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

Abstract

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 reesterifi cation 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)(15)(16)(17)(18).MGL is involved in energy balance through two important functions. Abbreviations: AA, arachidonic acid; AEA, arachidonoyl ethanolamide; 2-AG, 2-arachidonoyl glycerol; AUC, area under the curve; CB, cannabinoid; EC, endocannabinoid; HFD, high-fat diet; HOMA-IR, homeostatic model assessment of insulin resistance; iMGL, mice that overexpress monoacylglycerol lipase specifi cally in the intestinal mucosa; LFD, low-fat diet; MG, monoacylglycerol; MGL, monoacylglycerol lipase; OFTT, oral fat tolerance test; OGTT, oral glucose tolerance test; RER, respiratory exchange ratio .

Monoglyceride lipase deficiency affects hepatic cholesterol metabolism and lipid-dependent gut transit in ApoE−/− mice

“…Thus, we investigated intestinal lipid metabolism, particularly due to the reported delay in alimentary TG absorption in MGL−/− mice, albeit unaltered gut transit [31]. We found reduced lipid accumulation in the small intestine of DKO mice chronically fed WTD and after an oil gavage, and a slower appearance of TG and cholesterol in the circulation, indicative for delayed chylomicron secretion.…”

Recent discoveries on absorption of dietary fat: Presence, synthesis, and metabolism of cytoplasmic lipid droplets within enterocytes

“…Whole body Mgl- deficient mice have significantly less MAG hydrolase activity and massive accumulation of MAG species in multiple tissues, including small intestine [164, 165]. Whole body Mgl -deficient mice are either leaner compared to wild-type mice fed either a low or high fat diet [164], or of similar body weight with improved glucose tolerance and insulin sensitivity [165]. In addition, these mice display blunted intestinal TAG secretion without fat malabsorption, as determined by fecal fat content [164].…”

“…Whole body Mgl -deficient mice are either leaner compared to wild-type mice fed either a low or high fat diet [164], or of similar body weight with improved glucose tolerance and insulin sensitivity [165]. In addition, these mice display blunted intestinal TAG secretion without fat malabsorption, as determined by fecal fat content [164]. They also have reduced mRNA levels of genes involved in the G3P pathway and increased levels of genes involved in the MGAT pathway in enterocytes.…”

Characteristics and functions of lipid droplets and associated proteins in enterocytes

“…Intestinal CGI-58 appears thus required for efficient postprandial TRL secretion. Global MGL deletion in mice led to a markedly reduced intestinal TG secretion following an oral fat challenge, suggesting delayed lipid absorption [33]. Thus, intestinal depletion of enzymes involved in TG hydrolysis leads to LD accumulation in enterocytes.…”