Obesity is considered a growing public health crisis on a global scale, with an estimated one in eight people currently living with the condition. Researchers have long sought a range of clinical interventions for obesity, from injectable drugs to genetic counseling. New research from the Université de Montréal’s affiliated hospital research center points to a promising new intervention: modulating endocannabinoids in the brain, which may play a key role in both food intake and energy use. Below, we’ve outlined the research, which involves the brain enzyme ABHD6.
How Brain Enzyme ABHD6 Modulates Endocannabinoids
The aforementioned research was led by Université de Montréal medical professor Stephanie Fulton, who has already conducted extensive research on how the human nervous system regulates eating, physical activity, and mood. The latest discovery made by Fulton’s team shows that body weight control in mice is strongly linked to neurons in the nucleus accumbens, a region of the brain rich in endocannabinoids. Fulton’s team found that, by modulating endocannabinoids, they could effectively control body weight in mouse models. To execute this process, the researchers relied on the brain enzyme ABHD6, which is shown to degrade a key endocannabinoid molecule known as 2-arachidonoylglycerol (2-AG).
Inhibiting ABDH6 to Prevent Weight Gain
Fulton’s team built on previous research, which identified that inhibiting ABHD6 reduced body weight and effectively protected against diabetes. This time, they searched for more information about how the enzyme impacts appetite and body weight and whether inhibiting the enzyme could present a druggable solution.
To begin, they increased 2-AG levels in mice by deleting the gene encoding ABHD6 in the nucleus accumbens via an approach that includes adeno-associated viral (AAV) injections. As ABHD6 degrades 2-AG, removing the enzyme was expected to boost cannabinoid signaling, thus increasing the subjects’ food intake. “We expected that increasing 2-AG levels would stimulate food intake by increasing cannabinoid signaling,” said Fulton. However, the team found that, when they deleted the gene encoding ABHD6, “there was less motivation for food and greater interest in physical activity.” In practice, that meant that the mice chose to spend more time on a running wheel than the control group. The control group, meanwhile, became obese and lethargic, per Fulton. Ultimately, by inhibiting ABHD6, Fulton and her team were able to protect the mice from weight gain. “Together, these findings uncover unique mechanisms for the control of body weight and physical activity via central and mesoaccumbens ABHD6 regulation,” wrote the research team in the final paper discussion.
Is Brain Enzyme ABDH6 Inhibition Druggable?
This isn’t the first time researchers have aimed to control endocannabinoid signaling in humans. Nearly two decades ago, the anti-obesity drug Rimonabant was used to target cannabinoid receptors in the central nervous system. However, it was withdrawn from the market after people taking the drug reported depression and suicidal tendencies. Since then, researchers have been in pursuit of a more targeted mechanism to control endocannabinoid signaling without negative effects on mood. Fulton’s team may have done just that. “In our study, we also show that mice in which the gene encoding ABHD6 has been inhibited do not show signs of anxiety and depressive behavior,” said Fulton.
Researchers are still unclear as to whether the mechanisms targeted in mice will have the same effect in humans. Ultimately, though, Fulton’s team has helped pave the way for therapies to fight obesity.
To study obesity, Scantox Neuro offers an inducible type 2 diabetes mouse model created through a high-fat diet and the injection of streptozotocin, but we can also perform stereotactic AAV injections of your target gene. For the evaluation of diabetes symptoms, we can analyze body weight, glucose tolerance and insulin sensitivity, cholesterol, liver and inflammation markers, ROS, and many other parameters. In addition, several behavioral tests are readily available for the analysis of motor deficits, activity levels, and anxiety and depression.
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