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.

Orbital Signaling in Graves’ Orbitopathy

“…The FGF signalling pathway has also been shown to play a role in OAT expansion in GO ( 69 ). Our most recent study used RNA-seq analysis to demonstrate that FGFs, FGFR2, IGF-2 and IGF1-R were highly expressed in OAT compared with white adipose tissue, supporting the aforementioned successful trial of IGF1R inhibition in GO ( 56 ).…”

“…In addition, our most recent studies demonstrated a depot specific fatty acid-uptake driven adipogenesis with unique gene signatures in OAT. These result in hyperplastic-type expansion of adipocytes in GO ( 56 , 57 ). Taken together, these findings suggest a very distinctive mechanism underlying the orbital adipogenesis process.…”

The Role of Mitochondria-Linked Fatty-Acid Uptake-Driven Adipogenesis in Graves Orbitopathy

“…The identified pathways interact with TSHR / IGF1R signaling to play essential roles in the depot-specific OAT expansion in GO ( 2 ). Our recent work has demonstrated that OAT is a distinctive metabolic-quiescent fat depot that neither stores additional triglycerides (TAGs) in obesity ( 15 ) nor burns fatty acids (FAs) ( 11 ), in contrast to WAT and BAT (brown adipose tissue)/BRITE (BRown in whITE), respectively. OAT also displays a unique FA-uptake–driven adipogenesis mechanism, which occurs in addition to the hyperplastic expansion (increased adipocyte number) of PFs in OAT in GO ( 11 ).…”

“…Our recent work has demonstrated that OAT is a distinctive metabolic-quiescent fat depot that neither stores additional triglycerides (TAGs) in obesity ( 15 ) nor burns fatty acids (FAs) ( 11 ), in contrast to WAT and BAT (brown adipose tissue)/BRITE (BRown in whITE), respectively. OAT also displays a unique FA-uptake–driven adipogenesis mechanism, which occurs in addition to the hyperplastic expansion (increased adipocyte number) of PFs in OAT in GO ( 11 ). In particular, lower lipolytic activity with similar (low) FA synthesis accompanied by increased expression of a depot-specific FA transporter ( SLC27A6 ) were observed in OAT from healthy individuals (OAT-H) and GO patients (OAT-GO) compared with WAT ( 11 ).…”

“…OAT also displays a unique FA-uptake–driven adipogenesis mechanism, which occurs in addition to the hyperplastic expansion (increased adipocyte number) of PFs in OAT in GO ( 11 ). In particular, lower lipolytic activity with similar (low) FA synthesis accompanied by increased expression of a depot-specific FA transporter ( SLC27A6 ) were observed in OAT from healthy individuals (OAT-H) and GO patients (OAT-GO) compared with WAT ( 11 ).…”