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Updated: Mar 10, 2026
Body Composition and Metabolic Caging Analysis in High Fat Fed Mice
Published on: May 24, 2018
Pharmacological modulation of LMNA SRSF1-dependent splicing abrogates diet-induced obesity in mice
J Santo1, C Lopez-Herrera1, C Apolit1
1ABIVAX, Montpellier Cedex 5, 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.
Insights
A novel small molecule, ABX300, targets SRSF1 to reverse diet-induced obesity in mice. This drug restores metabolic balance and increases energy expenditure without affecting healthy individuals, offering a new obesity treatment strategy.
Area of Science:
- Metabolic research
- Molecular biology
- Drug discovery
Background:
- Obesity treatment requires novel strategies.
- LMNA gene alternative splicing (AS) produces isoforms affecting metabolism and lifespan.
- SRSF1 influences LMNA isoform production.
Purpose of the Study:
- To target SRSF1 for novel anti-obesity drug development.
- To investigate the role of SRSF1 in regulating LMNA alternative splicing.
- To identify small molecules that modulate SRSF1 activity.
Main Methods:
- Screening small molecules for SRSF1 interaction and LMNA AS modulation.
- Utilizing an LMNA luciferase reporter assay for molecule selection.
- Testing selected molecules in diet-induced obese (DIO) mice.
- Performing transcriptomic analysis on white adipose tissue.
Main Results:
- A small molecule, ABX300, specifically interacted with SRSF1's RS domain.
- ABX300 abolished DIO in mice, restoring adipose tissue homeostasis.
- ABX300 increased oxygen consumption and promoted lipid utilization in treated mice.
- Transcriptomic profiles in treated mice mirrored those of healthy controls.
Conclusions:
- Targeting SRSF1 with ABX300 corrects RNA biogenesis changes caused by obesity.
- This approach offers a novel therapeutic strategy for obesity treatment.
- ABX300 demonstrates potential as an anti-obesity drug by restoring metabolic balance.
