Researchers at CRCHUM found that targeting the enzyme ABHD6 in specific brain regions of mice reduces obesity without causing anxiety or depression. This discovery may lead to novel therapies for obesity and metabolic disorders.
Endocannabinoids in the brain are critical regulators of food intake and energy expenditure. Researchers at Université de Montréal’s affiliated hospital research center (CRCHUM) suggest that targeting these molecules could offer new strategies to combat obesity.
For years, Dr. Stephanie Fulton, a medical professor at Université de Montréal, and her team have been studying the mechanisms within the human nervous system that drive eating behavior, physical activity, and the interplay between metabolism and mood.
Their latest discovery, published in Nature Communications, takes that knowledge a step further.
In their study, first co-authors David Lau, an Université de Montréal doctoral student, and Stephanie Tobin, a former postdoctoral fellow, show that body-weight control in mice is strongly modulated by neurons in the nucleus accumbens, a region of the brain that’s rich in endocannabinoids and that helps regulate food reward and physical activity.
In the brain, the enzyme ABHD6 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—a finding made by the team of Marc Prentki, a researcher at the CRCHUM—the question arose as to 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 found that when we deleted the gene encoding ABHD6 in the nucleus accumbens in mice, there was less motivation for food and greater interest in physical activity,” said Fulton.
“The mice chose to spend more time on a running wheel as compared to the control group which became obese and lethargic.”
By injecting a targeted ABHD6 inhibitor into the brains of mice, her team was able to completely protect them from weight gain and obesity.
Can have opposite effects
The ability to target specific neuronal pathways in the brain to control weight is crucial for scientists today. Depending on the area of the brain targeted, inhibiting ABHD6 can have opposite effects.
In 2016, Fulton and her CRCHUM colleague Thierry Alquier showed that blocking ABHD6 in certain hypothalamic neurons made mice resistant to weight loss.
In the current study, however, the authors show that brain-wide inhibition of this molecule has a net effect of diminishing weight gain on a high-fat diet.
No signs of anxiety
“In our study, we also show that mice in which the gene encoding ABHD6 has been inhibited do not show signs of anxiety and depressive behavior,” said Fulton.
This is important 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 people taking the drug reported strong side effects: depression and suicidal tendencies.
Fulton’s team’s latest work helps pave the way for therapies to fight obesity and metabolic disorders such as type 2 diabetes, the scientists believe.
While ABHD6 drug inhibitors are being screened, it remains to be seen whether the mechanisms targeted by the researchers in mice will be the same in humans.
Reference: “ABHD6 loss-of-function in mesoaccumbens postsynaptic but not presynaptic neurons prevents diet-induced obesity in male mice” by David Lau, Stephanie Tobin, Horia Pribiag, Shingo Nakajima, Alexandre Fisette, Dominique Matthys, Anna Kristyna Franco Flores, Marie-Line Peyot, S. R. Murthy Madiraju, Marc Prentki, David Stellwagen, Thierry Alquier and Stephanie Fulton, 16 December 2024, Nature Communications.
DOI: 10.1038/s41467-024-54819-5
Funding: Canadian Institutes of Health Research, Montreal Diabetes Research Center, Diabetes Québec, Fonds de recherche du Québec
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