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Deleting the enzyme from mice doubled the food they ate, tripled their body fat.
After tediously tracking calories and willfully shunning cravings, many a dieter has likely dreamt of a simple switch that, when thrown, could shut down hunger and melt away pounds—and scientists may have just found it.
When researchers knocked down a single enzyme in the brains of mice, the rodents seemed to lose the ability to tell when they were full. They ate more than twice their usual amount of food at meal times and tripled their body fat within three weeks. And—most strikingly—when the researchers reversed the experiment, the mice just as quickly stopped eating so much. Data on the enzymatic switch, published Thursday in Science, suggests a possible target for future drugs to treat obesity in humans.
The enzyme is O-GlcNAc transferase, or OGT, which is known to work in a chemical pathway controlled by nutrients and metabolic hormones, particularly insulin. That pathway has long been linked with obesity. But researchers knew almost nothing about how the pathway linked to the metabolic disorder or OGT’s specific role.
To figure it out, researchers tried the simple genetic approach of deleting the enzyme from mice and looking to see what, if anything, changed. The researchers, led by Richard Huganir at Johns Hopkins University School of Medicine, used a virus-based genetic tool to take out the enzyme from the noggins of adult mice and quickly noted a shift in the altered rodents’ eating habits.
With the freedom to eat however much they wanted, the modified mice gulped down more than double what their non-genetically engineered counterparts had at each meal—though both groups ate about the same number of meals. Within three weeks, the OGT-deletion mice became fat, tripling their body fat with no gain in lean mass. But if the modified mice were only allowed to eat a normal amount of food, they stayed a healthy weight.
In a closer comparison of the modified and normal mice, the researchers noted that the loss of OGT was linked to changes in a specific region of the mousey brain: the hypothalamic paraventricular nucleus (PVN), which is known to be involved in regulating appetite. In normal mice, OGT-filled nerve cells in the PVN light up after eating a big meal, the researchers found. In the OGT-deletion mice, these nerve cells stayed quiet.
Using a light-based genetic trick, the researchers reactivated the quieted nerve cells, trying to reverse the effect of deleting OGT—and they did. With the PVN nerve cells fired up, the fat OGT-deletion mice independently cut down on their food intake within 24 hours.
Overall, the data suggests that the OGT enzyme is a critical switch in a feedback loop that senses food signals, such as metabolic hormones, then fires up nerve cells to shut off the desire to eat. Without a properly working switch, mice ate more or less than normal.
Because the OGT pathway has already been linked to obesity in humans, the researchers are hopeful that the data could lead to a way to modify—or correct—satiation signals in people to treat obesity.
The nutrient sensor OGT in PVN neurons regulates feeding | Science
After tediously tracking calories and willfully shunning cravings, many a dieter has likely dreamt of a simple switch that, when thrown, could shut down hunger and melt away pounds—and scientists may have just found it.
When researchers knocked down a single enzyme in the brains of mice, the rodents seemed to lose the ability to tell when they were full. They ate more than twice their usual amount of food at meal times and tripled their body fat within three weeks. And—most strikingly—when the researchers reversed the experiment, the mice just as quickly stopped eating so much. Data on the enzymatic switch, published Thursday in Science, suggests a possible target for future drugs to treat obesity in humans.
The enzyme is O-GlcNAc transferase, or OGT, which is known to work in a chemical pathway controlled by nutrients and metabolic hormones, particularly insulin. That pathway has long been linked with obesity. But researchers knew almost nothing about how the pathway linked to the metabolic disorder or OGT’s specific role.
To figure it out, researchers tried the simple genetic approach of deleting the enzyme from mice and looking to see what, if anything, changed. The researchers, led by Richard Huganir at Johns Hopkins University School of Medicine, used a virus-based genetic tool to take out the enzyme from the noggins of adult mice and quickly noted a shift in the altered rodents’ eating habits.
With the freedom to eat however much they wanted, the modified mice gulped down more than double what their non-genetically engineered counterparts had at each meal—though both groups ate about the same number of meals. Within three weeks, the OGT-deletion mice became fat, tripling their body fat with no gain in lean mass. But if the modified mice were only allowed to eat a normal amount of food, they stayed a healthy weight.
In a closer comparison of the modified and normal mice, the researchers noted that the loss of OGT was linked to changes in a specific region of the mousey brain: the hypothalamic paraventricular nucleus (PVN), which is known to be involved in regulating appetite. In normal mice, OGT-filled nerve cells in the PVN light up after eating a big meal, the researchers found. In the OGT-deletion mice, these nerve cells stayed quiet.
Using a light-based genetic trick, the researchers reactivated the quieted nerve cells, trying to reverse the effect of deleting OGT—and they did. With the PVN nerve cells fired up, the fat OGT-deletion mice independently cut down on their food intake within 24 hours.
Overall, the data suggests that the OGT enzyme is a critical switch in a feedback loop that senses food signals, such as metabolic hormones, then fires up nerve cells to shut off the desire to eat. Without a properly working switch, mice ate more or less than normal.
Because the OGT pathway has already been linked to obesity in humans, the researchers are hopeful that the data could lead to a way to modify—or correct—satiation signals in people to treat obesity.
The nutrient sensor OGT in PVN neurons regulates feeding | Science