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Animal Models

Pharmacological modulation of LMNA SRSF1-dependent splicing abrogates diet-induced obesity in mice

International Journal of Obesity volume 41, pages 390–401 (2017)Cite this article

Subjects

Abstract

Bakground/Objectives:

Intense drug discovery efforts in the metabolic field highlight the need for novel strategies for the treatment of obesity. Alternative splicing (AS) and/or polyadenylation enable the LMNA gene to express distinct protein isoforms that exert opposing effects on energy metabolism and lifespan. Here we aimed to use the splicing factor SRSF1 that contribute to the production of these different isoforms as a target to uncover new anti-obesity drug.

Subjects/Methods:

Small molecules modulating SR protein activity and splicing were tested for their abilities to interact with SRSF1 and to modulate LMNA (AS). Using an LMNA luciferase reporter we selected molecules that were tested in diet-induced obese (DIO) mice. Transcriptomic analyses were performed in the white adipose tissues from untreated and treated DIO mice and mice fed a chow diet.

Results:

We identified a small molecule that specifically interacted with the RS domain of SRSF1. ABX300 abolished DIO in mice, leading to restoration of adipose tissue homeostasis. In contrast, ABX300 had no effect on mice fed a standard chow diet. A global transcriptomic analysis revealed similar profiles of white adipose tissue from DIO mice treated with ABX300 and from untreated mice fed a chow diet. Mice treated with ABX300 exhibited an increase in O2 consumption and a switch in fuel preference toward lipids.

Conclusions:

Targeting SRSF1 with ABX300 compensates for changes in RNA biogenesis induced by fat accumulation and consequently represents a novel unexplored approach for the treatment of obesity.

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References

  1. Van Gaal LF, Mertens IL, De Block CE . Mechanisms linking obesity with cardiovascular disease. Nature 2006; 444: 875–880.

    Article  CAS  Google Scholar 

  2. Ford ES, Giles WH, Dietz WH . Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey. JAMA 2002; 287: 356–359.

    Article  Google Scholar 

  3. Saltiel AR . New therapeutic approaches for the treatment of obesity. Sci Transl Med 2016; 8: 323rv2.

    Article  Google Scholar 

  4. Spiegelman BM, Heinrich R . Biological control through regulated transcriptional coactivators. Cell 2004; 119: 157–167.

    Article  CAS  Google Scholar 

  5. Guan X-M, Chen H, Dobbelaar PH, Dong Y, Fong TM, Gagen K et al. Regulation of energy homeostasis by bombesin receptor subtype-3: selective receptor agonists for the treatment of obesity. Cell Metab 2010; 11: 101–112.

    Article  CAS  Google Scholar 

  6. Tseng Y-H, Cypess AM, Kahn CR . Cellular bioenergetics as a target for obesity therapy. Nat Rev Drug Discov 2010; 9: 465–482.

    Article  CAS  Google Scholar 

  7. Lopez-Mejia IC, De Toledo M, Chavey C, Lapasset L, Cavelier P, Lopez-Herrera C et al. Antagonistic functions of LMNA isoforms in energy expenditure and lifespan. EMBO Rep 2014; 15: 529–539.

    Article  CAS  Google Scholar 

  8. Worman HJ, Bonne G . ‘Laminopathies’: a wide spectrum of human diseases. Exp Cell Res 2007; 313: 2121–2133.

    Article  CAS  Google Scholar 

  9. Wilson KL, Zastrow MS, Lee KK . Lamins and disease: insights into nuclear infrastructure. Cell 2001; 104: 647–650.

    CAS  PubMed  Google Scholar 

  10. Navarro CL, Cau P, Lévy N . Molecular bases of progeroid syndromes. Hum Mol Genet 2006; 15 (Spec No 2): R151–R161.

    Article  CAS  Google Scholar 

  11. Eriksson M, Brown WT, Gordon LB, Glynn MW, Singer J, Scott L et al. Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome. Nature 2003; 423: 293–298.

    Article  CAS  Google Scholar 

  12. De Sandre-Giovannoli A, Bernard R, Cau P, Navarro C, Amiel J, Boccaccio I et al. Lamin a truncation in Hutchinson-Gilford progeria. Science 2003; 300: 2055.

    Article  CAS  Google Scholar 

  13. Arai Y, Takayama M, Abe Y, Hirose N . Adipokines and aging. J Atheroscler Thromb 2011; 18: 545–550.

    Article  CAS  Google Scholar 

  14. Lopez-Mejia IC, Vautrot V, De Toledo M, Behm-Ansmant I, Bourgeois CF, Navarro CL et al. A conserved splicing mechanism of the LMNA gene controls premature aging. Hum Mol Genet 2011; 20: 4540–4555.

    Article  CAS  Google Scholar 

  15. Vautrot V, Aigueperse C, Oillo-Blanloeil F, Hupont S, Stévenin J, Branlant C et al. Enhanced SRSF5 protein expression reinforces Lamin A mRNA production in HeLa cells and fibroblasts of progeria patients. Hum Mutat 2016; 37: 280–291.

    Article  CAS  Google Scholar 

  16. Tazi J, Bakkour N, Stamm S . Alternative splicing and disease. Biochim Biophys Acta 2009; 1792: 14–26.

    Article  CAS  Google Scholar 

  17. Soret J, Bakkour N, Maire S, Durand S, Zekri L, Gabut M et al. Selective modification of alternative splicing by indole derivatives that target serine-arginine-rich protein splicing factors. Proc Natl Acad Sci USA 2005; 102: 8764–8769.

    Article  CAS  Google Scholar 

  18. Bakkour N, Lin Y-L, Maire S, Ayadi L, Mahuteau-Betzer F, Nguyen CH et al. Small-molecule inhibition of HIV pre-mRNA splicing as a novel antiretroviral therapy to overcome drug resistance. PLoS Pathog 2007; 3: 1530–1539.

    Article  CAS  Google Scholar 

  19. Campos N, Myburgh R, Garcel A, Vautrin A, Lapasset L, Nadal ES et al. Long lasting control of viral rebound with a new drug ABX464 targeting Rev-mediated viral RNA biogenesis. Retrovirology 2015; 12: 30.

    Article  Google Scholar 

  20. Venables JP, Lapasset L, Gadea G, Fort P, Klinck R, Irimia M et al. MBNL1 and RBFOX2 cooperate to establish a splicing programme involved in pluripotent stem cell differentiation. Nat Commun 2013; 4: 2480.

    Article  Google Scholar 

  21. Makeyev EV, Maniatis T . Multilevel regulation of gene expression by microRNAs. Science 2008; 319: 1789–1790.

    Article  CAS  Google Scholar 

  22. McGregor RA, Choi MS . microRNAs in the regulation of adipogenesis and obesity. Curr Mol Med 2011; 11: 304–316.

    Article  CAS  Google Scholar 

  23. Wu H, Sun S, Tu K, Gao Y, Xie B, Krainer AR et al. A splicing-independent function of SF2/ASF in microRNA processing. Mol Cell 2010; 38: 67–77.

    Article  CAS  Google Scholar 

  24. Melamed Z, Levy A, Ashwal-Fluss R, Lev-Maor G, Mekahel K, Atias N et al. Alternative splicing regulates biogenesis of miRNAs located across exon-intron junctions. Mol Cell 2013; 50: 869–881.

    Article  CAS  Google Scholar 

  25. Ortega FJ, Moreno-Navarrete JM, Pardo G, Sabater M, Hummel M, Ferrer A et al. MiRNA expression profile of human subcutaneous adipose and during adipocyte differentiation. PLoS One 2010; 5: e9022.

    Article  Google Scholar 

  26. Lengacher S, Nehiri-Sitayeb T, Steiner N, Carneiro L, Favrod C, Preitner F et al. Resistance to diet-induced obesity and associated metabolic perturbations in haploinsufficient monocarboxylate transporter 1 mice. PLoS One 2013; 8: e82505.

    Article  Google Scholar 

  27. Cáceres JF, Screaton GR, Krainer AR . A specific subset of SR proteins shuttles continuously between the nucleus and the cytoplasm. Genes Dev 1998; 12: 55–66.

    Article  Google Scholar 

  28. Longman D, Johnstone IL, Cáceres JF . Functional characterization of SR and SR-related genes in Caenorhabditis elegans. EMBO J 2000; 19: 1625–1637.

    Article  CAS  Google Scholar 

  29. Li H, Cheng Y, Wu W, Liu Y, Wei N, Feng X et al. SRSF10 regulates alternative splicing and is required for adipocyte differentiation. Mol Cell Biol 2014; 34: 2198–2207.

    Article  Google Scholar 

  30. Jackson VM, Breen DM, Fortin J-P, Liou A, Kuzmiski JB, Loomis AK et al. Latest approaches for the treatment of obesity. Expert Opin Drug Discov 2015; 10: 825–839.

    Article  CAS  Google Scholar 

  31. Oldendorf WH . Lipid solubility and drug penetration of the blood brain barrier. Proc Soc Exp Biol Med 1974; 147: 813–815.

    Article  CAS  Google Scholar 

  32. Jung H-J, Coffinier C, Choe Y, Beigneux AP, Davies BSJ, Yang SH et al. Regulation of prelamin A but not lamin C by miR-9, a brain-specific microRNA. Proc Natl Acad Sci USA 2012; 109: E423–E431.

    Article  CAS  Google Scholar 

  33. Nissan X, Blondel S, Navarro C, Maury Y, Denis C, Girard M et al. Unique preservation of neural cells in Hutchinson- Gilford progeria syndrome is due to the expression of the neural-specific miR-9 microRNA. Cell Rep 2012; 2: 1–9.

    Article  CAS  Google Scholar 

  34. Tazi J, Durand S, Jeanteur P . The spliceosome: a novel multi-faceted target for therapy. Trends Biochem Sci 2005; 30: 469–478.

    Article  CAS  Google Scholar 

  35. Bonnal S, Vigevani L, Valcárcel J . The spliceosome as a target of novel antitumour drugs. Nat Rev Drug Discov 2012; 11: 847–859.

    Article  CAS  Google Scholar 

  36. Pandit S, Zhou Y, Shiue L, Coutinho-Mansfield G, Li H, Qiu J et al. Genome-wide analysis reveals SR protein cooperation and competition in regulated splicing. Mol Cell 2013; 50: 223–235.

    Article  CAS  Google Scholar 

  37. Sanford JR, Coutinho P, Hackett JA, Wang X, Ranahan W, Cáceres JF . Identification of nuclear and cytoplasmic mRNA targets for the shuttling protein SF2/ASF. PLoS One 2008; 3: e3369.

    Article  Google Scholar 

  38. Maslon MM, Heras SR, Bellora N, Eyras E, Cáceres JF . The translational landscape of the splicing factor SRSF1 and its role in mitosis. Elife 2014; 3: e02028.

    Article  Google Scholar 

  39. Passetti F, Ferreira CG, Costa FF . The impact of microRNAs and alternative splicing in pharmacogenomics. Pharmacogenomics J 2009; 9: 1–13.

    Article  CAS  Google Scholar 

  40. Fu X-D, Ares M . Context-dependent control of alternative splicing by RNA-binding proteins. Nat Rev Genet 2014; 15: 689–701.

    Article  CAS  Google Scholar 

  41. Kwan T, Benovoy D, Dias C, Gurd S, Provencher C, Beaulieu P et al. Genome-wide analysis of transcript isoform variation in humans. Nat Genet 2008; 40: 225–231.

    Article  CAS  Google Scholar 

  42. Heneghan HM, Miller N, Kerin MJ . Role of microRNAs in obesity and the metabolic syndrome. Obes Rev 2010; 11: 354–361.

    Article  CAS  Google Scholar 

  43. Mori MA, Thomou T, Boucher J, Lee KY, Lallukka S, Kim JK et al. Altered miRNA processing disrupts brown/white adipocyte determination and associates with lipodystrophy. J Clin Invest 2014; 124: 3339–3351.

    Article  CAS  Google Scholar 

  44. Ebert MS, Sharp PA . Roles for microRNAs in conferring robustness to biological processes. Cell 2012; 149: 515–524.

    Article  CAS  Google Scholar 

  45. Mori M, Nakagami H, Rodriguez-Araujo G, Nimura K, Kaneda Y . Essential role for miR-196a in brown adipogenesis of white fat progenitor cells. PLoS Biol 2012; 10: e1001314.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We are grateful to the Montpellier-RIO imaging platform (Montpellier, France), the Histology Experimental Network of Montpellier and the IGMM animal facilities. We are grateful to Roscoe Klinck (Université de Sherbrooke), Pierre de la Grange (Genosplice) and Edouard Bertrand for the SRSF1-GFP HeLa cells. The screening reported in this paper was performed within the France-BioImaging national research infrastructure, at MRI, Montpellier. France-BioImaging is supported by the French National Research Agency through the ‘Investments for the Future’ program (ANR-10-INSB-04). We thank Julien Bellis, Sylvain de Rossi and Virginie Georget for conducting the screening and microscopy imaging. We thank also Laurie Gayte for her help during the in vivo experiments This work was supported by the collaborative laboratory ABIVAX, OSEO-ISI CaReNA grant and Fondation pour la Recherche Médicale (FRM) grant (Equipe FRM 2011—no. DEQ20111223745). JT is a senior member of the Institut Universitaire de France. CLH is an ESR fellow of the EU FP7 Marie Curie ITN RNPnet program (289007). ICLM was supported by a graduate fellowship from the Ministère Délégué à la Recherche et aux Technologies and CNRS.

Author information

Author notes

  1. J Santo, C Lopez-Herrera and C Apolit: These authors contributed equally to this work.

Authors and Affiliations

  1. ABIVAX, Montpellier Cedex 5, France

    J Santo, C Lopez-Herrera, C Apolit, L Lapasset, R Najman, P Fornarelli & D Scherrer

  2. Institut de Génétique Moléculaire de Montpellier, CNRS UMR 5535, University of Montpellier, Montpellier Cedex 5, France

    Y Bareche, C Chavey, S Capozi, I C Lopez-Mejía & J Tazi

  3. Institut Curie, PSL Research University, CNRS, INSERM, Orsay, France

    F Mahuteau-Betzer, R Najman & P Fornarelli

  4. Institut de Biologie de Valrose, UMR CNRS 7277—UMR INSERM 1091, Université de Nice Sophia Antipolis, Faculté de Médecine, Nice Cedex 2, France

    G Béranger & E-Z Amri

  5. UMR Dynamique Musculaire et Métabolisme, INRA—CAMPUS SUPAGRO 2 place Viala, Montpellier Cedex 2, France

    F Casas

  6. Université de Montpellier, UFR Pharmacie, Montpellier, France

    B Pau

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Correspondence to J Tazi.

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Santo, J., Lopez-Herrera, C., Apolit, C. et al. Pharmacological modulation of LMNA SRSF1-dependent splicing abrogates diet-induced obesity in mice. Int J Obes 41, 390–401 (2017). https://doi.org/10.1038/ijo.2016.220

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