비만 관련 염증, 인슐린 저항, 간 지방증의 반전을 위한 Fas 활성화 신호 차단

Abstract

Obesity and its associated complications have affected more than 50% of the world population. Moderate level of chronic inflammation associated with the obesity contributes towards obesity co-morbidities such as type II diabetes, glucose intolerance, atherosclerosis, hepatic steatosis etc. and is thus considered as silent killer. Adipose tissue being the metabolic responsive organ is the start point, and simultaneously the victim of inflammation induced by nutritional stress. As a consequence of spreading of inflammation, along with adipose tissue, other insulin responsive organs such as liver and muscle become insulin resistant, eventually turning off the systemic and whole body insulin sensitivity. Adipocytes along with the infiltrated macrophages in adipose tissue are the key contributors towards inflammatory milieu. Fas receptor (CD95), expressed both on adipocytes and macrophages, upon activation, trigger alternative inflammatory pathway producing wide range of cytokines, which contribute towards inflammation eventually impairing the insulin signaling. Understanding this non-conventional role of Fas (CD95) in development of inflammation, we hypothesized that blocking Fas with respect to obesity associated inflammation, in adipose tissue, would reverse the inflammatory condition in obese mice and ameliorate the obesity-associated problems. In this study, we have modified an existing Fas targeting peptide (FTP) and developed a novel, functionally distinct, polymeric form of FTP called poly-FTP (pFTP). We here show that, blocking of Fas signaling in adipocytes and infiltrated macrophages by pFTP treatment, inhibits the feed forward loop that contributes towards the amplified recruitment of adipose tissue macrophages (ATMs), M2 to M1 macrophage polarization, adipocyte apoptosis, production of inflammatory cytokines and insulin resistance. Ultimately, treatment of pFTP reversed the inflammation, insulin resistance and hepatosteatosis by Fas inhibition in high fat diet induced obesity mouse model. Our results indicated that blocking Fas-mediated inflammation in adipose tissue may use as a therapeutic reagent in obesity associated inflammation, insulin resistance and hepatosteatosis.