Targeting a brain enzyme to curb obesity

Endocannabinoids in the brain play a key role in food intake and energy use. Modulating the action of these molecules could help fight obesity, say researchers at Université de Montréal’s affiliated hospital research centre (CRCHUM).

For years, Université de Montréal medical professor Stephanie Fulton and her team have been unravelling the mechanisms in the human nervous system that control people’s need to eat and to engage in physical activity, and how their metabolism affects their 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 signalling, 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 behaviour,” 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.

Science writing: Bruno Geoffroy

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About this study  

“ABHD6 loss-of-function in mesoaccumbens postsynaptic but not presynaptic neurons prevents diet-induced obesity in male mice,” by David Lau and Stephanie Tobin under the supervision of Stephanie Fulton et al. was published Dec. 16, 2024 in Nature Communications. Funding was provided by the Canadian Institutes of Health, the Montreal Diabetes Research Center, Diabetes Québec and the Fonds de recherche du Québec. The research was supported by the CRCHUM’s small-animal phenotyping and imaging core platforms.

About the CHUM Research Centre (CRCHUM)  

Université de Montréal's affiliated hospital research centre, the CRCHUM, is one of North America’s leading hospital research centres. It strives to improve the health of adults through a continuum of research spanning disciplines such as basic science, clinical research and population health. About 2,130 people work at CRCHUM. These include more than 550 researchers and nearly 530 graduate students and postdoctoral fellows. crchum.com 

About Université de Montréal  

Deeply rooted in Montréal and dedicated to its international mission, Université de Montréal is one of the top universities in the French-speaking world. Founded in 1878, Université de Montréal today has 13 faculties and schools, and together with its two affiliated schools, HEC Montréal and Polytechnique Montréal, constitutes the largest centre of higher education and research in Québec and one of the major centres in North America. It brings together 2,300 professors and researchers and has close to 67,000 students. umontreal.ca