Targeting Brain Enzymes to Combat Obesity: A New Frontier in Weight Control

The fight against obesity has taken a step forward with new research highlighting how the brain’s endocannabinoid system influences food intake and physical activity. A team of researchers at the Université de Montréal’s CRCHUM has discovered that modulating a specific brain enzyme could help curb weight gain and protect against obesity-related diseases. Their findings, recently published in Nature Communications, shed light on the role of neurons in the brain’s reward system in regulating body weight.

What’s New: Brain Enzyme Manipulation Reduces Obesity in Mice

The study focused on an enzyme called ABHD6, which breaks down 2-arachidonoylglycerol (2-AG), a molecule that impacts the brain’s endocannabinoid system. Researchers found that deleting the gene encoding ABHD6 in the nucleus accumbens, a brain region tied to food reward and physical activity, had surprising effects. Instead of increasing food consumption as expected, the mice displayed reduced interest in eating and became more physically active. The team also demonstrated that injecting an ABHD6 inhibitor into the brains of mice protected them from weight gain and obesity, even on a high-fat diet.

Interestingly, the effects of ABHD6 inhibition can vary depending on the brain region targeted. While previous research showed that blocking ABHD6 in hypothalamic neurons caused resistance to weight loss, this new study revealed that brain-wide inhibition had an overall effect of preventing weight gain.

Why It Matters: A Safer Path Toward Obesity Treatment

This breakthrough could lead to innovative therapies for obesity and metabolic disorders, such as type 2 diabetes. Importantly, the study found no evidence of anxiety or depressive behaviors in mice after ABHD6 inhibition—a critical finding given the troubled history of weight-loss drugs targeting the endocannabinoid system. For example, Rimonabant, an anti-obesity drug introduced in the 2000s, was withdrawn after severe psychiatric side effects were reported.

Stephanie Fulton, lead researcher and Université de Montréal medical professor, emphasized the potential of targeting specific brain pathways for obesity treatment without adverse mental health effects. While ABHD6 inhibitors are still being tested, the study provides a foundation for further exploration of brain-based strategies to combat obesity in humans.

By unraveling how neuronal mechanisms influence food motivation and physical activity, this research offers hope for safer and more effective obesity interventions. If the findings translate to humans, they could mark a turning point in how we treat metabolic disorders.