Scientists identify a key molecular driver of fat formation
There is a lot we know about what drives weight gain in humans, with behaviors like unhealthy eating and a lack of exercise a couple of well-known contributors. But beneath the surface there is a whole lot genetic and cellular machinery at play, and by digging into the science behind it researchers hope to unearth new ways of tackling obesity. Among those is a team at the University of Texas Southwestern Medical Center, which has published a new paper detailing a previously unknown mechanism that appears to regulate fat formation in mammals.
The research team was investigating the properties of microRNAs, a small class of molecules that play a role in the expression of genes. More specifically, they set out to study a particular family of microRNAs called miR-26 known to influence things like cancer suppression and insulin sensitivity, suspecting that they could also play a role in the expansion of white fat tissue in the body.
“Since microRNAs like miR-26 normally reduce the levels of genes that they target, we looked for genes whose abundance increases in fat cell progenitors that lack miR-26,” Professor of Molecular Biology and study co-author Joshua Mendell explains to New Atlas. “This revealed FBXL19 as a miR-26 target gene that is strongly regulated by this microRNA. Next, we asked what happens when we inhibit the function of FBXL19. To our surprise, this dramatically inhibited fat cell formation. Conversely, increasing the levels of FBXL19 resulted in greatly enhanced fat cell formation.”
The team performed these experiments on mice, and until recently wouldn’t have had the technology to do so. Scientists had been unable to study the functions of miR-26 molecules in any great detail because of the difficulties in removing the genes that produce them. Enter the CRISPR/Cas9 gene-editing tool, which continues to bring great advances in the world of genetics research.
Mendell and lead author of the study Dr. Asha Acharya used CRISPR/Cas9 to remove all three genes that produce the miR-26 family from the mouse genome. The mice treated in this way developed normally in their early stages, but then went onto exhibit a two- or three-fold increase in white fat tissue when they hit adulthood.
Conversely, mice that the team genetically engineered to possess heightened levels of miR-26 were studied alongside a group of normal mice. Both were fed a high-fat diet and the normal mice experienced dramatic weight gain and an increase in fat content of 40 percent, as to be expected. The engineered mice with excess miR-26, meanwhile, were “strongly resistant” to weight gain and maintained a healthy physique. What’s more, these mice also exhibited lower levels of blood sugar.
“We have shown that increasing miR-26 abundance has beneficial effects in animal models, such as suppressing obesity as shown in the present study and suppressing liver and intestinal tumors, as we showed previously,” Mendell tells us. “At the same time, we have not yet observed any toxic effects of increasing miR-26 levels.”
Identifying this mechanism is a very promising development when it comes to tackling obesity, but translating the discovery into forms of treatment will be a long undertaking. From here the team will look to explore how exactly FBXL19 drives fat cell formation and the possibility that mechanisms downstream of it could also be therapeutic targets for obesity. Only with a proper understanding of this machinery would ways of manipulating it be tested in humans, with agents that carry small RNAs into the human body for this purpose one distant, but distinct possibility.
“Delivery of small RNAs such as microRNAs is an active area of research in academic laboratories and in pharmaceutical companies, says Mendell. “Therefore, we are hopeful that it might be possible to one day directly deliver the microRNA as a possible therapeutic agent.”
The team published its research in the journal Genes & Development.
Source: University of Texas Southwestern