Tissue-specific roles of monoacylglycerol (MAG) in metabolic diseases
1Laboratory of Translational Obesity Research, New York University Grossman School of Medicine, New York, NY, USA
2Translational Research Institute, AdventHealth, Orlando, FL, USA
3Holman Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, New York University Grossman School of Medicine, New York, NY, USA
*Correspondence: Min Young Park, E-mail: MinYoung.Park@AdventHealth.com; José O. Alemán, E-mail: Jose.AlemanDiaz@AdventHealth.com.Abstract
Monoacylglycerol (MAG) is an important bioactive lipid metabolite/intermediate, playing crucial roles in energy homeostasis and cellular signaling. This review explores MAG’s chemical structure, classification, and metabolic pathways. We also discuss the emerging evidence for MAG as a signaling molecule, with particular emphasis on their interactions with cannabinoid receptor 1 and cannabinoid receptor 2 and G-protein-coupled receptor 119. We focus on examining the diverse and tissue-specific functions of MAG in the context of metabolic diseases, including the roles of MAG in nutrient absorption, appetite regulation, obesity, glucose homeostasis, and lipid metabolism. Furthermore, we address therapeutic approaches in modulating MAG metabolism and challenges in development, considering the complexity of targeting peripheral tissues. This review provides insights into the multifaceted roles of MAG in metabolic health and disease, paving the way for novel therapeutic strategies in the management of metabolic disorders.
1. Introduction
Lipid metabolism is essential to cell survival as it provides an energy source, structural component, and signaling molecules. A class of lipids called glycerolipids is characterized by a glycerol backbone with long-chain hydrocarbons via carboxylic acid ester linkages [1]. Monoacylglycerol (MAG), one of the glycerolipids, is composed of one fatty acid attached to glycerol. MAG mainly contributes to lipid homeostasis as a precursor in triacylglycerol (TAG) synthesis and an intermediate metabolite during lipolysis, in which its end products, glycerol and fatty acids, are released for energy expenditure. Dysregulated MAG metabolism contributes to hyperlipidemia, hepatic steatosis, and insulin resistance. For example, monoacylglycerol acyltransferase 2 (MGAT2) overactivity in the liver and intestine promotes TAG accumulation and metabolic dysfunction [2]. Moreover, monoacylglycerol lipase (MAGL) hydrolyzes MAG into fatty acid and glycerol, playing a crucial role in TAG hydrolysis and endocannabinoid signaling, with implications for liver diseases and fatty acid metabolism [3].
In addition to being a substrate and intermediary in lipid metabolism, MAGs are emerging as important signaling molecules. In central and peripheral tissues, they influence insulin secretion, adipose browning, and neurotransmission [4]. Also, MAG signaling modulates macrophage phenotype in adipose tissue, influencing chronic inflammation [5]. The most extensively studied MAG is 2-arachidonoylglycerol (2-AG), which is also known as an endocannabinoid. It acts through binding to its receptor, cannabinoid receptor 1 (CB1R) and cannabinoid receptor 2 (CB2R) [6]. In the forebrain, signaling through CB1R regulates energy homeostasis and appetite. MAG also exhibits cell/tissue-specific roles via CB2R signaling [7,8]. These findings emphasize the impact and diverse roles of MAGs in metabolic regulation and their potential as therapeutic targets.
This mini-review paper covers how MAGs impact metabolic regulation, including nutrient absorption, appetite control, energy homeostasis (diabetes and obesity), cardiovascular function, and immunity. At the end, we address current and potential uses of MAG for therapeutic approaches, as MGAT inhibitors are being explored to suppress TAG synthesis and treat obesity-related liver disease, and inhibitors for MAGL or its isoforms may improve insulin sensitivity and reduce inflammation by preserving signaling MAG species.
2. MAG and its metabolism
2.1 Description of MAG chemical structure and classification
MAG is a glycerolipid that consists of a glycerol backbone esterified with a fatty acid moiety. Depending on the position of the fatty acid on the glycerol, MAGs can be classified as either 1-MAG or 2-MAG, with the fatty acid attached to the first or second carbon, respectively. This structure provides MAGs with amphiphilic properties, but their solubility relies on the carbon number and saturation degree of the attached fatty acid [9]. As expected, MAGs with longer chain lengths (≥10 carbon atoms) have low solubility in buffer alone but increased solubility in bile salt solutions. For example, 1-oleoylglycerol and 2-oleoylglycerol (2-OG) are solubilized identically by bile-salt solutions, but 2-palmitoylglycerol (2-PG) has a higher solubility than 1-palmitoylglycerol due to the lower melting point of 2-PG. Nevertheless, their amphipathic nature makes MAGs dynamic, important intermediates in lipid metabolism and functional in both the aqueous environment of cells and lipid membranes.
2.2 Endogenous MAG synthesis and degradation
Endogenous MAGs are short-lived, intermediary lipids that derive mostly from the degradation of phospholipid and neutral lipids [10]. Being the most extensively studied MAG, 2-AG primarily originates from membrane phospholipids through the sequential action of phospholipase C (PLC) and diacylglycerol lipase (DAGL). Upon activation of G protein-coupled receptors (GPCRs), PLC converts phosphatidyl bisphosphate (PIP2) to inositol trisphosphate (IP3) and diacylglycerol (DAG). DAG is then hydrolyzed by DAGL, producing 2-MAG (eg, 2-AG) [11]. Alternative pathways of 2-AG synthesis derive from the extracellular cleavage of 2-arachidonoyl-lysophospholipids by glycerophosphodiesterase 3, lipid phosphate phosphatases, and two members of ecto-nucleotide pyrophosphatase/phosphodiesterases (ENPP6-7) [12]. 2-AG can also be synthesized by dephosphorylation of arachidonoyl-lysophosphatidic acid (LPA) or by the sequential action of PLA1 and lysophospholipase C (lyso-PLC) [13,14]. It is also worth noting that some factors affect the biosynthesis of MAGs, such as oxyradical stress increases the biosynthesis of 2-AG via involvement of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase [12].
Once synthesized, MAG is degraded by MAGL, producing glycerol and fatty acid (Figure 1). In addition to MAGL being a primary enzyme (~85%), 2-MAG can be also hydrolyzed by fatty acid amide hydrolase, α/β-serine hydrolase domain 6 (ABHD6) (4%), and α/β-serine hydrolase domain 12 (9%) in mouse brain [24]. Subcellular localization and/or cell/tissue-specific expression might also contribute to 2-AG degradation. For example, ABHD6 is primarily expressed in GABAergic neurons and astrocytes located postsynaptically [15]. Also, expression levels of ABHD6 are relatively higher compared to MAGL in J774 macrophages [20].
Among MAGs, 2-AG has been studied extensively in the brain as it acts as a signaling molecule in the central nervous system. The synthesis and metabolism of 2-AG in the brain are highly cell type-specific. In neurons and astrocytes, DAGL α is the primary enzyme responsible for 2-AG synthesis, activated downstream of G protein-coupled and glutamate receptor stimulation [25–27]. DAGL β predominantly mediates 2-AG synthesis in microglia, representing a distinct biosynthetic pathway in the brain’s resident immune cells [26]. Regarding 2-AG degradation, at least eight different enzymes participate [28]. MAGL is the major hydrolytic enzyme in neurons and astrocytes; in astrocytes specifically, MAGL-mediated conversion of 2-AG to arachidonic acid is coupled to downstream cyclooxygenase-2 (COX-2) activity and constitutes an important source of neuroinflammatory prostaglandins [26,29]. In microglia, α/β-hydrolase domain-containing protein 12 (ABHD12) serves as the principal hydrolase for secreted extracellular 2-AG, modulating cannabinoid receptor activation and microglial immune homeostasis [26]. This cell type-specific partitioning of 2-AG biosynthesis and catabolism has important implications for the interpretation of tissue-level endocannabinoid measurements and the design of cell-selective therapeutic strategies. These highlight that multiple enzymes are intricately orchestrated and regulate MAG homeostasis and suggest MAG hydrolysis as a therapeutic target.
2.3 Exogenous sources of MAGs
MAG also derives from the absorption of TAG in various dietary sources, such as butter and oils. Dietary TAGs are hydrolyzed into DAG, and subsequently to MAGs by pancreatic lipase [30]. In the intestinal lumen, MAGs are absorbed at the brush border of enterocytes primarily via passive diffusion [31]. MAG uptake can also be facilitated via specific transport proteins in human intestinal Caco-2 cells [32]. In this study, the authors demonstrate that trypsin preincubation decreased sn-2-monoolein uptake, and competition studies with oleic acid inhibited sn-2-monoolein uptake. This suggests a common uptake pathway for MAG and fatty acids, and a plasma membrane fatty acid binding protein as a putative carrier. Moreover, Lagakos et al have shown that the rate of MAG transfer is 7-fold faster from liver fatty-acid binding protein (FABP) to phospholipid membranes than from membranes to membranes by using transfer of a fluorescent MAG analog [33]. Although equilibrium binding affinities of MAG were ∼2-fold lower when compared to fatty acids, these results provide strong support for MAG as a physiological ligand for liver FABP and further suggest that liver FABP functions in the transport of MAG, as well as hepatic degradation of 2-MAG [34].
Once entering enterocytes, MAGs are re-esterified into TAGs in the endoplasmic reticulum. Along with cholesterol and phospholipids, newly formed TAGs are packaged into chylomicrons. Circulating chylomicrons then transport lipids into various tissues, including adipose tissue for energy storage and muscle for energy utilization, respectively.
Moreover, intracellular MAG can be derived from the hydrolysis of TAG. TAG is hydrolyzed by adipose triglyceride lipase (ATGL), generating DAG. Subsequently, hormone-sensitive lipase (DAGL/HSL) catalyzes the breakdown of DAG into MAG and fatty acid. Regulation of MAG synthesis is influenced by various factors, including fatty acid availability, hormonal signals, and lipase activity [35–38].
3. Role of MAGs in metabolism
MAGs can act both as substrate/intermediate to regulate anabolic and catabolic pathways in lipid metabolism. MAG could be converted to DAG by MGAT and subsequently to TAG by diacylglycerol acyltransferases (DGAT) for excess energy storage. On the other hand, MAGs can serve as precursors for key fatty acids, such as arachidonic acid, oleic acid, or palmitic acid, which can be utilized to generate ATP. MAGL is the major enzyme catalyzing the hydrolysis of MAGs into glycerol and fatty acids (Figure 1) [10]. MAG structure and its concentrations may also impact its hydrolysis, leading to different enzyme affinity. MAGL prefers 2-MAGs; therefore, 2-MAGs exhibit more bioactive compared to 1-MAG, while ABHD6, an isoform of MAGL, has a stronger preference for relatively more hydrophilic 1-AG than 2-AG [15,39,40]. Also, cell-specific expression and activities of MAGL and its isoforms (ABHD6 and ABHD12) are major in vivo determinants of 2-AG and arachidonic acid levels in the brain, spleen, lung, and liver [26,29,41]. Beyond hydrolytic metabolism, 2-AG can also serve as a direct substrate for COX-2, which oxygenates 2-AG to prostaglandin glycerol ester (PG-G) and, to a lesser extent, hydroxyeicosatetraenoic acids [21]. PG-G is further metabolized into other prostaglandins (Section “MAG and inflammation/immunity”). These suggest that 2-AG is subject to context-dependent metabolism, where substrate availability, allosteric competition, and inflammatory conditions can influence its conversion into bioactive prostaglandins, and COX-2-mediated oxygenation may modulate 2-AG signaling for its action as an endocannabinoid [42–44]. Moreover, 2-OG hydrolysis liberates oleic acid, which contributes to promoting anti-inflammation [45]. Also, phosphorylation of 2-AG by acyl glycerol kinase(s) creates LPA [46], which can activate different cellular responses including cell proliferation, differentiation, and inflammation via the GPCR-mediated MAPK, PI3K/Akt, or JNK/P38 MAPK pathway [47]. Finally, lipoxygenases can oxidize 2-AG, producing hydroperoxy derivatives of 2-AG [48]. Therefore, 2-AG regulation by metabolic enzymes coordinates overall cellular consequences.
3.2 Signaling molecules
3.2.1 MAGs as bioactive lipids and its receptors/binding proteins
In addition to being a precursor or product in lipid metabolism, MAGs play a role as a signaling molecule. Individual MAGs exhibit tissue-specific interactions with receptors/proteins, including cannabinoid receptor, fatty acid binding protein, G-protein-coupled receptor 119 (GPR119), and retinoic acid binding protein, and activating/leading to various signaling pathways.
(i) CB1R and CB2R: 2-AG has been the most intensively studied MAG for its role as an endocannabinoid, and it binds both G-protein-coupled receptors, known as CB1R and CB2R, activating pro- and anti-inflammatory signaling pathways. CB1R is predominantly expressed throughout the brain [57], whereas CB2R has 44% amino acid homology to CB1R and is primarily localized on cells of the immune system [58,59]. CB1R can interact with either Gαi/o or Gβγ subunits. In Kupffer cells, Gαi/o-coupled CB1R induces inflammation via RhoA-NFκB p65 nuclear translocation activation, releasing tumor necrosis factor alpha (TNF-α) and interleukin (IL)-6 in liver fibrosis [60]. In adipocytes, Gβγ-coupled CB1R reduces cyclic adenosine monophosphate (cAMP), protein kinase A (PKA) phosphorylation, and adenosine 5′-monophosphate-activated protein kinase (AMPK) activation, stimulating ERK1/2, which induces lipogenesis and increases fat storage [61]. On the other hand, CB2R predominantly recruits Gαi/o proteins and can activate the PLC/IP3/Ca2+ pathway, leading to nuclear factor E2-related factor 2 (Nrf2) translocation and heme oxygenase 1 (HO-1) signaling, which reduces TNF-α and IL-6 while inducing IL-10 secretion (Figure 2) [67]. Although less described, CB2R can also induce other signaling pathways, including PKA activation via a pro-inflammatory response [71].
The relevance of CB1R and CB2R with metabolic dysregulation has been demonstrated in the brain, adipose tissue, and adipose tissue macrophages (ATM). CB1R blockade attenuates diet-induced obesity-associated inflammation through alterations in ATM miRNA expression that promote M2 ATM polarization and macrophage egress from adipose tissue [72,73]. Although CB2R is predominantly expressed in the myeloid lineage, its low expression was also detected, reflecting resident macrophages [74]. In addition, administration of the CB2R-selective agonist JWH-133 was found to attenuate inflammation in white adipose tissue of diet-induced obese mice by restraining M1 macrophage polarization via the Nrf2/HO-1 pathway [67], and beneficial effects on fat mass and adipocyte size were also reported after administration of the less selective CB2R agonist JWH-015 [75].
(ii) GPR119: GPR119, a GPCR expressed in pancreatic β-cells and enteroendocrine cells, has emerged as a promising target for type 2 diabetes treatment [68]. GPR119 agonists include N-oleoylethanolamine [76], N-Oleoyl-dopamine [77], lysophosphatidylcholine [78], and 2-OG [69]. Despite their structural similarities between GPR119 and cannabinoid receptors, the endogenous ligands of GPR119 and CB1R selectively recognize their own receptors [79]. Also, GPR119 is highly expressed in pancreatic β cells and intestinal enteroendocrine L cells [80], while cannabinoid receptors are more widely distributed in various tissues as well as the gastrointestinal tract. Activation of GPR119 by endogenous lipids like MAGs and synthetic agonists increases intracellular cAMP, leading to enhanced glucose-dependent insulin secretion and incretin hormone release [81]. For example, studies have shown that GPR119 agonists improve glucose tolerance in mice through glucagon-like peptide-1 (GLP-1) and cholecystokinin (CCK) release, with effects dependent on receptor activation [70]. Also, Mandoe et al reported that the 2-MAG moiety of dietary fat appears to be responsible for the fat-induced release of GLP-1 in humans [82,83]. The receptor exhibits broad and biased signaling, including Gαs, Gαq, and Gαi pathways, as well as β-arrestin recruitment [70]. Synthetic GPR119 agonists have demonstrated potential in regulating glucose homeostasis and reducing body weight in rodent models, making them attractive candidates for treating type 2 diabetes and related metabolic disorders [81]. Hansen et al also reported that 2-OG is a GPR119 and signals GLP-1 release in the human intestine [69].
Other proteins that are demonstrated to interact with MAGs include retinol-binding protein 2 (RBP2), a member of FABP, as shown that intestinal MAG concentration rises in the absence of Rbp2 in intestinal (jejunum) cells. Purification of human RBP2 examined the highest affinity of sn-1 and sn-2 MAGs containing polyunsaturated C18-C20 acyl chains, suggesting that Rbp2 modulates MAG metabolism and its downstream signaling [84]. In addition, Lagakos et al demonstrated that MAG binds to liver FABP (FABP1) in vitro and mouse liver cytosol [33]. As discussed in section 2.3, MAG is shown to bind liver FABP, which is expressed in both liver and intestinal mucosa, and its global deletion altered FA and MAG metabolism. In line with potential aspects of MAGs as a signaling molecule, Shanbhag et al reported that neuronal calcium sensor Hippocalcin is a putative protein ligand for 1-PG via a chemoproteomics approach, suggesting a modulation of calcium sensing and downstream signaling in the mammalian brain.
5. Pharmacological approaches in MAG metabolism
Current pharmacological approaches in drug development for modulating MAG metabolism are summarized in Figure 3.
5.1 MAGL inhibitor
MAGL inhibitors have been developed for therapeutic applications in inflammation, neurodegenerative disease, and cancer, including carbamates, disulfides, ureas, and tetrahydrolipstatin (THL)-based inhibitors. These compounds act on MAGL’s property as a serine hydrolase and target active cysteine residues [146]. Several reviews suggest the potential aspects of MAGL inhibitors as drug targets for obesity, and various strategies led to application and development; however, targeting peripheral MAGL inhibitor development is ongoing to minimize adverse effects on the CNS. MAGL inhibitors can be categorized into two classes: irreversible and reversible. Although a covalent, irreversible inhibitor JZL184 was effective in alleviating inflammation, pain [147,148], it had major adverse effects on the CNS, and chronic administration of irreversible inhibitors as they have been shown to elicit CB1R downregulation and physical dependence over time [149]. This finding led scientists to divert their attention to the development of more reversible inhibitors acting in peripheral tissues. Authors discovered an orally bioavailable reversible MAGL inhibitor, LEI-515, which increases 2-AG peripherally, not in the brain, using high-throughput screening and a medicinal chemistry program [150]. LEI-515 attenuated liver necrosis, oxidative stress, and inflammation in a CCl4-induced acute liver injury model, without eliciting negative side effects in the CNS [141]. Further preclinical work is needed to fully characterize the potential of MAGL modulation in obesity-related outcomes, as the endocannabinoid system plays a crucial role in metabolic homeostasis, and alternative strategies that exploit the beneficial therapeutic effects of MAGL inhibition without inducing deleterious consequences are highly desirable.
5.2 MGAT inhibitor
Recent progress in the phenotypic characterization of mice deficient in MGAT or DGAT has revealed important roles of these enzymes in the regulation of energy homeostasis and insulin signaling [151–153]. Among MGAT isoforms, MGAT2 has garnered particular interest due to its predominant intestinal expression and its established role as the primary route for dietary fat re-esterification and absorption, and energy homeostasis (discussed in Section “Energy metabolism”). Selective inhibition of MGAT2 may thus provide novel treatment for obesity, diabetes, cardiovascular disorders, MASLD, and their related metabolic complications with improved efficacy and tolerability compared to other lipid-lowering approaches [109,154,155]. Several MGAT2 inhibitors have been developed and shown efficacy across preclinical and clinical settings. Barlind et al identified and optimized novel MGAT2 inhibitors, demonstrating significant reductions in plasma TAG concentrations in animal studies [156]. A novel oral MGAT2 inhibitor, S-309309 suppressed body weight gain and enhanced beta-oxidation in a high-fat diet mouse model [157], and subsequently demonstrated safety and tolerability in a phase I clinical trial [158].
MGAT2 inhibitor in HepG2 cells showed more effectiveness in lowering lipid accumulation [159], and pharmacological MGAT2 inhibition with Compound A improved hyperlipidemia, obesity, and diabetes in mice [139]. The therapeutic relevance of blocking this pathway is further supported by the MGAT2 inhibitor BMS-963272, which reduced liver fibrosis and inflammation in murine NASH models and, in a Phase 1 clinical trial in adults with obesity, produced significant body weight reduction and elevated GLP-1 and PYY levels, providing translational evidence linking MGAT2 inhibition to both hepatic and systemic metabolic benefits [111]. A patent review highlights the development of isozyme-selective inhibitors for MGAT and related acyltransferases, which may offer more targeted therapeutic options [160]. These advances in MGAT inhibitor research show promise to treat metabolic syndrome and associated cardiovascular risks.
5.3 CB1R antagonist
Pharmacological administration for the modulation of CB1R or CB2R have been tested as a therapeutic approach for obesity. Cannabinoid CB1R antagonists have emerged as a promising therapeutic approach for obesity treatment [161]. Rimonabant (SR141716A), the first CB1R selective antagonist approved and used in clinical practice, has shown to significantly reduce body weight and improve metabolic parameters such as insulin sensitivity, lipid profiles, and waist circumference in multiple clinical trials [162–164]. However, psychiatric side effects led to its withdrawal from the market [165]. Recent research focused on developing peripherally restricted CB1R antagonists to maintain efficacy while minimizing central nervous system-related adverse effects [166]. The development of CB1R antagonists has been largely based on modifications to rimonabant’s 1,5-diarylpyrazole structure [164]; however, additional strategies have been explored, including increasing polar surface area, decreasing lipophilicity, and designing neutral antagonists and allosteric inhibitors [167]. Despite challenges, CB1R antagonists remain a promising avenue for obesity treatment, with ongoing efforts to optimize their safety and efficacy profiles [168]. Another selective, peripheral CB1R antagonist, TXX-522 ameliorated insulin resistance in high-fat diet-induced obese mice [144]. This group confirmed that there was no impact on food intake in this model, validating the limited brain penetration of this compound with the potential to control obesity and related metabolic disorders. Also, the CB1R inverse agonist JD5037 has been reported to ameliorate diet-induced obesity, improving metabolic parameters without central side effects, suggesting its potential to reduce cardiometabolic risk [169]. Currently, a monoclonal antibody targeting peripheral CB1R is undertaking Phase 2 trials (Skye Bioscience), showing post-treatment maintenance of weight loss, and a second-generation inverse agonist CRB-913 is in a Phase 1 trial (Corbus Pharma) with enhanced lipolysis and energy metabolism resulting in a reduction in appetite and body weight. These candidate drugs may be potent anti-obesity medicines as standalone and/or in combination with FDA-approved incretin mimetics (eg, semaglutide, tirzepatide).
5.4 CB2R agonist/antagonist
CB2R agonist JWH-133 has been shown to reduce inflammation and characteristics of obesity in human primary subcutaneous adipocytes [104]. This effect was confirmed by CB2R blockade with AM630 where inflammatory adipokine release and fat storage were increased and reduced browning. Similarly, injection of CB2R agonist JWH-133 decreased body weight, food intake, adipocyte size, and fat mass in high-fat diet-fed mice [75]. It was associated with increased fasting plasma non-esterified fatty acids and decreased fasting insulin, TAG, indicating CB2R activation increases lipolysis and an anxiolytic response. In addition, CB2R agonist JWH-133 at 5 to 10 mg/kg BW reduced body weight gain and M1-associated cytokine production and improved insulin sensitivity in a diet-induced obesity mouse model via the Nrf2/HO-1 pathway [71], suggesting CB2R activation potentiates a protective role in obesity and metabolic dysregulation. However, another study assessed that both CB2R agonist AM1241 and antagonist AM630 have shown reduced circulating leptin levels without weight loss, similarly by pharmacological administration in a diet-induced mouse obesity model [170]. Together, CB2R -mediated signaling contributes to inflammation and obesity, but further investigations would support delineating specific pathways of action.
5.5 GPR119 agonist
GPR119, a GPCR expressed in pancreatic β-cells and gastrointestinal enteroendocrine cells, has emerged as a promising target for treating type 2 diabetes and obesity [80,81]. 2-OG has been identified as a ligand/agonist for GPR119, and its role in promoting incretin production has been described [69]. Orally available GPR119 agonists have demonstrated the ability to lower blood glucose without causing hypoglycemia, slow diabetes progression, and reduce food intake and body weight in animal models [171]. These agonists offer a unique dual mechanism of action, elevating both insulin and incretin levels in a nutrient-dependent manner [172,173]. Along with several GPR119 agonists entering clinical trials and showing promising results in glycemic control and incretin release, MAG holds potential for improving type 2 diabetes treatment [174].
6. Considerations and limitations in MAG research
2-AG plays crucial roles both as an intermediate in lipid metabolism and as a signaling molecule [175]. Thus, measurement of 2-AG from tissue samples represents both “signaling” and “metabolic-intermediate” levels of 2-AG, and it is likely that only a small fraction of the 2-AG measured in tissue samples is functioning as an endocannabinoid [176]. Additionally, most current studies measure MAGs by extracting whole tissues and running liquid chromatography-mass spectrometry (LC-MS) on the homogenate at one time point [177,178]. This challenges the interpretation of whether measured MAGs come from rapidly changing signaling pools or from larger, slow turnover pools used for general lipid storage metabolism. Alternative/accurate options for specific cell population/cell-specific lipidomics include isolated/sorted cells using fluorescence-activated cell sorting in several studies or chemical conjugation strategies for single-cell MS analysis; however, MAGs, relatively at low abundance, remain to be further expanded and tailored for improved detection at higher resolution [179].
7. Conclusions
This review highlighted the complex interplay between MAGs and various physiological processes across different tissues. MAGs serve as important intermediates in both anabolic and catabolic pathways of lipid metabolism, influencing energy storage and utilization. MAGs, particularly 2-AG and 2-OG, also function as signaling molecules through interactions with cannabinoid receptors (CB1R and CB2R) as well as GPR119, respectively, influencing inflammation, cardiovascular function, and insulin secretion. Tissue-specific actions of MAGs in the intestinal epithelium, adipose tissue, liver, and central nervous system contribute to the pathophysiology of obesity and type 2 diabetes, and liver disease. Lastly, reviewing therapeutic targets of MAG metabolism, including MGAT, MAGL, cannabinoid receptor, and GPR119, provides insights into pivotal aspects of MAG for further research.
Conflicts of interest
The authors declare no conflict of interest.
Funding
This work was supported by NIH grants (K08-DK117064 and P01-HL160470).