Distinctive features of orbital adipose tissue (OAT) in Graves' orbitopathy

Zhang, Lei, Evans, Anna, von Ruhland, Chris, Draman, Mohd Shazli, Edkins, Sarah, Vincent, Amy E., Berlinguer-Palmini, Rolando, Rees, D. Aled, Haridas, Anjana S, Morris, Dan, Tee, Andrew R., Ludgate, Marian, Turnbull, Doug M., Karpe, Fredrik and Dayan, Colin M. 2020. Distinctive features of orbital adipose tissue (OAT) in Graves' orbitopathy. International Journal of Molecular Sciences 21 (23) , 9145. 10.3390/ijms21239145

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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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Additional Information:	This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited
Publisher:	MDPI
ISSN:	1422-0067
Date of First Compliant Deposit:	3 December 2020
Date of Acceptance:	28 November 2020
Last Modified:	11 Dec 2020 03:17
URI:	http://orca.cf.ac.uk/id/eprint/136757

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