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.
Highlights
Licensee MDPI, Basel, Switzerland.Obesity is a significant and ever-growing public health concern defined by a body mass index (BMI) of greater than 30 kg/m2
We identified 11 preclinical studies involving the genetic manipulation of Faah, Mgll, or Dagla that reported obesity-related outcomes
Our review focused on obesity-related outcomes associated with manipulation of or variation in three key enzymes: fatty acid amide hydrolase (FAAH), an enzyme responsible for degradation of many bioactive lipids, especially AEA; monoacylglycerol lipase (MAGL), another enzyme responsible for degradation, especially 2-AG; and diacylglycerol lipase (DAGL), an enzyme involved in the synthesis of 2-AG
Summary
Licensee MDPI, Basel, Switzerland.Obesity is a significant and ever-growing public health concern defined by a body mass index (BMI) of greater than 30 kg/m2. The latest data from the NCD Risk Factor Collaboration showed that in 2016, almost 2 billion adults (39% of the global adult population) were estimated to be overweight (BMI ≥ 25 kg/m2 ) and 671 million (12% of the global adult population). Pharmaceuticals 2021, 14, 1316 of 21 showed that in 2016, almost 2 billion adults (39% of the global adult population) were estimated to be overweight (BMI ≥ 25 kg/m2) and 671 million (12% of the global adult population) had obesity [2]. Obesity has been associated withII numerous adverseand health outcomes, disease [3], and has both direct (medical) and indirect (nonmedical) costs that pose including increased incidence of type II diabetes, cancers, and cardiovascular disease [3],a significant global economic burden [4]
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