Tumor necrosis factor alpha improves glucose homeostasis in diabetic mice independent with tumor necrosis factor receptor 1 and tumor necrosis factor receptor 2

Type 2 diabetes is a serious threat to human health all over the world. It is particularly important to look for the pathogenesis of type 2 diabetes. Researchers have found that obesity was associated with a broad chronic inflammatory response and type 2 diabetes. And tumor necrosis factor alpha (TNF-α) is one of the most important cytokines related with obesity. To explore the functional role of TNF-α in the regulation of glucose homeostasis, TNF-α receptor 1 and TNF-α receptor 2 double knockout (TNFR1/R2 DKO) mouse model were used in our study. After high fat diet (HFD) feeding, we detected that the insulin resistance was dramatically improved and circulated TNF-α was upregulated in TNFR1/R2 DKO mice. Surprisingly, glucose homeostasis was worsened, when we down regulate the levels of plasma TNF-α in TNFR1/R2 DKO mice by administering Adeno associated virus-shRNA-TNF-α (AAV-shTNF-α). Subsequently, in ob/ob mice, we confirmed that the glucose homeostasis could be improved when we up regulate the levels of plasma TNF-α by administering Adeno associated virus-TNF-α (AAV-TNF-α). Our findings suggested that TNFR1 and TNFR2 may not be the only receptors for TNF-α and TNF-α probably plays a positive role in reducing insulin resistance via a TNFRs-independent way in diabetic mice.