Targeting an enzyme in the brain to counter obesity

For years, Stephanie Fulton, professor of nutrition at the University of Montreal and researcher at the CHUM Research Center (CRCHUM), and her team have been dissecting the neural mechanisms that control food motivation and that linked to physical activity as well as the influence of metabolism on mood. Their latest discovery goes in this direction.

In the magazine Nature Communications, David Lau, doctoral student in his laboratory, and Stéphanie Tobin, former postdoctoral intern, first co-authors of the study, show that weight control is largely played out in the nucleus accumbens, a region of the brain rich in endocannabinoids and active in particular in the regulation food reward and physical activity.

In the brain, the ABHD6 enzyme degrades a key endocannabinoid known as 2-arachidonoylglycerol (2-AG).

When Marc Prentki, collaborator, also professor in the Department of Nutrition at UdeM and researcher at CRCHUM, discovered in 2016 that inhibition of ABHD6 throughout the body reduced body weight and protected against diabetes, the question has arisen as to what this enzyme does in the brain to influence appetite and body weight.

“We expected that increasing 2-AG levels would stimulate food intake by increasing cannabinoid signaling, but we paradoxically found that when we deleted the gene encoding ABHD6 in the nucleus accumbens of mice, there had less motivation for food and a greater interest in physical activity, says Stephanie Fulton. The mice also chose to spend more time on an exercise wheel than the control group, who became obese and lethargic.

By injecting a targeted ABHD6 inhibitor into the brains of mice, his 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 crucial for scientists today. Because, depending on the region of the brain targeted, inhibition of ABHD6 can have harmful effects.

In 2016, Stephanie Fulton and Thierry Alquier, also a researcher at 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 brain-wide inhibition of this molecule has the effect of decreasing weight gain in the context of a high-fat diet.

A good mood

“In our study, we also show that mice in which the gene coding for ABHD6 has been inhibited do not show signs of anxiety or depressive behaviors,” says Stephanie Fulton.

An important fact is 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 opens the way to therapies to combat obesity and metabolic disorders such as type 2 diabetes.

Although ABHD6 inhibitors are being screened, it remains to be seen whether the mechanisms scientists are targeting in mice will be the same in humans.

About this study

The article “ABHD6 loss-of-function in mesoaccumbens postsynaptic but not presynaptic neurons prevents diet-induced obesity in male mice,” by David Lau and Stéphanie Tobin, under the supervision of Stephanie Fulton and colleagues, has been published online December 16, 2024 in the magazine Nature Communications.

This research was funded by the Canadian Institutes of Health Research, the Montreal Diabetes Research Center, Diabète Québec and the Fonds de recherche du Québec. They were supported by the team from the small animal phenotyping and imaging platform at the CHUM Research Center.