Distinctive features of orbital adipose tissue (Oat) in graves’ orbitopathy

Abstract

Depot specific expansion of orbital‐adipose‐tissue (OAT) in Graves’ Orbitopathy (GO) is associated with lipid metabolism signaling defects. We hypothesize that the unique adipocyte biology of OAT facilitates its expansion in GO. A comprehensive comparison of OAT and white-adipose‐tissue (WAT) was performed by light/electron‐microscopy, lipidomic and transcriptional analysis using ex vivo WAT, healthy OAT (OAT‐H) and OAT from GO (OAT‐GO). OAT‐H/OAT‐ GO have a single lipid‐vacuole and low mitochondrial number. Lower lipolytic activity and smaller adipocytes of OAT‐H/OAT‐GO, accompanied by similar essential linoleic fatty acid (FA) and (low) FA synthesis to WAT, revealed a hyperplastic OAT expansion through external FA‐uptake via abundant SLC27A6 (FA‐transporter) expression. Mitochondrial dysfunction of OAT in GO was apparent, as evidenced by the increased mRNA expression of uncoupling protein 1 (UCP1) and mitofusin‐2 (MFN2) in OAT‐GO compared to OAT‐H. Transcriptional profiles of OAT‐H revealed high expression of Iroquois homeobox‐family (IRX‐3&5), and low expression in HOX‐family/TBX5 (essential for WAT/BAT (brown‐adipose‐tissue)/BRITE (BRown‐in‐whITE) development). We demonstrated unique features of OAT not presented in either WAT or BAT/BRITE. This study reveals that the pathologically enhanced FA‐uptake driven hyperplastic expansion of OAT in GO is associated with a depot specific mechanism (the SLC27A6 FA‐transporter) and mitochondrial dysfunction. We uncovered that OAT functions as a distinctive fat depot, providing novel insights into adipocyte biology and the pathological development of OAT expansion in GO.