Luminal Leptin Impairs Intestinal Tight Junction Function in vitro through JAK2‐dependent Signaling Pathway

Abstract

Tight junction (TJ) integrity is a critical for maintaining intestinal barrier function and inflammation. Obesity is also known to alter intestinal function partly through an impairment of intestine TJ integrity. Leptin is associated with inflammation and obesity. However, the role of leptin in TJ function is unknown. This study aimed to investigate the effect of leptin on intestinal TJ integrity in vitro using Caco‐2 BBe cells. Leptin addition to apical compartment, but not in basolateral compartment, caused TJ barrier dysfunction as judged by transepithelial electrical resistance and dextran fluxes. TJ dysfunction by luminal leptin was associated with reduced levels of gene expression related to TJ‐associated proteins, zonula occludens‐3, claudin‐5, and occludin. In addition, leptin treatment caused reduction in total protein level of occludin. Moreover, activation of the Janus family of tyrosine kinase/signal transducer and activator of transcription (JAK2/STAT3) axis has been also observed upon leptin treatment. Conversely, a JAK2 specific inhibitor or a PI3K specific inhibitor pretreatment abolished leptin activity on TJ integrity, indicating an involvement of JAK2 and PI3K signaling pathways in leptin‐impaired TJ function. Therefore, our results reveal previously unknown function of luminal leptin, which potentially links between obesity and its associated intestinal TJ dysfunction.