In the brain, endocannabinoids play a key role in food intake and energy expenditure. Modulating the effect of these molecules could help fight obesity.
For years, Stephanie Fulton, a professor of nutrition at the University of Montreal and researcher at the CHUM Research Centre (CRCHUM), and her team have been dissecting the neural mechanisms that control food motivation and physical activity motivation, as well as the influence of metabolism on mood. Their latest discovery aligns with this research.
Weight control largely takes place in the nucleus accumbens, a region of the brain rich in endocannabinoids and particularly active in regulating food reward and physical activity. In the brain, the enzyme ABHD6 degrades a key endocannabinoid known as 2-arachidonoylglycerol (2-AG).
When Marc Prentki, a collaborator and also a professor in the Department of Nutrition at the University of Montreal and researcher at the CRCHUM, discovered in 2016 that inhibiting ABHD6 throughout the body reduced body weight and protected against diabetes, the question arose as to what this enzyme does in the brain to influence appetite and body weight.
"We expected that increased levels of 2-AG would stimulate food intake by enhancing 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 a greater interest in physical activity," explains Stephanie Fulton. "The mice also chose to spend more time on an exercise wheel than the control group, which became obese and lethargic."
By injecting a targeted ABHD6 inhibitor into the brains of mice, her team managed to completely protect them from weight gain and obesity.
Not all neurons are the same
The ability to target specific neural pathways in the brain to control weight is now crucial for scientists. Because, depending on the region of the brain targeted, the inhibition of ABHD6 can have harmful effects.
In 2016, Stephanie Fulton and Thierry Alquier, also a researcher at the CRCHUM, showed that blocking ABHD6 in certain neurons of the hypothalamus in mice made them unable to lose weight.
In the current study, however, the authors establish that inhibiting this molecule throughout the brain has the effect of reducing weight gain in the context of a high-fat diet.
A stable mood
"In our study, we also show that mice in which the gene encoding ABHD6 has been inhibited do not exhibit signs of anxiety or depressive behaviors," says Stephanie Fulton.
This is an important fact, given that Rimonabant, a weight-loss drug that targeted cannabinoid receptors in the central nervous system, was withdrawn from the market in the late 2000s after patients reported cases of depression and suicidal tendencies.
The researcher's latest work paves the way for therapies to combat obesity and metabolic disorders such as type 2 diabetes.
Although ABHD6 inhibitors are currently being selected, it remains to be seen whether the mechanisms targeted by scientists in mice will be the same in humans.