Breakthrough Discovery at CRCHUM: Novel Approach to Combating Obesity without Negative Effects
Scientists at the Centre de recherche de l’Institut universitaire de Montréal (CRCHUM) have made a significant breakthrough in the fight against obesity. Their research, published in Nature Communications, suggests that targeting the enzyme ABHD6 in specific brain regions of mice can reduce obesity without adverse side effects like anxiety or depression. This discovery opens new avenues for potential treatments for obesity and metabolic disorders.
Endocannabinoids and Their Role in Energy Regulation
Endocannabinoids, molecules naturally present in the brain, play a crucial role in regulating food intake and energy expenditure. Studies by CRCHUM researchers, particularly those led by Dr. Stephanie Fulton, a professor at Université de Montréal, have focused on understanding how these molecules influence eating behaviors, physical activity, and the relationship between metabolism and mood.
The ABHD6 Enzyme and Its Impact on Weight
In their latest study, Nature Communications published research showing that the enzyme ABHD6, which breaks down a key endocannabinoid called 2-arachidonoylglycerol (2-AG), plays an essential role in body-weight control in mice. Specifically, the study explored how ABHD6 functions in the nucleus accumbens, a brain region rich in endocannabinoids that regulates food reward and physical activity.
Building on earlier research, which found that inhibiting ABHD6 throughout the body reduced weight and protected against diabetes, the study addressed the role of this enzyme specifically in the brain. Surprisingly, deleting ABHD6 in the nucleus accumbens decreased food motivation while increasing physical activity instead of stimulating food intake as initially expected.
“When we deleted the gene encoding ABHD6 in the nucleus accumbens in mice, they spent more time on a running wheel as compared to the control group, which became obese and lethargic,” commented Dr. Stephanie Fulton.
The Paradoxical Effect of ABHD6 Inhibition
The research revealed that blocking ABHD6 in specific brain regions could have contrasting effects. Previous studies by Fulton and her colleague Thierry Alquier demonstrated that inhibiting ABHD6 in certain hypothalamic neurons made mice resistant to weight loss. However, the current study showed that brain-wide ABHD6 inhibition led to a overall reduction in weight gain on a high-fat diet.
No Anxiety or Depression
An important advantage of this method is the absence of anxious or depressive behaviors. Previous attempts to treat obesity through cannabinoid receptors, such as Rimonabant, were discontinued due to these side effects. Dr. Fulton’s team found that mice without ABHD6 in the nucleus accumbens did not exhibit signs of anxiety or depression, making this approach a safer alternative.
“Our study shows that mice with inhibited ABHD6 gene encoding do not show signs of anxiety and depressive behavior,” Dr. Fulton explained.
Implications for Future Treatments
The discovery has significant implications for developing therapies to combat obesity and metabolic disorders such as type 2 diabetes. While drug inhibitors of ABHD6 are currently being evaluated, it is yet to be determined if the mechanisms observed in mice will have the same effects in humans.
This promising research could lead to novel treatments that effectively manage obesity without the undesirable side effects seen in past medications.
Reference: “ABHD6 loss-of-function in mesoaccumbens postsynaptic but not presynaptic neurons prevents diet-induced obesity in male mice” by David Lau, Stephanie Tobin, Horia Pribiag, Shingo Nakajima, Alexandre Fisette, Dominique Matthys, Anna Kristyna Franco Flores, Marie-Line Peyot, S. R. Murthy Madiraju, Marc Prentki, David Stellwagen, Thierry Alquier, and Stephanie Fulton, 16 December 2024, Nature Communications.
DOI: 10.1038/s41467-024-54819-5
Funding for this study came from the Canadian Institutes of Health Research, Montreal Diabetes Research Center, Diabetes Québec, and Fonds de recherche du Québec.
Conclusion
The groundbreaking research conducted at CRCHUM provides a promising avenue for future obesity treatments. By targeting the ABHD6 enzyme in specific brain regions, scientists could develop safer and more effective therapies for obesity and related metabolic disorders. This discovery represents a significant step forward in the ongoing battle against the global obesity epidemic.
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