An off-switch for obesity: An enzyme within the brain controls overeating.
A paper published in the latest edition of the journal Science has revealed a key enzyme that acts as a control for overeating and obesity. Though the enzyme O-GlcNAc transferase (OGT) was known to be involved in both neuronal development and insulin signalling, the enzyme’s precise role in the mature brain was largely unknown.
Geneticists refer to the removal or inactivation of a gene from an organism as a “knockout“. Previous work with OGT has revealed that knocking out OGT in mice led to embryonic lethality, where developing embryos are unable to reach term. This essential role of OGT during development meant that Olof Lagerlöf and his colleagues at Johns Hopkins University had to first develop a special type of mouse known as a conditional knockout in order to study the effect of eliminating OGT in the mature mouse. Using the Cre-lox system, the researchers were able to develop mice in which OGT would be knocked out only within a very specific set of the brain’s neurons (those expressing the gene CaMKII), and only in response to the drug tamoxifen.
When the researchers performed conditional knockout experiments, the results were striking. Though the knockout mice ate only as frequently as their unmodified peers, they consumed twice as much food. If food access was restricted, the mice would maintain their normal body weights. However, if given unrestricted access to food, the mice quickly became obese.
Within three weeks of knocking out the OGT enzyme, the genetically modified mice had tripled their amount of body fat. The modified mice both ate more, and spent longer periods of time eating.
The researchers noted that loss of OGT was associated with changes in a region of the brain known as the paraventricular nucleus (PVN). Further study of those neurons revealed that when OGT was knocked out, the excitatory postsynaptic current (mEPSC) frequency of the PVN neurons was decreased by 72%, indicating that the neurons had undergone a kind of silencing. In an inspired series of subsequent experiments, the study’s authors used light-based optogenetic techniques to stimulate the PVN neurons. When these neurons were stimulated, the food consumption of the knockout mice decreased significantly.
Using a series of experiments blending traditional Cre-lox conditional knockout with cutting edge optogenetic techniques, the Johns Hopkins based research team has identified an important new target for obesity research, and perhaps someday, a target for therapeutic applications.
Obesity is a growing issue worldwide, an issue that is a product of culture, economics, and evolution. Only very recently within our evolutionary history have we suffered from an excess of calorically dense food. Tendencies towards calorically rich foods, which would have preserved men and women in leaner times, now undermine our health. With the discovery of potential off-switches for overeating, such as OGT, future technology may silence the worst tendencies of our evolutionary history to enable a leaner future that is not so hungry.
Ajitha Thanabalasuriar, Ph.D. – Postdoctoral Fellow, the University of Calgary