Summary: A new study reveals that modulating endocannabinoids in the brain can reduce food intake and boost physical activity, offering a promising path to combat obesity. Researchers found that inhibiting the enzyme ABHD6 in the brain’s nucleus accumbens reduced mice’s motivation for food while increasing their interest in exercise.
Unlike previous weight-loss drugs, this approach showed no signs of anxiety or depression in the mice. These findings could lead to safer therapies for obesity and metabolic disorders like type 2 diabetes, though more research is needed to confirm similar effects in humans.
Key Facts
- ABHD6 Role: Blocking ABHD6 in the brain reduced food motivation and promoted physical activity.
- Safe for Mood: Inhibiting ABHD6 showed no signs of anxiety or depressive behavior in mice.
- Obesity Treatment Potential: Findings could guide safer therapies for obesity and metabolic disorders.
Source: University of Montreal
Endocannabinoids in the brain play a key role in food intake and energy use. Modulating the action of these molecules could help fight obesity, say researchers at Université de Montréal’s affiliated hospital research centre (CRCHUM).
For years, Université de Montréal medical professor Stephanie Fulton and her team have been unravelling the mechanisms in the human nervous system that control people’s need to eat and to engage in physical activity, and how their metabolism affects their mood.
Their latest discovery, published in Nature Communications, takes that knowledge a step further.
In their study, first co-authors David Lau, an Université de Montréal doctoral student, and Stephanie Tobin, a former postdoctoral fellow, show that body-weight control in mice is strongly modulated by neurons in the nucleus accumbens, a region of the brain that’s rich in endocannabinoids and that helps regulate food reward and physical activity.
In the brain, the enzyme ABHD6 degrades a key endocannabinoid molecule known as 2-arachidonoylglycerol (2-AG).
With the discovery in 2016 that whole-body inhibition of ABHD6 reduced body weight and protected against diabetes—a finding made by the team of Marc Prentki, a researcher at the CRCHUM—the question arose as to what this enzyme does in the brain to affect appetite and body weight.
“We expected that increasing 2-AG levels would stimulate food intake by increasing cannabinoid signalling, but paradoxically found that when we deleted the gene encoding ABHD6 in the nucleus accumbens in mice, there was less motivation for food and greater interest in physical activity,” said Fulton.
“The mice chose to spend more time on a running wheel as compared to the control group which became obese and lethargic.”
By injecting a targeted ABHD6 inhibitor into the brains of mice, her team was able to completely protect them from weight gain and obesity.
Can have opposite effects
The ability to target specific neuronal pathways in the brain to control weight is crucial for scientists today. Depending on the area of the brain targeted, inhibiting ABHD6 can have opposite effects.
In 2016, Fulton and her CRCHUM colleague Thierry Alquier showed that blocking ABHD6 in certain hypothalamic neurons made mice resistant to weight loss.
In the current study, however, the authors show that brain-wide inhibition of this molecule has a net effect of diminishing weight gain on a high-fat diet.
No signs of anxiety
“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 behaviour,” said Fulton.
This is important given that Rimonabant, a weight-loss drug that targeted cannabinoid receptors in the central nervous system, was withdrawn from the market in the late 2000s after people taking the drug reported strong side effects: depression and suicidal tendencies.
Fulton’s team’s latest work helps pave the way for therapies to fight obesity and metabolic disorders such as type 2 diabetes, the scientists believe.
While ABHD6 drug inhibitors are being screened, it remains to be seen whether the mechanisms targeted by the researchers in mice will be the same in humans.
Funding: Funding was provided by the Canadian Institutes of Health, the Montreal Diabetes Research Center, Diabetes Québec and the Fonds de recherche du Québec.
The research was supported by the CRCHUM’s small-animal phenotyping and imaging core platforms.
About this neuroscience and obesity research news
Author: Bruno Geoffroy
Source: University of Montreal
Contact: Bruno Geoffroy – University of Montreal
Image: The image is credited to Neuroscience News
Original Research: Open access.
“ABHD6 loss-of-function in mesoaccumbens postsynaptic but not presynaptic neurons prevents diet-induced obesity in male mice” by Stephanie Fulton et al. Nature Communications
Abstract
ABHD6 loss-of-function in mesoaccumbens postsynaptic but not presynaptic neurons prevents diet-induced obesity in male mice
α/β-hydrolase domain 6 (ABHD6) is a lipase linked to physiological functions affecting energy metabolism. Brain ABHD6 degrades 2-arachidonoylglycerol and thereby modifies cannabinoid receptor signalling.
However, its functional role within mesoaccumbens circuitry critical for motivated behaviour and considerably modulated by endocannabinoids was unknown.
Using three viral approaches, we show that control of the nucleus accumbens by neuronal ABHD6 is a key determinant of body weight and reward-directed behaviour in male mice.
Contrary to expected outcomes associated with increasing endocannabinoid tone, loss of ABHD6 in nucleus accumbens, but not ventral tegmental area, neurons completely prevents diet-induced obesity, reduces food- and drug-seeking and enhances physical activity without affecting anxiodepressive behaviour.
These effects are explained by attenuated inhibitory synaptic transmission onto medium spiny neurons.
ABHD6 deletion in nucleus accumbens neurons and dopamine ventral tegmental area neurons produces contrasting effects on effortful responding for food. Intraventricular infusions of an ABHD6 inhibitor also restrain appetite and promote weight loss.
Together, these results reveal functional specificity of pre- and post-synaptic mesoaccumbens neuronal ABHD6 to differentially control energy balance and propose ABHD6 inhibition as a potential anti-obesity tool.
