DescriptionSn-2-MG is a major product of dietary lipid digestion, yet its intestinal metabolism has not been investigated beyond its anabolic processing. Recently, a potential for sn-2-MG catabolism in the enterocyte has been proposed. Thus, we examined the regulation of the two known MG metabolizing enzymes, monoacylglycerol acyltransferase (MGAT) and monoacylglycerol lipase (MGL), in mouse small intestine and liver during development and under nutritional modifications. Furthermore, intestinal MGL function was explored by generating transgenic mice (iMGL mice) overexpressing MGL specifically in small intestinal enterocytes.
Dynamic changes in MG metabolism were observed during mouse ontogeny. Hepatic MGL and MGAT expression showed a reciprocal regulation under apparent transcriptional control whereas intestinal MG metabolism did not exhibit any inverse regulation: MGAT2 protein expression and activity were markedly induced during lactation, and then declined. MGL activity increased rapidly at birth and was maintained thereafter. Moreover, discordances in mRNA, protein, and activity levels of intestinal MGAT and MGL were observed, suggesting complex regulatory mechanisms involved in their expression. In addition, intestinal MGL was significantly up-regulated by a high fat diet, indicating its potential role in lipid assimilation.
During high fat feeding, iMGL mice exhibited an obese phenotype secondary to hyperphagia and hypometabolic rate compared to wild type littermates. Dietary lipid absorption and intracellular TG reesterification in iMGL mice intestine were intact. Interestingly, the level of cellular 2-arachidonoyl glycerol (2-AG), one of the endocannabinoids (EC), and cannabinoid receptor 1 (CB1) expression were decreased in iMGL mice intestine. Antagonism of EC signaling is known to reduce appetite and adiposity, and MGL terminates EC signaling by hydrolyzing 2-AG. Here we have a paradox in that intestinal MGL induction caused a phenotype associated with EC system activation rather than termination. While the molecular mechanisms underlying this paradox remain to be elucidated, these studies are the first to indicate that intestinal MG levels significantly affect whole body energy balance via altering appetite and metabolic rate. Thus, we propose a new function for intestinal MG, in which MGL activity is associated with regulatory mechanisms for energy homeostasis, possibly through appetite signaling systems.