cell membranes. The biosynthesis of TAG thus serves many physiological functions. Because it is highly reduced and anhydrous, TAG is the primary energy substrate stored in adipose tissues to sustain animals during fasting. TAG is also synthesized in the liver for the assembly and secretion of VLDL to transport neutral lipids to other tissues, as well as in the mammary gland for the formation of milk fat globules to deliver fatty acids and other lipid-soluble nutrients to mammalian neonates.In the intestine, TAG synthesis is prominent for its role in the absorption of dietary fat ( 2, 3 ). TAG forms the bulk of animal fats and plant oils. It accounts for approximately 95% of dietary fat, depending on the food sources, with the rest as phospholipids and trace amounts of sterols, lipid-soluble vitamins, and other lipophilic components. Because of its hydrophobicity, TAG does not traverse the cellular membrane. Its absorption involves hydrolysis to fatty acids and monoacylglycerol (MAG) in the intestinal lumen, lipid uptake by the enterocytes, resynthesis of TAG, and assembly and secretion of ApoB-containing chylomicrons for delivery of TAG and other lipid-soluble nutrients. Like with most nutrients, the absorption of TAG occurs mostly in the proximal half of the intestine and less so in the distal intestine, where specifi c compounds, such as bile acids and vitamin B12, are absorbed. The activity of TAG synthesis coincides with the absorption of dietary fat along the length of the intestine, and it is more active in Press, September 17, 2014 DOI 10.1194 Abbreviations: ACSL, acyl-CoA synthetase; AGPAT, 1-acylglycerol-3-phosphate acyltransferase; ATGL, adipose triglyceride lipase; CD36, cluster of differentiation; CGI-58, comparative gene identifi cation-58; Cideb, cell death-inducing DNA fragmentation factor 45 (DFF45) -like effector b; DAG, diacylglycerol; DGAT, acyl-CoA:diacylglycerol acyltransferase; ER, endoplasmic reticulum; FABP, fatty acid binding protein; GLP-1, glucagon-like peptide 1; GPAT, glycerol-3-phosphate acyltransferase; G3P, glycerol-3-phosphate; IFABP, intestine-type fatty acid binding protein; LFABP, liver-type fatty acid binding protein; MAG, monoacylglycerol; MBOAT, membrane-bound O-acyltransferase; MGAT, acylCoA:monoacylglycerol acyltransferase; MTP, microsomal triacylglycerol transfer protein; PA, phosphatidic acid; PAP, phosphatidic acid phosphatase; TAG, triacylglycerol (triglyceride ). Published, JLR Papers in

Background: Global MGAT2 knock-out mice are protected from obesity. Results: Intestine-specific MGAT2 knock-out mice showed increased energy expenditure and were protected against excess weight gain and metabolic disorders induced by high fat feeding. Conclusion: Intestinal triacylglycerol metabolism is crucial in regulating systemic energy balance. Significance: Intestinal MGAT2 may be a feasible intervention target for diseases associated with excess caloric intake.

This article is available online at http://www.jlr.org assembly of chylomicrons, which transport the absorbed dietary fat and other lipid-soluble nutrients in the circulation ( 2, 3 ). MGAT activity has also been reported in a few other tissues of vertebrates, including liver and adipose tissues ( 4,5 ), where its physiological roles remain to be determined. In contrast, enzymes that catalyze triacylglycerol synthesis through sequential acylation of glycerol-3-phosphate are expressed in most cells, and this alternative GPAT pathway is dominant in most tissues ( 6 ).Three homologous genes, Mogat1-3 , have been identifi ed to encode MGAT enzymes in mammals ( 7-10 ). Among them, Mogat2 is highly expressed in the intestine of both humans and rodents ( 8,11 ). Consistent with an essential role in intestinal fat absorption, mice with the gene disrupted ( Mogat2 Ϫ / Ϫ ) are protected from obesity and other metabolic disorders induced by high-fat feeding ( 12 ). However, these mice consume and absorb normal quantities of fat. Associated with a delay in the entry of dietary fat into the circulation, Mogat2 Ϫ / Ϫ mice exhibit an unexpected increase in energy expenditure, accounting for decreases in metabolic effi ciency ( 12 ). Interestingly, Mogat2 Ϫ / Ϫ mice exhibit increases in energy expenditure even when fed a fat-free diet, and inactivating MGAT2 in the absence of high-fat feeding also protects the hyperphagic Agouti yellow mouse from excess weight gain ( 13 ). These fi ndings suggest that intestinal MGAT2 regulates systemic energy metabolism but cannot rule out a role of the low levels of MGAT2 expression in other tissues, including brown and white adipose tissues ( 12 ). Indeed, in the adipose tissues of genetically identical C57Bl/6J mice, the expression levels of MGAT2 are higher in mice that gain more weight in response to high-fat feeding ( 14 ), suggesting that MGAT2 may play a functional role in that tissue. To test the hypothesis that MGAT2 in the intestine mediates triacylglycerol synthesis required for maximizing the Abstract Acyl CoA:monoacylglycerol acyltransferase (MGAT) catalyzes the resynthesis of triacylglycerol, a crucial step in the absorption of dietary fat. Mice lacking the gene Mogat2 , which codes for an MGAT highly expressed in the small intestine, are resistant to obesity and other metabolic disorders induced by high-fat feeding. Interestingly, these Mogat2 ؊ / ؊ mice absorb normal amounts of dietary fat but exhibit a reduced rate of fat absorption, increased energy expenditure, decreased respiratory exchange ratio, and impaired metabolic effi ciency. MGAT2 is expressed in tissues besides intestine. To test the hypothesis that intestinal MGAT2 enhances metabolic effi ciency and promotes the storage of metabolic fuels, we introduced the human MOGAT2 gene driven by the intestine-specifi c villin promoter into Mogat2 ؊ / ؊ mice. We found that the expression of MOGAT2 in the intestine increased intestinal MGAT activity, restored fat absorption rate, partially corrected energy expenditure, and pr...

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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