glyceryl-2-arachidonate and Metabolic-Syndrome

Lipid metabolism dysregulation underlies chronic pathologies such as obesity, diabetes and cancer. Besides their role in structure and energy storage, lipids are also important signalling molecules regulating multiple biological functions. Thus, understanding the precise lipid metabolism enzymatic steps that are altered in some pathological conditions is helpful for designing better treatment strategies. Several monoacylglycerol (MAG) species are only recently being recognized as signalling lipid molecules in different tissues. Recent studies indicated the importance of the ubiquitously expressed serine hydrolase α/β-hydrolase domain 6 (ABHD6), which is a MAG hydrolase, in regulating signalling competent MAG in both central and peripheral tissues. The central and peripheral function of the endocannabinoid 2-arachidonoylglycerol, which is a 2-MAG, and its breakdown by both ABHD6 and classical MAG lipase has been well documented. ABHD6 and its substrate MAG appear to be involved in the regulation of various physiological and pathological processes including insulin secretion, adipose browning, food intake, neurotransmission, autoimmune disorders, neurological and metabolic diseases as well as cancer. Diverse cellular targets such as mammalian unc13-1 (Munc13-1), PPARs, GPR119 and CB1/2 receptors, for MAG-mediated signalling processes have been proposed in different cell types. The purpose of this review is to provide a comprehensive summary of the current state of knowledge regarding ABHD6/MAG signalling and its possible therapeutic implications.

Topics: Animals; Arachidonic Acids; Diabetes Mellitus, Type 2; Endocannabinoids; Energy Metabolism; Enzyme Inhibitors; Gene Expression Regulation, Enzymologic; Glycerides; Humans; Ligands; Metabolic Syndrome; Models, Biological; Monoacylglycerol Lipases; Monoglycerides; Nerve Tissue Proteins; Obesity; Organ Specificity; Peroxisome Proliferator-Activated Receptors; Receptors, G-Protein-Coupled; Second Messenger Systems; Substrate Specificity; TRPV Cation Channels

2-Arachidonoyl-glycerol (2-AG) and arachidonyl-ethanolamide (AEA) are endocannabinoids that have been implicated in many physiologic disorders, including obesity, metabolic syndromes, hepatic diseases, pain, neurologic disorders, and inflammation. Their immunomodulatory effects are numerous and are not always mediated by cannabinoid receptors, reflecting the presence of an arachidonic acid (AA) molecule in their structure, the latter being the precursor of numerous bioactive lipids that are pro- or anti-inflammatory. 2-AG and AEA can thus serve as a source of AA but can also be metabolized by most eicosanoid biosynthetic enzymes, yielding additional lipids. In this regard, enhancing endocannabinoid levels by using endocannabinoid hydrolysis inhibitors is likely to augment the levels of these lipids that could regulate inflammatory cell functions. This review summarizes the metabolic pathways involved in the biosynthesis and metabolism of AEA and 2-AG, as well as the biologic effects of the 2-AG and AEA lipidomes in the regulation of inflammation.

Topics: Animals; Arachidonic Acids; Dendritic Cells; Endocannabinoids; Glycerides; Humans; Inflammation; Lipid Metabolism; Liver Diseases; Lymphocytes; Metabolic Syndrome; Neurodegenerative Diseases; Obesity; Pain; Phosphatidic Acids; Polyunsaturated Alkamides; Receptors, Cannabinoid