RESEARCHERS have uncovered a groundbreaking role for endocannabinoids in regulating food intake, energy use, and body weight. Their findings suggest that modulating these brain molecules could offer new strategies to combat obesity and related metabolic disorders.
The study builds on years of research into the neural mechanisms controlling appetite, physical activity, and metabolism. Focusing on the nucleus accumbens, a brain region rich in endocannabinoids that governs food reward and physical activity, the team examined the enzyme ABHD6, which breaks down the key endocannabinoid molecule 2-arachidonoylglycerol (2-AG).
While earlier studies revealed that blocking ABHD6 system-wide could reduce body weight and protect against diabetes, the investigated its effects in the brain. Surprisingly, mice engineered to lack ABHD6 in their nucleus accumbens showed reduced motivation for food and increased interest in exercise, preferring time on a running wheel over overeating.
“When we deleted the gene encoding ABHD6, the mice resisted obesity and became more active,” explained the authors. Using targeted brain injections of an ABHD6 inhibitor, the researchers successfully prevented weight gain in mice on a high-fat diet.
This discovery underscores the importance of targeting specific brain pathways to control weight. However, the effects of ABHD6 inhibition vary by brain region. Previous studies showed that blocking ABHD6 in hypothalamic neurons made mice resistant to weight loss, but the latest research demonstrated a net reduction in weight gain when the enzyme was inhibited across the brain.
Crucially, the study found no signs of anxiety or depression in the modified mice, a key concern with past cannabinoid-related treatments like Rimonabant, which was withdrawn over severe side effects.
While ABHD6 inhibitors are under development, researchers caution that further studies are needed to confirm if these findings translate to humans. Nonetheless, the work offers hope for innovative therapies targeting obesity and metabolic diseases like Type 2 diabetes.
Reference
Lau D et al. ABHD6 loss-of-function in mesoaccumbens postsynaptic but not presynaptic neurons prevents diet-induced obesity in male mice. Nat Commun. 2024;15(1):10652.
