Objective: This study was aimed at revealing a new mechanism mediated by IL-6/Stat3 signaling pathway on islet failure in high fat diet-induced obesity through activation of inflammation.
Methods: We produced mice with non-obesity, moderate obesity and severe obesity respectively by feeding with normal diet (control), three months’ high fat diet (HFD-3M) and six months’ high fat diet (HFD-6M). Then 200 islets were isolated from the three groups and lysed for RNA extraction, following RNA-Seq analysis with MAPS (Multiplex Analysis of PolyA-linked Sequences) approach. Normal islets were cultured in vitro for IL-6 stimulation and mice with stat3 specific deletion in islet were used to prevent HFD-resulted islet failure.
Results: Mice with HFD for three months and six months show significantly higher fast glucose and severe glucose intolerance than control and the morphology of islets from HFD group was obviously abnormal. Additionally, these diabetic symptoms were aggravated in pace with HFD feeding. Further analysis of RNA-seq shows that the expressions of hormones secreted by different endocrine cells were all down-regulated, including INS1, GCG, SST and PPY. On the other hand, expression of IL-6/Stat3 pathway related genes were significantly elevated, including IL-6, CCL2, CCL5, CCL11, CCL28, Tnfrsf11 and NF-kB. Stat3 in islets from HFD-3M and HFD-6M group was also activated by phosphorylation of Y705. Cultured islets with IL-6 treatment show impaired insulin secretion and increased inflammation level. Notably, mice with stat3 specific deletion in islet were able to attenuate the HFD-induced increase of inflammation and secretory deficiency of islet.
Conclusions: HFD-induced obesity resulted in islet failure and the high level of serum IL-6 participate in the obesity induced islet failure through IL-6/Stat3 pathway mediated inflammation.
Z. Jiang: None. F. Teng: None. Y. Xu: None.
National Natural Science Foundation of China (81600597)