Deficiency of MGAT2 increases energy expenditure without high-fat feeding and protects genetically obese mice from excessive weight gain

Nelson, David W.; Gao, Yu Tang; Spencer, Nicole; Banh, Taylor; Yen, Chi‐Liang Eric

doi:10.1194/jlr.m016840

Cited by 41 publications

(56 citation statements)

References 36 publications

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“…Interestingly, the oral fat challenge results are similar to those in MGAT2-and DGAT1-defi cient mice, that, despite having quantitatively normal intestinal fat absorption overall, also have largely reduced TG appearance rates in OFTTs ( 6,59 ). Both knockout strains are also resistant to diet-induced obesity and have increased energy expenditure through upregulation of FA oxidation ( 6,7,60 ). Given that intestinespecifi c expression of MGAT2 ( 61 ) or DGAT1 ( 62 ) partially or completely abolishes the lean phenotype in their respective global knockouts, it is possible that intestinal TG metabolism and secretion is a critical determinant of fat utilization and body composition.…”

Section: Discussionsupporting

confidence: 48%

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

Douglass

Zhou

et al. 2015

Journal of Lipid Research

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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 .

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Section: Discussionsupporting

confidence: 48%

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

Douglass

Zhou

et al. 2015

Journal of Lipid Research

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“…The underlying physiological mechanisms involve a transient decrease in food intake and a persistent increase in energy expenditure ( 7,8 ). Unexpectedly, the increase in energy expenditure does not require high-fat feeding, and MGAT2 defi ciency also protects Agouti mice from excess weight gain ( 9 ). Findings from both gain-and loss-of-function mouse models indicate that MGAT2 in the intestine is a major contributor but incompletely accounts for the Abstract Acyl-CoA:monoacylglycerol acyltransferase (MGAT) 2 catalyzes triacylglycerol (TAG) synthesis, required in intestinal fat absorption.…”

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confidence: 99%

Adult-onset deficiency of acyl CoA:monoacylglycerol acyltransferase 2 protects mice from diet-induced obesity and glucose intolerance

Banh¹,

Nelson²,

Gao

et al. 2015

Journal of Lipid Research

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ids and metabolic energy. TAG synthesis in most cells starts with acylation of glycerol-3-phosphate, followed by two additional acylation steps, whereas in some cells it uses monoacylglycerol (MAG) as the initial acyl acceptor. AcylCoA:monoacylglycerol acyltransferase (MGAT) catalyzes the latter pathway and generates diacylglycerol for the fi nal acylation step ( 1 ). As MAG is mostly a degradation product of TAG, the MGAT pathway is thought to be important for recycling of TAG. Indeed, the best-characterized MGAT function is in the absorption of dietary fat. During the process, dietary TAG is hydrolyzed in the intestinal lumen to MAG and fatty acids. After uptake, the hydrolysis products are resynthesized to TAG in enterocytes for the assembly of chylomicron, which in turn delivers dietary lipids to peripheral tissues ( 2 ).Among three identifi ed genes encoding MGAT enzymes, Mogat2 is highly expressed in the intestine of both rodents and humans ( 3-6 ). Supporting the role of MGAT2 as an intestinal MGAT mediating fat absorption, constitutive global inactivation of the enzyme, through germ-line transmission of a null mutation in Mogat2 , greatly reduces intestinal MGAT activity and delays fat absorption ( 7 ). Interestingly, these Mogat2 Ϫ / Ϫ mice absorb a normal quantity of fat but are protected from obesity and other metabolic disorders induced by high-fat feeding. The underlying physiological mechanisms involve a transient decrease in food intake and a persistent increase in energy expenditure ( 7,8 ). Unexpectedly, the increase in energy expenditure does not require high-fat feeding, and MGAT2 defi ciency also protects Agouti mice from excess weight gain ( 9 ). Findings from both gain-and loss-of-function mouse models indicate that MGAT2 in the intestine is a major contributor but incompletely accounts for the Abstract Acyl-CoA:monoacylglycerol acyltransferase (MGAT) 2 catalyzes triacylglycerol (TAG) synthesis, required in intestinal fat absorption. We previously demonstrated that mice without a functional MGAT2-coding gene ( Mogat2) exhibit increased energy expenditure and resistance to obesity induced by excess calories. One critical question raised is whether lacking MGAT2 during early development is required for the metabolic phenotypes in adult mice. In this study, we found that Mogat2 ؊ / ؊ pups grew slower than wildtype littermates during the suckling period. To determine whether inactivating MGAT2 in adult mice is suffi cient to confer resistance to diet-induced obesity, we generated mice with an inducible Mogat2 -inactivating mutation. Mice with adult-onset MGAT2 defi ciency ( Mogat2 AKO ) exhibited a transient decrease in food intake like Mogat2 ؊ / ؊ mice when fed a high-fat diet and a moderate increase in energy expenditure after acclimatization. They gained less weight than littermate controls, but the difference was smaller than that between wild-type and Mogat2 ؊ / ؊ mice. The moderate reduction in weight gain was associated with reduced hepatic TAG and improved glucose tolerance. Similar pr...

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“…Furthermore, these mice demonstrated increased oxygen consumption without high-fat feeding, and MGAT2 was expected to modulate energy expenditure. 7,8) These results implied that inhibition of MGAT2 could be an attractive mechanism for reduction of fat absorption and treatment of obesity and associated metabolic disorders.Some small molecule MGAT2 inhibitors have been disclosed. [9][10][11][12][13][14][15] As shown in Fig.…”

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confidence: 97%

Identification of 2-[2-(4-<i>tert</i>-Butylphenyl)ethyl]-<i>N</i>-[4-(3-cyclopentylpropyl)-2-fluorophenyl]-1,2,3,4-tetrahydroisoquinoline-6-sulfonamide as an Orally Active MGAT2 Inhibitor

Busujima

Tanaka

Iwakiri

et al. 2016

CHEMICAL & PHARMACEUTICAL BULLETIN

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We previously reported 2-[2-(4-tert-butylphenyl)ethyl]-N-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-6-sulfonamide 2 as on orally available monoacylglycerol acyltransferase 2 (MGAT2) inhibitor which exhibited an in vivo efficacy at an oral dose of 100 mg/kg in a mouse oral lipid tolerance test. Further optimization of compound 2 to improve the intrinsic potency culminated in the identification of compound 11. Compound 11 showed a >50-fold lower IC 50 against human MGAT2 enzyme than 2. Oral administration of 11 at a dose of 3 mg/kg in the oral lipid tolerance test resulted in significant suppression of triglyceride synthesis.Key words monoacylglycerol acyltransferase 2; fat absorption; oral lipid tolerance test; tetrahydroisoquinoline A rapid increases of obesity, type 2 diabetes and cardiovascular disease have become a huge issue in the world's industrialized countries. The unmet medical need for the treatment of these diseases has promoted the identification of many new targets, one of which is the inhibition of triacylglycerol synthesis.Dietary-derived fats are degraded in the gastrointestinal tract and then taken up by small-intestinal epithelial cells. Acyl CoA : monoacylglycerol acyltransferase (MGAT), which catalyzes the synthesis of diacylglycerol from monoacylglycerol and acyl-CoA, plays a crucial role in triglyceride (TG) re-synthesis in the small intestine. 1) After re-synthesis into neutral fats in the cells, 2) the neutral fats are packaged into chylomicrons, secreted into the lymphatics, and taken up into body. Therefore, the inhibition of activity of this enzyme is expected to suppress re-synthesis of TG and lead to reduce fat absorption.Three isoforms of MGAT enzyme have been identified, [3][4][5] and MGAT2 is highly expressed in small intestine in both humans and mice.1) The phenotype of MGAT2 deficient mice has been already reported.6) These mice were viable and fertile without apparent abnormalities. After these mice were orally given dietary oil (oral lipid tolerance test), plasma TG levels of these mice were significantly lower than those of the wild type. In addition, MGAT2 knock-out mice showed resistance to obesity, glucose intolerance, and hypercholesterolemia induced by a high fat diet. Furthermore, these mice demonstrated increased oxygen consumption without high-fat feeding, and MGAT2 was expected to modulate energy expenditure. 7,8) These results implied that inhibition of MGAT2 could be an attractive mechanism for reduction of fat absorption and treatment of obesity and associated metabolic disorders.Some small molecule MGAT2 inhibitors have been disclosed. [9][10][11][12][13][14][15] As shown in Fig. 1, AstraZeneca's compound 1 reported in the literature showed potent MGAT2 inhibitory activity and a significant reduction of plasma TG concentration after an oral administration at a dose of 150 mg/kg in mice oral lipid tolerance test. [16][17][18] We have also reported an orally available MGAT2 inhibitor, 19) 2-[2-(4-tert-butylphenyl)-ethyl]-N-(4-fluorophenyl)-1,2,3,4-tetrahydrois...

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Deficiency of MGAT2 increases energy expenditure without high-fat feeding and protects genetically obese mice from excessive weight gain

Cited by 41 publications

References 36 publications

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

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

Adult-onset deficiency of acyl CoA:monoacylglycerol acyltransferase 2 protects mice from diet-induced obesity and glucose intolerance

Identification of 2-[2-(4-<i>tert</i>-Butylphenyl)ethyl]-<i>N</i>-[4-(3-cyclopentylpropyl)-2-fluorophenyl]-1,2,3,4-tetrahydroisoquinoline-6-sulfonamide as an Orally Active MGAT2 Inhibitor

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