Abstract
Obesity epidemic continues to spread and obesity rates are increasing in the world. In addition to public health effort to reduce obesity, there is a need to better understand the underlying biology to enable more effective treatment and the discovery of new pharmacological agents. Abhydrolase domain-containing protein 11 (ABHD11) is a serine hydrolase enzyme, localized in mitochondria, that can synthesize the endocannabinoid 2-arachidonoyl glycerol (2AG) in vitro. In vivo preclinical studies demonstrated that knock-out ABHD11 mice have a similar 2AG level as WT mice and exhibit a lean metabolic phenotype. Such mice resist to weight gain in Diet Induced Obesity studies (DIO) and display normal biochemical plasma parameters. Metabolic and transcriptomic analyses on serum and tissues of ABHD11 KO mice from DIO studies show a modulation in bile salts associated with reduced fat intestinal absorption. These data suggest that modulating ABHD11 signaling pathway could be of therapeutic value for the treatment of metabolic disorders.
Highlights
The prevalence of obesity is increasing and affects 650 million people, becoming one of the foremost global health threats [1] [2]
We have identified Abhydrolase domain-containing protein 11 (ABHD11) as a 29kDa DAG lipase that can synthesize in vitro the endocannabinoid, 2-Arachidonoyl glycerol (2-AG) from 1-stearoyl-2-arachidonoyl-sn-glycerol as a substrate
This rare developmental disease leads to supravalvular aortic stenosis, mental retardation, overfriendliness, and specific facial features. These patients present metabolic abnormalities including decreased triglycerides (TG) [22] and lower body mass [23], but the direct association is not established yet. To determine if this enzyme plays a role in obesity, mice deprived of ABHD11 (KO ABHD11) were phenotyped in a high fat diet (HFD) study and we have shown that the absence of ABHD11 leads to resistance to weight gain
Summary
The prevalence of obesity is increasing and affects 650 million people, becoming one of the foremost global health threats [1] [2]. Obesity can seriously impair health through a broad range of complications such as cardiovascular diseases, type 1 and 2 diabetes, cancer, musculoskeletal disorders, psychosocial imbalances and reduced quality of life. Lifestyle modification is an integral part of the weight management journey, but is often insufficient on its own, and needs to be complimented by pharmacological and surgical add-on treatments to achieve greater and more sustainable weight loss, as appropriate. There are so far a limited number of pharmacological agents that are effective and safe for managing obesity [3].
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