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

adipocytes adipose tissue linc-GALNTL6-4 obesity triglycerides

Journal

Molecular metabolism
ISSN: 2212-8778
Titre abrégé: Mol Metab
Pays: Germany
ID NLM: 101605730

Informations de publication

Date de publication:
01 Oct 2024
Historique:
received: 02 09 2024
accepted: 24 09 2024
medline: 4 10 2024
pubmed: 4 10 2024
entrez: 3 10 2024
Statut: aheadofprint

Résumé

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. 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. 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. 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.

Sections du résumé

BACKGROUND 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 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 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 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.

Identifiants

DOI: 10.1016/j.molmet.2024.102040 PMID: 39362599
pubmed: 39362599
pii: S2212-8778(24)00171-6
doi: 10.1016/j.molmet.2024.102040
pii:
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

102040

Informations de copyright

Copyright © 2024 The Author(s). Published by Elsevier GmbH.. All rights reserved.

Auteurs

Aina Lluch (A)

Institut d'Investigació Biomèdica de Girona (IDIBGI) - Girona, Spain; CIBER de la Fisiología de la Obesidad y la Nutrición (CIBEROBN) - Madrid, Spain.

Jèssica Latorre (J)

Institut d'Investigació Biomèdica de Girona (IDIBGI) - Girona, Spain; CIBER de la Fisiología de la Obesidad y la Nutrición (CIBEROBN) - Madrid, Spain. Electronic address: jessica.latorre@uvic.cat.

Núria Oliveras-Cañellas (N)

Institut d'Investigació Biomèdica de Girona (IDIBGI) - Girona, Spain; CIBER de la Fisiología de la Obesidad y la Nutrición (CIBEROBN) - Madrid, Spain.

Ana Fernández-Sánchez (A)

Institut d'Investigació Biomèdica de Girona (IDIBGI) - Girona, Spain.

José M Moreno-Navarrete (JM)

Institut d'Investigació Biomèdica de Girona (IDIBGI) - Girona, Spain; CIBER de la Fisiología de la Obesidad y la Nutrición (CIBEROBN) - Madrid, Spain.

Anna Castells-Nobau (A)

Institut d'Investigació Biomèdica de Girona (IDIBGI) - Girona, Spain; CIBER de la Fisiología de la Obesidad y la Nutrición (CIBEROBN) - Madrid, Spain.

Ferran Comas (F)

Institut d'Investigació Biomèdica de Girona (IDIBGI) - Girona, Spain.

Maria Buxò (M)

Institut d'Investigació Biomèdica de Girona (IDIBGI) - Girona, Spain.

José I Rodríguez-Hermosa (JI)

Institut d'Investigació Biomèdica de Girona (IDIBGI) - Girona, Spain; School of Medicine, University of Girona (UdG) - Girona, Spain.

María Ballester (M)

Animal Breeding and Genetics Programme, Institute for Research and Technology in Food and Agriculture (IRTA), Torre Marimon - Caldes de Montbui, Spain.

Isabel Espadas (I)

Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER), Consejo Superior de Investigaciones Científicas (CSIC), University Pablo de Olavide - Seville, Spain.

Alejandro Martin-Montalvo (A)

Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER), Consejo Superior de Investigaciones Científicas (CSIC), University Pablo de Olavide - Seville, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM) - Madrid, Spain.

Birong Zhang (B)

Systems Immunity Research Institute, Cardiff University - Cardiff, United Kingdom.

You Zhou (Y)

Systems Immunity Research Institute, Cardiff University - Cardiff, United Kingdom.

Ralph Burkhardt (R)

Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Regensburg - Regensburg, Germany.

Marcus Höring (M)

Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Regensburg - Regensburg, Germany.

Gerhard Liebisch (G)

Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Regensburg - Regensburg, Germany.

Ainara Castellanos-Rubio (A)

CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM) - Madrid, Spain; Universidad del País Vasco/Euskal Herriko Unibertsitatea (UPV/EHU) - Bizkaia, Spain; Ikerbasque, Basque Foundation for Science - Bilbao, Spain.

Izortze Santin (I)

CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM) - Madrid, Spain; Universidad del País Vasco/Euskal Herriko Unibertsitatea (UPV/EHU) - Bizkaia, Spain; Instituto de Investigación Sanitaria Biocruces Bizkaia - Bizkaia, Spain.

Asha Kar (A)

Bioinformatics Interdepartmental Program, UCLA - Los Angeles (CA), USA; Department of Human Genetics, David Geffen School of Medicine at UCLA - Los Angeles (CA), USA.

Markku Laakso (M)

Department of Medicine, University of Eastern Finland and Kuopio University Hospital - Kuopio, Finland.

Päivi Pajukanta (P)

Bioinformatics Interdepartmental Program, UCLA - Los Angeles (CA), USA; Department of Human Genetics, David Geffen School of Medicine at UCLA - Los Angeles (CA), USA; Institute for Precision Health, David Geffen School of Medicine at UCLA - Los Angeles (CA), USA.

Vesa M Olkkonen (VM)

Minerva Foundation Institute for Medical Research, University of Helsinki - Helsinki, Finland.

José M Fernández-Real (JM)

Institut d'Investigació Biomèdica de Girona (IDIBGI) - Girona, Spain; CIBER de la Fisiología de la Obesidad y la Nutrición (CIBEROBN) - Madrid, Spain; School of Medicine, University of Girona (UdG) - Girona, Spain. Electronic address: jmfreal@idibgi.org.

Francisco J Ortega (FJ)

Institut d'Investigació Biomèdica de Girona (IDIBGI) - Girona, Spain; CIBER de la Fisiología de la Obesidad y la Nutrición (CIBEROBN) - Madrid, Spain. Electronic address: fortega@idibgi.org.

Classifications MeSH