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Inactivate or block the activity of an enzyme inside fat cells may become a pathway to decrease obesity and related health disorders, at least in mice, says research published in the journal
Nature Metabolism and directed by
Institute of Life Sciences of the University of Michigan (USA).
The study focused on an enzyme called histone deacetylase 6 (or HDAC6) as a pathway to decrease obesity by improving the brain’s ability to detect the hormone leptin.
As excess energy accumulates as fat in animals, including mice and humans, fat cells release more leptin into the body’s circulation.
this hormone helps restore the body’s energy balance by signaling the brain to decrease appetite and increase calorie burning.
“When this role of leptin was first discovered, it was thought that it would be the ‘silver bullet’ to treat obesity», says Işin Çakir, lead author of the study. “If leptin can reduce food intake and increase energy burn, then more leptin should help reduce obesity. But it turned out that was not the case.
The problem is that the body becomes desensitized to leptin as obesity increases, so even high levels of circulating leptin do not alter appetite or energy expenditure. This is valid for both mice and humans.
Now this team has identified a way to make mice more sensitive to the leptin their bodies are already producing, thereby inducing weight loss and improving metabolic health.
The researchers treated obese mice that had been fed a high-fat diet with a compound that inhibits HDAC6. Within a few weeks, the body weight of the mice decreased almost 25%; and unlike the weight loss that often occurs with caloric restriction, the decrease in mass was almost entirely due to fat tissue (50% decrease in fat mass), with little loss in lean muscle mass.
The team also saw significant improvements in the overall metabolic health of the mice. They did not experience the decrease in energy expenditure that normally accompanies decreased food intake, and they showed improvements in both liver health and glucose tolerance, indicating they were less likely to develop diabetes.
Lean mice treated with the same compound did not lose body mass, nor did obese mice that were genetically unable to produce leptin.
These results verify that high levels of leptin must already be present for the inhibition of HDAC6 reduce obesity, and that altering HDAC6 activity can regulate body weight by increasing natural leptin sensitivity.
While the results in mice are encouraging, Çakir stresses that the findings are still a long way from translating into treatments for obesity in humans.
“There are many compounds that have been shown to reduce obesity in mice but do not have the same effect in humans, or that might reduce weight in humans but are not safe,” he acknowledges.
The more potent HDAC6 inhibitors have the potential to cause toxicity when part of the molecule breaks down in the human body. This toxicity might be manageable in treatments for some types of cancer, for example, but not for diabetes or obesity. To overcome this obstacle, Çakir and his colleagues have now begun to develop HDAC inhibitors that lack the potentially toxic portion but still have the same activity once morest HDAC6 in rodents.
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