Compounds present in the brain, called endocannabinoids, could open a new way to treat obesity. According to research published in ‘Nature Communications‘, modulating the action of these molecules could help combat obesity.
Endocannabinoids are known to play a critical role in food intake and energy use.
For years, the professor of medicine at University of Montreal (Canada), Stephanie Fultonand his team have been unraveling the mechanisms of the human nervous system that control people’s need to eat and be physically active, and how their metabolism affects their mood.
This study shows that body weight control in mice is strongly modulated by neurons in the nucleus accumbens, a brain region rich in endocannabinoids that helps regulate food reward and physical activity.
In the brain, the ABHD6 enzyme degrades a key endocannabinoid molecule known as 2-arachidonoylglycerol (2-AG).
With the discovery in 2016 that whole-body inhibition of ABHD6 reduced body weight and protected against diabetes, the question arose of what this enzyme does in the brain to affect appetite and body weight.
“We expected that increasing 2-AG levels would stimulate food intake by increasing cannabinoid signaling, but paradoxically we found that when we deleted the gene encoding ABHD6 in the nucleus accumbens of mice, there was less motivation for food and greater interest in physical activity,” says Fulton.
“The mice decided to spend more time on a running wheel compared to the control group, which became obese and lethargic.”
By injecting a specific ABHD6 inhibitor into the brains of mice, his team was able to completely protect them from weight gain and obesity.
The ability to target specific neural pathways in the brain to control weight is crucial for scientists today. Depending on which area of the brain is targeted, inhibiting ABHD6 can have opposite effects.
Inhibition of this molecule at the brain level has a net effect of reducing weight gain with a high-fat diet.
In 2016, Fulton and his CRCHUM colleague Thierry Alquier showed that blocking ABHD6 in certain hypothalamic neurons made mice resistant to weight loss.
However, in the current study, the authors show that inhibition of this molecule at the brain level has a net effect of reducing weight gain with a high-fat diet.
“In our study we also showed that mice in which the gene encoding ABHD6 has been inhibited do not show signs of anxiety or depressive behavior,” says Fulton.
This is important since Rimonabanta weight-loss drug that targeted cannabinoid receptors in the central nervous system, was taken off the market in the late 2000s after people taking the drug reported strong side effects: depression and suicidal tendencies.
The latest work from Fulton’s team helps pave the way for therapies to combat obesity and metabolic disorders such as type 2 diabetes, scientists believe.
Although ABHD6 inhibitors are being tested, it remains to be seen whether the mechanisms addressed by researchers in mice will be the same in humans.
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