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This molecule, when inactivated, reduces obesity

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New research from the University of Michigan Life Sciences Institute shows that inhibiting an enzyme inside fat cells reduces obesity and related health issues in mice.

The research looked at histone deacetylase 6 (or HDAC6) as a means to reduce obesity by enhancing the brain’s ability to recognize the hormone leptin.

Fat cells release more leptin into the body’s circulation as extra energy accumulates in the form of fat in animals, including mice and humans. By directing the brain to lower appetite and enhance calorie expenditure, this hormone aids in the restoration of the body’s energy balance.

“When this role of leptin was first discovered, people thought it would be the silver bullet to treating obesity,” according to the study lead author Işin Çakir. “If leptin can lower food intake and increase energy burning, then more leptin should help lower obesity. But that turned out not to be the case.”

The difficulty is that as obesity progresses, the body becomes less responsive to leptin, so even higher amounts of circulating leptin have little effect on hunger or energy expenditure. This applies to both mice and humans.

Çakir and his colleagues have discovered a way to render mice more sensitive to the leptin their bodies produce naturally, resulting in weight loss and improved metabolic health.

The researchers used a drug that suppresses HDAC6 to treat obese mice who had been fed a high-fat diet. The mice’s body weight dropped by about 25% in just a few weeks, and unlike the weight loss that often occurs with calorie restriction, the loss in mass was almost completely from fat tissue (a 50% reduction in fat mass), with no loss of lean muscle mass.

The mice’s overall metabolic health also improved significantly, according to the researchers. They didn’t have the drop in energy expenditure that usually comes with a reduction in food intake, and their liver health and glucose tolerance improved, indicating they were less likely to acquire diabetes.

Obese mice who were genetically unable to generate leptin did not lose weight when given the same chemical as lean mice. These findings show that high amounts of leptin are required for HDAC6 inhibition to reduce obesity, and that changing HDAC6 activity can regulate body weight by enhancing natural leptin sensitivity.

While the findings in mice are promising, the author cautions that they are still a long way from being translated into human obesity therapy.

“There are a lot of compounds that have been shown to reduce obesity in mice but don’t have the same effect in humans, or that might reduce weight in humans but are not safe,” he adds. “Obviously, the most important questions are: Is HDAC6 inhibition going to have the same effect in humans, and is it going to be safe? And a lot more research is needed before we will have answers to those questions.”

Most powerful HDAC6 inhibitors have the potential to produce toxicity when a component of the molecule breaks down in the human body. This toxicity may be tolerated in some cancer treatments, but not in those for diabetes or obesity diseases.

To get around this problem, the team is working on HDAC inhibitors that don’t have the possibly harmful part but still have the same activity against HDAC6 in rodents.

Source: 10.1038/s42255-021-00515-3

Image Credit: Getty

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