A new study, involving researchers at the Big Data Institute, has shown for the first time that a little-known gene, SLTM, plays a direct role in how fat is stored inside human cells. While large population studies had previously linked rare variants in SLTM to higher body mass index (BMI), its function at a cellular level was unknown until now.
The study, published in the American Journal of Human Genetics, provides the first experimental evidence of the gene’s role in fat accumulation, a key step in establishing a causal link between SLTM and obesity.
The study combined large-scale biobank analysis with functional experiments in human fat cells. They analysed genetic data from over 400,000 UK Biobank participants, scanning nearly 19,000 genes for rare variants linked to nine different measures of obesity and fat distribution, such as BMI, waist-to-hip ratio and body fat percentage. This analysis flagged 69 genes as significantly associated with at least one of the nine measures. Several of these genes showed a "dose-response" relationship, where increasingly damaging gene variants correlated with stronger effects – a pattern that often points to a successful drug target.
To move beyond these statistical associations, the researchers selected 14 of the candidate genes for laboratory testing. Using CRISPR-Cas9 technology, they systematically reduced the expression of each gene in cultured human fat cells. The experiments revealed that knocking down four of the genes significantly altered fat storage. The most critical finding was that perturbing the SLTM gene led to a significant reduction in fat accumulation, pointing to its direct role in regulating how fat is deposited inside cells.
This discovery could open a new therapeutic avenue for treating obesity. Most current weight-loss medications, such as Ozempic, work by targeting neuro-hormonal pathways to suppress appetite, and very few treatments act directly on fat tissue itself.
Dr Nikolas Baya, Postdoctoral Researcher at the Big Data Institute and the Department of Statistics, said ‘By identifying a gene that directly influences fat storage, our study suggests it may be possible to develop strategies that alter how the body stores fat rather than focusing on food intake.’
In bridging the gap between population genetics and cellular function, the study provides the first functional demonstration of SLTM’s role in fat cells and establishes a powerful model for how future discoveries in the biology of obesity can be made.