Global deletion of MGL in mice delays lipid absorption and alters energy homeostasis and diet-induced obesity

Monoacylglycerols (MGs) are intermediates within a large network of lipid molecules used for energy production, energy storage, membrane components, and signaling. Extracellular hydrolysis of dietary TG in circulating lipoproteins yields FFAs and sn-2 MG, which are then taken up by cells (1, 2). MGs are also produced intracellularly from membrane phospholipids and the consecutive action of phospholipase C and diacylglycerol lipase, or from the hydrolysis of stored TG by adipose TG lipase (ATGL) and hormone sensitive lipase (HSL) (2–5). The ultimate fate of intracellular MGs is hydrolysis to FFAs and glycerol or reesterification by acyltransferases into diacylglycerol and TG (6, 7). MG lipase (MGL) is considered the rate-determining enzyme in MG catabolism. MGL accounts for roughly 85% of MG hydrolysis in the brain, with the remainder being catalyzed by the enzymes ABHD6 and ABHD12 (8, 9). MGL is expressed in many other tissues as well, including brain, liver, skeletal muscle, adipose, and intestine (10–13). Within cells, MGL localizes to both the cytosolic and membrane fractions and hydrolyzes sn-1 and sn-2 MGs of varying acyl chain lengths and degrees of unsaturation, with almost no activity toward other lipids, such as TG and lyso-phospholipids (10, 14–18). MGL is involved in energy balance through two important functions. First, in its well-established role of mobilizing cellular lipid stores in adipose and other tissues, MGL makes glycerol and FFAs available for a variety of purposes, including β-oxidation. Second, MGL has been recently shown to be a key regulator of levels of the endocannabinoid (EC), 2-arachidonoyl glycerol (2-AG) (19). 2-AG, along with arachidonoyl ethanolamide (AEA) (also known as anandamide), are the two most prominent endogenous ligands of the cannabinoid (CB) receptors CB1 and CB2 (20). While the EC system is involved in the regulation of many physiological systems throughout the body, the net metabolic effect of CB1 activation, acutely, is energy accumulation (20). In the brain, this is mediated by hypothalamic potentiation of orexigenic pathways that stimulate eating behaviors and which are reinforced by the mesolimbic dopamine reward system (21–24). Peripheral CB1 stimulation also enhances fat uptake in adipose tissue, increases de novo lipogenesis in the liver, and decreases energy expenditure in muscle (25–28). Notably, EC activity in the gut also appears to affect eating behaviors, as peripheral administration of CB1 agonists induce acute hyperphagia, an effect potentially mediated by CB1 receptors on vagal afferents that innervate the gastrointestinal tract (29, 30). Studies of both in vivo pharmacological inhibition and genetic knockout of MGL have focused primarily on its role in the EC system. The potent MGL inhibitor, JZL184, causes 8-fold increases in brain 2-AG levels and cannabimimetic behavioral effects in mice, such as analgesia, hypolocomotion, catalepsy, and hypothermia, the so-called CB tetrad (8, 31). Interestingly, however, in contrast to acute 2-AG elevation, prolonged 2-AG elevation following chronic administration of JZL184 results in desensitization of the central EC system, likely caused by tonic activation of CB1 (32–34). Studies in MGL−/− mice recapitulate the effect of chronically elevated 2-AG, demonstrated by CB1 agonist-induced cross-tolerance and a lack of change in core body temperature, locomotion, or nociceptive sensitivity (19, 32). Some metabolic changes have been reported in MGL−/− mice, including reduced lipolysis in adipocytes and improved insulin sensitivity after 12 weeks of very high-fat feeding (35). However, MGL−/− mice have not been found to have increased body weight gain relative to WT mice, as might be expected from elevated 2-AG levels. In fact, one study of MGL−/− mice showed a reduction in body weight, whereas another showed no change, relative to WT mice (19, 35). In previous studies, we identified MGL transcript and protein expression in rat and mouse small intestinal mucosa; and subsequent studies in mice revealed that normally low levels of MGL expression and activity in adult mucosa could be increased through high-fat feeding, suggesting nutritional regulation and a possible role for MGL in dietary lipid assimilation (36, 37). To further explore this potential role of intestinal MGL, we generated a transgenic mouse that overexpressed MGL specifically in the intestinal mucosa (iMGL mice) (13). LC/MS analyses showed decreased mucosal levels of MG, notably 2-AG, as well as decreased levels of AEA. While the iMGL mice showed normal intestinal FA and MG metabolism, they developed a remarkably obese phenotype after only 3 weeks of 40% kcal HFD feeding, which was secondary to hyperphagia and decreased energy expenditure (13). The increased body weight and fat mass, as well as the hyperphagia, of iMGL mice were perhaps unexpected, given the known orexigenic effects of central CB receptor activation, yet in line with the reported absence of hyperphagia secondary to MGL deletion (35, 38). We suggested, therefore, that gut 2-AG may possibly act as a satiety signal (13). To further understand the role of MGL in energy homeostasis in the present study, we examined the effects of 12 weeks of semipurified low-fat diet (LFD) and high-fat diet (HFD) feeding in MGL−/− mice. Overall, the results demonstrate systemic changes that led to a leaner phenotype in LFD-fed mice and an improved metabolic serum profile in HFD-fed mice. Further, MGL−/− mice displayed a marked reduction in the rate of intestinal lipid secretion and a blunting of postprandial lipemia following an oral fat bolus. Therefore, it is possible that inhibiting MGL may be a useful strategy for the treatment of metabolic disorders, including obesity and its comorbidities.