Study reveals brain enzyme inhibition reduces obesity in mice

Endocannabinoids in the brain are pivotal in regulating food intake and energy use, and modulating their activity could offer new approaches to combat obesity.

Researchers at the Université de Montréal’s affiliated hospital research centre (CRCHUM) have made significant progress in understanding how these brain molecules influence body weight.

Stephanie Fulton, a Université de Montréal medical professor, and her team have long studied the nervous system’s mechanisms controlling appetite, physical activity, and the interplay between metabolism and mood. Their latest research, published in Nature Communications, demonstrates how the enzyme ABHD6 in the brain plays a crucial role in regulating weight by modulating endocannabinoid activity.

The study, led by doctoral student David Lau and former postdoctoral fellow Stephanie Tobin, reveals that neurons in the nucleus accumbens, a brain region rich in endocannabinoids, strongly influence food reward and physical activity. ABHD6 degrades a key endocannabinoid molecule, 2-arachidonoylglycerol (2-AG), which affects these behaviours.

Surprisingly, the researchers found that deleting the gene encoding ABHD6 in the nucleus accumbens reduced food motivation and increased physical activity in mice. Instead of overeating, the mice became more active, preferring to spend time on a running wheel, unlike the control group, which became obese and lethargic. Injecting a targeted ABHD6 inhibitor directly into the brains of the mice effectively protected them from weight gain and obesity, even on a high-fat diet.

The ability to selectively target specific neuronal pathways to influence weight is a critical advancement. While previous studies showed that blocking ABHD6 in certain hypothalamic neurons prevented weight loss, the current research demonstrates that brain-wide inhibition reduces weight gain without adverse side effects.

Importantly, mice treated with ABHD6 inhibitors did not exhibit signs of anxiety or depression, a notable contrast to the failed weight-loss drug Rimonabant, which was withdrawn due to severe psychological side effects. This finding underscores the potential of ABHD6-targeting therapies to combat obesity and metabolic disorders like type 2 diabetes without compromising mental health.

While ABHD6 inhibitors are under investigation, researchers caution that it remains uncertain whether the mechanisms observed in mice will translate directly to humans. Still, this work provides promising insights into developing safer and more effective treatments for obesity and related conditions.