A novel long non-coding RNA connects obesity to impaired adipocyte function

Lluch, Aina, Latorre, Jèssica, Oliveras-Cañellas, Núria, Fernández-Sánchez, Ana, Moreno-Navarrete, José M., Castells-Nobau, Anna, Comas, Ferran, Buxò, Maria, Rodríguez-Hermosa, José I., Ballester, María, Espadas, Isabel, Martin-Montalvo, Alejandro, Zhang, Birong, Zhou, You ORCID: https://orcid.org/0000-0002-1743-1291, Burkhardt, Ralph, Höring, Marcus, Liebisch, Gerhard, Castellanos-Rubio, Ainara, Santin, Izortze, Kar, Asha, Laakso, Markku, Pajukanta, Päivi, Olkkonen, Vesa M., Fernández-Real, José M. and Ortega, Francisco J. 2024. A novel long non-coding RNA connects obesity to impaired adipocyte function. Molecular Metabolism 90 , 102040. 10.1016/j.molmet.2024.102040

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Abstract

Background Long non-coding RNAs (lncRNAs) can perform tasks of key relevance in fat cells, contributing, when defective, to the burden of obesity and its sequelae. Here, scrutiny of adipose tissue transcriptomes before and after bariatric surgery (GSE53378) granted identification of 496 lncRNAs linked to the obese phenotype. Only expression of linc-GALNTL6-4 displayed an average recovery over 2-fold and FDR-adjusted p-value <0.0001 after weight loss. The aim of the present study was to investigate the impact on adipocyte function and potential clinical value of impaired adipose linc-GALNTL6-4 in obese subjects. Methods We employed transcriptomic analysis of public dataset GSE199063, and cross validations in two large transversal cohorts to report evidence of a previously unknown association of adipose linc-GALNTL6-4 with obesity. We then performed functional analyses in human adipocyte cultures, genome-wide transcriptomics, and untargeted lipidomics in cell models of loss and gain of function to explore the molecular implications of its associations with obesity and weight loss. Results The expression of linc-GALNTL6-4 in human adipose tissue is adipocyte-specific and co-segregates with obesity, being normalized upon weight loss. This co-segregation is demonstrated in two longitudinal weight loss studies and two cross-sectional samples. While compromised expression of linc-GALNTL6-4 in obese subjects is primarily due to the inflammatory component in the context of obesity, adipogenesis requires the transcriptional upregulation of linc-GALNTL6-4, the expression of which reaches an apex in terminally differentiated adipocytes. Functionally, we demonstrated that the knockdown of linc-GALNTL6-4 impairs adipogenesis, induces alterations in the lipidome, and leads to the downregulation of genes related to cell cycle, while propelling in adipocytes inflammation, impaired fatty acid metabolism, and altered gene expression patterns, including that of apolipoprotein C1 (APOC1). Conversely, the genetic gain of linc-GALNTL6-4 ameliorated differentiation and adipocyte phenotype, putatively by constraining APOC1, also contributing to the metabolism of triglycerides in adipose. Conclusions Current data unveil the unforeseen connection of adipocyte-specific linc-GALNTL6-4 as a modulator of lipid homeostasis challenged by excessive body weight and meta-inflammation.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Additional Information:	License information from Publisher: LICENSE 1: URL: http://creativecommons.org/licenses/by/4.0/, Start Date: 2024-09-24
Publisher:	Elsevier
ISSN:	2212-8778
Date of First Compliant Deposit:	16 October 2024
Date of Acceptance:	24 September 2024
Last Modified:	11 Nov 2024 15:00
URI:	https://orca.cardiff.ac.uk/id/eprint/172940

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