An adipose lncRAP2-Igf2bp2 complex enhances adipogenesis and energy expenditure by stabilizing target mRNAs
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lncRAP2 is a conserved cytoplasmic lncRNA enriched in adipose tissue and required for adipogenesis. Using purification and in vivo interactome analyses, we show that lncRAP2 forms complexes with proteins that stabilize mRNAs and modulate translation, among them Igf2bp2. Surveying transcriptome-wide Igf2bp2 client mRNAs in white adipocytes reveals selective binding to mRNAs encoding adipogenic regulators and energy expenditure effectors, including adiponectin. These same target proteins are downregulated when either Igf2bp2 or lncRAP2 is downregulated, hindering adipocyte lipolysis. Proteomics and ribosome profiling show this occurs predominantly through mRNA accumulation, as lncRAP2-Igf2bp2 complex binding does not impact translation efficiency. Phenome-wide association studies reveal specific associations of genetic variants within both lncRAP2 and Igf2bp2 with body mass and type 2 diabetes, and both lncRAP2 and Igf2bp2 are suppressed in adipose depots of obese and diabetic individuals. Thus, the lncRAP2-Igf2bp2 complex potentiates adipose development and energy expenditure and is associated with susceptibility to obesity-linked diabetes.
| Originalsprog | Engelsk |
|---|---|
| Artikelnummer | 103680 |
| Tidsskrift | iScience |
| Vol/bind | 25 |
| Udgave nummer | 1 |
| Antal sider | 25 |
| ISSN | 2589-0042 |
| DOI | |
| Status | Udgivet - 2022 |
Bibliografisk note
Funding Information:
We thank the imaging, proteomics, bioinformatics, and genome core facilities at the Whitehead Institute for technical support. We also thank Drs. Alexander Bartelt, Wenqian Hu, and Lei Sun for critical discussions. J.R.A.-D. is a Howard Hughes Medical Institute Fellow of the Life Sciences Research Foundation. This research was supported by fellowship Kn1106/1-1 from the Deutsche Forschungsgemeinschaft to M.K. and National Institute of Health grants DK068348 and DK047618 to H.F.L.
Funding Information:
We thank the imaging, proteomics, bioinformatics, and genome core facilities at the Whitehead Institute for technical support. We also thank Drs. Alexander Bartelt, Wenqian Hu, and Lei Sun for critical discussions. J.R.A.-D. is a Howard Hughes Medical Institute Fellow of the Life Sciences Research Foundation. This research was supported by fellowship Kn1106/1-1 from the Deutsche Forschungsgemeinschaft to M.K. and National Institute of Health grants DK068348 and DK047618 to H.F.L. J.R.A.-D. M.K. and S.W. performed experiments; J.R.A.-D. M.K. and H.F.L. designed the research, interpreted results, and wrote the manuscript. The authors declare no competing interests.
Publisher Copyright:
© 2021 The Author(s)
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