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Canna~Fangled Abstracts

Potential of Fatty Acid Amide Hydrolase (FAAH), Monoacylglycerol Lipase (MAGL), and Diacylglycerol Lipase (DAGL) Enzymes as Targets for Obesity Treatment: A Narrative Review

By December 17, 2021December 30th, 2021No Comments
Review
. 2021 Dec 17;14(12):1316.

doi: 10.3390/ph14121316.

Justin Matheson 1, Xin Ming Matthew Zhou 1 2, Zoe Bourgault 1 2, Bernard Le Foll 1 2 3 4 5 6
Affiliations 

Free PMC article

Abstract

The endocannabinoid system (ECS) plays an integral role in maintaining metabolic homeostasis and may affect hunger, caloric intake, and nutrient absorption. Obesity has been associated with higher levels of the endogenous cannabinoid transmitters (endocannabinoids). Therefore, the ECS is an important target in obesity treatment. Modulating the enzymes that synthesize and degrade endocannabinoids, namely fatty acid amide hydrolase (FAAH), monoacylglycerol lipase (MAGL), and diacylglycerol lipase (DAGL), may be a promising strategy to treat obesity. This review aims to synthesize all studies investigating pharmacological or genetic manipulation of FAAH, MAGL, or DAGL enzymes in association with obesity-related measures. Pharmacological inhibition or genetic deletion of FAAH tended to promote an obesogenic state in animal models, though the relationships between human FAAH polymorphisms and obesity-related outcomes were heterogeneous, which could be due to FAAH having both pro-appetitive and anti-appetitive substrates. Genetic deletion of Mgll and Dagla as well as pharmacological inhibition of DAGL tended to reduce body weight and improve metabolic state in animal studies, though the effects of Mgll manipulation were tissue-dependent. Monitoring changes in body weight in ongoing clinical trials of FAAH inhibitors may clarify whether FAAH inhibition is a potential therapeutic strategy for treatment obesity. More preclinical work is needed to characterize the role of MAGL and DAGL modulation in obesity-related outcomes.

 

Keywords: DAGL; FAAH; MAGL; endocannabinoid system; obesity.

Conflict of interest statement

Bernard Le Foll has obtained funding from Pfizer Inc. (GRAND Awards, including salary support) for investigator-initiated projects. Le Foll has obtained funding from Indivior for a clinical trial sponsored by Indivior. Le Foll has in-kind donations of cannabis products from Aurora Cannabis Enterprises Inc. and study medication donations from Pfizer Inc. (varenicline for smoking cessation) and Bioprojet Pharma. He was also provided a coil for a Transcranial magnetic stimulation (TMS) study from Brainsway. Le Foll has obtained industry funding from Canopy Growth Corporation (through research grants handled by the Centre for Addiction and Mental Health and the University of Toronto), Bioprojet Pharma, Alcohol Countermeasure Systems (ACS), and Alkermes. Lastly, Le Foll has received in kind donations of nabiximols from GW Pharmaceuticals for past studies funded by CIHR and NIH. He has participated in a session of a National Advisory Board Meeting (Emerging Trends BUP-XR) for Indivior Canada and has been consultant for Shinogi. He is supported by CAMH, a clinician-scientist award from the department of Family and Community Medicine of the University of Toronto and a Chair in Addiction Psychiatry from the department of Psychiatry of University of Toronto. Justin Matheson is currently supported by a Mitacs grant obtained by Le Foll in partnership with Canopy.

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