title: Pharmacological modulation of LMNA SRSF1-dependent splicing abrogates diet-induced obesity in mice.
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.
  
  
  
  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.
  
  
  
  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 O2consumption and a switch in fuel preference toward lipids.
  
  
  
  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.
authors.affiliation: ABIVAX, Montpellier Cedex 5, France.
authors.forename: J
authors.initials: J
authors.lastname: Santo
authors.affiliation: ABIVAX, Montpellier Cedex 5, France.
authors.forename: C
authors.initials: C
authors.lastname: Lopez-Herrera
authors.affiliation: ABIVAX, Montpellier Cedex 5, France.
authors.forename: C
authors.initials: C
authors.lastname: Apolit
authors.affiliation: Institut de Génétique Moléculaire de Montpellier, CNRS UMR 5535, University of Montpellier, Montpellier Cedex 5, France.
authors.forename: Y
authors.initials: Y
authors.lastname: Bareche
authors.affiliation: ABIVAX, Montpellier Cedex 5, France.
authors.forename: L
authors.initials: L
authors.lastname: Lapasset
authors.affiliation: Institut de Génétique Moléculaire de Montpellier, CNRS UMR 5535, University of Montpellier, Montpellier Cedex 5, France.
authors.forename: C
authors.initials: C
authors.lastname: Chavey
authors.affiliation: Institut de Génétique Moléculaire de Montpellier, CNRS UMR 5535, University of Montpellier, Montpellier Cedex 5, France.
authors.forename: S
authors.initials: S
authors.lastname: Capozi
authors.affiliation: Institut Curie, PSL Research University, CNRS, INSERM, Orsay, France.
authors.forename: F
authors.initials: F
authors.lastname: Mahuteau-Betzer
authors.affiliation: ABIVAX, Montpellier Cedex 5, France.|Institut Curie, PSL Research University, CNRS, INSERM, Orsay, France.
authors.forename: R
authors.initials: R
authors.lastname: Najman
authors.affiliation: ABIVAX, Montpellier Cedex 5, France.|Institut Curie, PSL Research University, CNRS, INSERM, Orsay, France.
authors.forename: P
authors.initials: P
authors.lastname: Fornarelli
authors.affiliation: Institut de Génétique Moléculaire de Montpellier, CNRS UMR 5535, University of Montpellier, Montpellier Cedex 5, France.
authors.forename: I C
authors.initials: IC
authors.lastname: Lopez-Mejía
authors.affiliation: Institut de Biologie de Valrose, UMR CNRS 7277-UMR INSERM 1091, Université de Nice Sophia Antipolis, Faculté de Médecine, Nice Cedex 2, France.
authors.forename: G
authors.initials: G
authors.lastname: Béranger
authors.affiliation: UMR Dynamique Musculaire et Métabolisme, INRA-CAMPUS SUPAGRO 2 place Viala, Montpellier Cedex 2, France.
authors.forename: F
authors.initials: F
authors.lastname: Casas
authors.affiliation: Institut de Biologie de Valrose, UMR CNRS 7277-UMR INSERM 1091, Université de Nice Sophia Antipolis, Faculté de Médecine, Nice Cedex 2, France.
authors.forename: E-Z
authors.initials: EZ
authors.lastname: Amri
authors.affiliation: Université de Montpellier, UFR Pharmacie, Montpellier, France.
authors.forename: B
authors.initials: B
authors.lastname: Pau
authors.affiliation: ABIVAX, Montpellier Cedex 5, France.
authors.forename: D
authors.initials: D
authors.lastname: Scherrer
authors.affiliation: Institut de Génétique Moléculaire de Montpellier, CNRS UMR 5535, University of Montpellier, Montpellier Cedex 5, France.
authors.forename: J
authors.initials: J
authors.lastname: Tazi
mesh_terms: D017398:Alternative Splicing / Q000187:drug effects*; D000818:Animals; D019440:Anti-Obesity Agents / Q000494:pharmacology* / Q000627:therapeutic use; D059305:Diet, High-Fat / Q000009:adverse effects; D004195:Disease Models, Animal; D004734:Energy Metabolism / Q000187:drug effects; D005455:Fluorescent Antibody Technique; D034904:Lamin Type A / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009765:Obesity / Q000188:drug therapy* / Q000473:pathology*; D000068103:Serine-Arginine Splicing Factors / Q000378:metabolism
chemical_list: D019440:Anti-Obesity Agents; D034904:Lamin Type A; C576142:Lmna protein, mouse; D000068103:Serine-Arginine Splicing Factors