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Int J Obes (Lond). 2017 Mar;41(3):390-401. doi: 10.1038/ijo.2016.220. Epub 2016 Dec 5.

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

Author information

1
ABIVAX, Montpellier Cedex 5, France.
2
Institut de Génétique Moléculaire de Montpellier, CNRS UMR 5535, University of Montpellier, Montpellier Cedex 5, France.
3
Institut Curie, PSL Research University, CNRS, INSERM, Orsay, France.
4
Institut de Biologie de Valrose, UMR CNRS 7277-UMR INSERM 1091, Université de Nice Sophia Antipolis, Faculté de Médecine, Nice Cedex 2, France.
5
UMR Dynamique Musculaire et Métabolisme, INRA-CAMPUS SUPAGRO 2 place Viala, Montpellier Cedex 2, France.
6
Université de Montpellier, UFR Pharmacie, Montpellier, France.

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.

PMID:
27916986
DOI:
10.1038/ijo.2016.220
[Indexed for MEDLINE]

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