3β and active β‐catenin as well as Wnt pathway downstream genes (p < 0.05). The deletion of TNF‐α significantly increased both mRNA and protein expression of PPARγ and C/EBPα, two critical genes which are key determinants of adipogenesis. All these data collectively indicate that depletion of TNF‐α may ameliorate HFD‐induced obesity, potentially via altering Wnt‐signaling and determinants of adipogenesis.Support or Funding InformationThis project is supported by USDA grants (2014‐67017‐21762 and MAS00454) and the Pilot grant from Rays of Hope Center for Breast Cancer Research