Tue. May 30th, 2023
Littermates were injected with a control virus (right) or a virus that knocked out O-GlcNAcTransferase (OGT) (left) into a subpopulation of cells in the brain's hypothalamus.  The OGT knockout caused the mouse to eat twice as much as its sibling.  This photo was taken about five weeks after the virus injection.

Littermates were injected with a control virus (right) or a virus that knocked out O-GlcNAcTransferase (OGT) (left) into a subpopulation of cells in the brain’s hypothalamus. The OGT knockout caused the mouse to eat twice as much as its sibling. This photo was taken about five weeks after the virus injection.

After laboriously tracking calories and deliberately avoiding cravings, many a dieter has probably dreamed of a simple switch that, when deployed, could halt hunger and melt 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 mealtimes and tripled their body fat within three weeks. And – most notably – when the researchers flipped the experiment, the mice stopped eating so much just as quickly. Data on the enzymatic switch, published Thursday in Sciencesuggests 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, especially insulin. That pathway has long been associated with obesity. But researchers knew almost nothing about how the pathway related to the metabolic disorder or the specific role of OGT.

To find out, researchers tried the simple genetic approach of removing the enzyme from mice and seeing if anything changed. The researchers, led by Richard Huganir of the Johns Hopkins University School of Medicine, used a virus-based genetic tool to extract the enzyme from the noggins of adult mice and quickly noticed a shift in the rodents’ altered eating habits.

With the freedom to eat as much as they wanted, the modified mice ate more than double what their non-genetically engineered counterparts ate at each meal, even though both groups ate about the same number of meals. Within three weeks, the OGT deletion mice gained weight, tripling their body fat with no gain in lean body mass. But if the modified mice were allowed to eat only a normal amount of food, they maintained a healthy weight.

In a closer comparison of the modified and normal mice, the researchers noted that the loss of OGT was related to changes in a specific region of the mouse brain: the hypothalamic paraventricular nucleus (PVN), known to be involved in regulating the appetite. In normal mice, the OGT-filled nerve cells in the PVN light up after eating a large meal, the researchers found. In the OGT deletion mice, these nerve cells remained silent.

Using a light-based genetic trick, the researchers activated the rested nerve cells, attempting to reverse the effect of clearing OGT – and they did. With the PVN nerve cells activated, the overweight OGT deletion mice independently reduced their food intake within 24 hours.

Overall, the data suggest that the OGT enzyme is a critical switch in a feedback loop that senses food signals, such as metabolic hormones, and then activates nerve cells to shut down the desire to eat. Without a properly functioning switch, mice ate more or less than normal.

Because the OGT pathway has already been linked to obesity in humans, the researchers hope the data could lead to a way to modify or correct satiety signals in humans to treat obesity.

Science2015. DOI: 10.1126/science.aad5494 (About DOIs).

By akfire1

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