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Human thermogenic adipocyte regulation by the long noncoding RNA LINC00473

Nature Metabolism volume 2, pages 397–412 (2020)Cite this article

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Abstract

Human thermogenic adipose tissue mitigates metabolic disease, thus raising much interest in understanding its development and function. Here, we show that human thermogenic adipocytes specifically express a primate-specific long noncoding RNA (lncRNA), LINC00473, which is highly correlated with UCP1 expression and is decreased in obesity and type-2 diabetes. LINC00473 is detected in progenitor cells, and increases following differentiation and in response to cyclic AMP (cAMP). In contrast to other known adipocyte long intergenic noncoding RNAs, LINC00473 shuttles out of the nucleus, colocalizes and can be cross-linked to mitochondrial and lipid droplet proteins. Up- or downregulation of LINC00473 results in reciprocal alterations in lipolysis, respiration and transcription of genes associated with mitochondrial oxidative metabolism. Depletion of PLIN1 results in impaired cAMP-responsive LINC00473 expression and lipolysis, indicating bidirectional interactions among PLIN1, LINC00473 and mitochondrial oxidative functions. Thus, we suggest that LINC00473 is a key regulator of human thermogenic adipocyte function and reveal a role for a lncRNA in interorganelle communication and human energy metabolism.

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Fig. 1: Comparison of gene expression in primary adipocytes from thermogenic and non-thermogenic human adipose tissue.
Fig. 2: LINC00473 expression is associated with thermogenic adipocyte development.
Fig. 3: Translocation of LINC00473 to mitochondria-lipid droplet interphase.
Fig. 4: Interactions among LINC00473, mitochondria and PLIN1.
Fig. 5: Functional role of LINC00473.
Fig. 6: Transcriptomic changes in response to modulation of LINC00473.
Fig. 7: Mechanisms of induction of LINC00473.
Fig. 8: Phylogenetic analysis and conceptual function model for LINC00473.

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Data availability

Sequences of all oligonucleotides used in this study are included in Supplementary Table 9. GEO accession numbers for the RNA-seq data in this manuscript are GSE150119 and GSE148896. Further information and requests for resources and reagents should be directed to, and will be fulfilled by, S.C. (silvia.corvera@umassmed.edu).

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Acknowledgements

This study was supported by NIH grant no. DK089101-04, to S.C. We acknowledge the use of services from the UMASS Bioinformatics Core, supported by NIH CTSA grant no. UL1 TR000161-05, and from the UMASS SCOPE core for high-resolution confocal imaging. K.-V.T. was supported by NIH grant no. 5T32HL120823-03. The Centre for Physical Activity Research is supported by grants from TrygFonden (nos. 101390 and 20045). During the study period, the Centre of Inflammation and Metabolism was supported by a grant from the Danish National Research Foundation (no. DNRF55). S.N. was further supported by the Danish Council for Independent Research, Medical Sciences (no. 4092-00492B) and by the Novo Nordisk Foundation (NNF18OC0052979). N.Z.J., C.N.-B. and T.J.L. were funded by the Danish Diabetes Academy supported by the Novo Nordisk Foundation. E.L.B., B.E. and M.L. were supported by internal funding from the Novo Nordisk Foundation Center for Basic Metabolic Research, an independent research centre at the University of Copenhagen partially funded by an unrestricted donation from the Novo Nordisk Foundation (no. NNF18CC0034900).

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  1. These authors contributed equally: Khanh-Van Tran, Erin L. Brown.

  2. These authors jointly supervised this work: Silvia Corvera, Søren Nielsen.

Authors and Affiliations

  1. Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, USA

    Khanh-Van Tran, Tiffany DeSouza, Qin Yang, Zinger Yang, Anand Desai, So Yun Min, Raziel Rojas-Rodriguez, Timothy Fitzgibbons & Silvia Corvera

  2. Department of Medicine, Division of Cardiovascular Medicine, University of Massachusetts Medical School, Worcester, MA, USA

    Khanh-Van Tran & Timothy Fitzgibbons

  3. Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Science, University of Copenhagen, Copenhagen, Denmark

    Erin L. Brown, Morten Lundh, Anthony M. Mozzicato, Atul S. Deshmukh, Brice Emanuelli & Camilla Scheele

  4. The Centre of Inflammation and Metabolism and the Centre for Physical Activity Research, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

    Naja Zenius Jespersen, Cecilie Nandrup-Bus, Therese Juhlin Larsen, Mai Charlotte Krogh Severinsen, Bente Klarlund Pedersen, Camilla Scheele & Søren Nielsen

  5. Novo Nordisk Research Centre Oxford, University of Oxford, Oxford, UK

    Amir Feizi

  6. Novo Nordisk A/S, Discovery Biology & Technology Boinformatics, Maaloev, Denmark

    Hanni Willenbrock

  7. Department of Surgery, Division of Vascular and Endovascular Surgery, University of Massachusetts Medical School, Worcester, MA, USA

    Kimberly Malka

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Contributions

S.C. and S.N. supervised this work. K.-V.T., E.L.B., T.D., C.N.-B., S.Y.M., M.L., T.J.L., B.E., B.K.P., T.F., C.S., S.N. and S.C. conducted hypothesis generation, conceptual design, data analysis and manuscript preparation. K.-V.T., E.L.B., T.D., N.Z.J., C.N.-B., Q.Y., Z.Y., A.D., S.Y.M., R.R.-R., A.F., H.W., M.C.K.S., K.M., A.M.M., A.S.D., S.C. and S.N. conducted experiments and data analysis.

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Correspondence to Silvia Corvera.

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Tran, KV., Brown, E.L., DeSouza, T. et al. Human thermogenic adipocyte regulation by the long noncoding RNA LINC00473. Nat Metab 2, 397–412 (2020). https://doi.org/10.1038/s42255-020-0205-x

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