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The role of mitochondria-linked fatty-acid uptake-driven adipogenesis in Graves’ Orbitopathy

Zhang, Lei, Rai, Pavandeep, Miwa, Satomi, Draman, Mohd, Rees, D Aled, Haridas, Anjana S., Morris, Daniel S., Tee, Andrew R., Ludgate, Marian, Turnbull, Doug M. and Dayan, Colin M. 2021. The role of mitochondria-linked fatty-acid uptake-driven adipogenesis in Graves’ Orbitopathy. Endocrinology 162 (12) , bqab188. 10.1210/endocr/bqab188
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Abstract

Context Depot-specific expansion of orbital adipose tissue (OAT) in Graves orbitopathy (GO; an autoimmune condition producing proptosis, visual impairment and reduced quality of life) is associated with fatty acid (FA)-uptake–driven adipogenesis in preadipocytes/fibroblasts (PFs). Objective This work sought a role for mitochondria in OAT adipogenesis in GO. Methods Confluent PFs from healthy OAT (OAT-H), OAT from GO (OAT-GO) and white adipose tissue in culture medium compared with culture medium containing a mixed hormonal cocktail as adipogenic medium (ADM), or culture-medium containing FA-supplementation, oleate:palmitate:linoleate (45:30:25%) with/without different concentration of mitochondrial biosubstrate adenosine 5′-diphosphate/guanosine 5′-diphosphate (ADP/GDP), AICAR (adenosine analogue), or inhibitor oligomycin-A for 17 days. Main outcome measures included oil-red-O staining and foci count of differentiated adipocytes for in vitro adipogenesis, flow cytometry, relative quantitative polymerase chain reaction, MTS-assay/106 cells, total cellular-ATP detection kit, and Seahorse-XFe96-Analyzer for mitochondria and oxidative-phosphorylation (OXPHOS)/glycolysis-ATP production analysis. Results During early adipogenesis before adipocyte formation (days 0, 4, and7), we observed OAT-specific cellular ATP production via mitochondrial OXPHOS in PFs both from OAT-H and OAT-GO, and substantially disrupted OXPHOS-ATP/glycolysis-ATP production in PFs from OAT-GO, for example, a 40% reduction in OXPHOS-ATP and trend-increased glycolysis-ATP production on days 4 and 7 compared with day 0, which contrasted with the stable levels in OAT-H. FA supplementation in culture-medium triggered adipogenesis in PFs both from OAT-H and OAT-GO, which was substantially enhanced by 1-mM GDP reaching 7% to 18% of ADM adipogenesis. The FA-uptake–driven adipogenesis was diminished by oligomycin-A but unaffected by treatment with ADP or AICAR. Furthermore, we observed a significant positive correlation between FA-uptake–driven adipogenesis by GDP and the ratios of OXPHOS-ATP/glycolysis-ATP through adipogenesis of PFs from OAT-GO. Conclusion Our study confirmed that FA uptake can drive OAT adipogenesis and revealed a fundamental role for mitochondria-OXPHOS in GO development, which provides potential for therapeutic interventions.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Publisher: Endocrine Society
ISSN: 0013-7227
Date of First Compliant Deposit: 1 September 2021
Date of Acceptance: 1 September 2021
Last Modified: 17 May 2022 17:40
URI: https://orca.cardiff.ac.uk/id/eprint/143799

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