Two Molecules May Aid Battle Against Obesity

There’s no silver bullet against obesity, but researchers at UT Southwestern Medical Center have identified two molecules that have a golden future in this battle.

The molecules, called microRNA-378 and microRNA-378*, are created by a gene involved in metabolism and energy function. The pair of microRNAs act in a feedback mechanism to fine-tune energy use, and blocking their action could be a way to treat obesity, Type 2 diabetes, and other diet-related health risks.

Eric Olson, Ph.D.

"We are especially excited about these findings because they open a new entry point into the mechanisms of metabolism and they suggest a potential therapeutic strategy for controlling obesity through modulating these microRNAs,"  said Eric Olson, Ph.D., Chairman of Molecular Biology, and senior author of the study, which was published online Sept. 4 in the Proceedings of the National Academy of Sciences. Researchers from Virginia Tech University collaborated with Dr. Olson and his team.

MicroRNAs, discovered in the 1990s, are tiny bits of RNA that block or boost protein production in cells by interacting with messenger RNA – much larger pieces that carry genetic information between DNA and a cell's protein-manufacturing machinery.

When mice were genetically engineered to lack miR-378 and miR-378*, they remained lean and healthy even when fed a high-fat diet, and were more responsive to insulin. The molecules also boosted the activity of mitochondria, the "energy plants" of cells.

Dr. Olson is co-founder and Chief Scientific Advisor of miRagen Therapeutics, a company focused on developing drugs that target miRs. Dr. Olson's research primarily involves heart and muscle function, but the current study shows the importance of miRs in fat tissue.

In the current study, the researchers concentrated on a gene called Ppargc1b, which helps regulate metabolism, mitochondrial function, circadian rhythm, and other functions. Part of the gene codes for a protein called PGC-1β (peroxisome proliferator-activated receptor γ coactivator 1β), and part generates miR-378 and miR-378*. In ordinary mice, a high-fat diet triggers activity of Ppargc1b, miR-378, and miR-378*.

The researchers genetically modified mice to lack miRNAmiR-378, and miR-378*. On a normal diet, the mutant mice appeared the same as their unmodified littermates, but when both groups were fed high-fat chow, the modified mice resisted the diet's usual ill effects - they did not become fat, their blood-sugar levels remained normal, and their blood levels of triglycerides were lower than those of the normal mice.

The researchers found that miR-378 and miR-378* target the enzyme CRAT (carnitine O-acetyltransferase), a key enzyme in mitochondrial metabolism of fatty acids, and Med13, a gene regulator. The specificity of this effect may be exploitable in finding new ways to fight obesity.