Intestine-specific expression of acyl CoA:diacylglycerol acyltransferase 1 reverses resistance to diet-induced hepatic steatosis and obesity in Dgat1 mice

Gao

Spencer

et al. 2011

for assimilation and thus exert a lower thermic effect of food (diet-induced thermogenesis) (3)(4)(5). Individuals that assimilate dietary fat effi ciently to meet their needs between meals have an advantage in enduring starvation. Thus, genes conferring this trait may be selected through evolution. During times of continuous abundance, however, individuals thrifty of energy substrates and high in metabolic effi ciency are prone to accumulating fuel surpluses in adipose and other tissues ( 6, 7 ). In humans, excessive fat accumulation is associated with metabolic diseases, including obesity, hepatic steatosis, and insulin resistance, which plague many industrialized parts of the world ( 8, 9 ).The absorption of dietary fat involves the resynthesis of digested triacylglycerol in enterocytes, mainly through a pathway catalyzed by acyl CoA:monoacylglycerol acyltransferase (MGAT) ( 10 ). Three related genes have been identifi ed that code for MGAT; among them, only Mogat2 is highly expressed in the small intestine of both mice and humans ( 11-15 ). Thus, Mogat2 probably encodes the intestinal MGAT activity, although Mogat3 is also found in the distal intestine in humans ( 14 ).Consistent with a role of MGAT2 in promoting conservation of dietary fat, mice lacking the enzyme ( Mogat2 Ϫ / Ϫ ) are resistant to obesity and other metabolic disorders induced by high-fat feeding ( 16,17 ؊ / ؊ mice expended energy and lost weight like wild-type controls. To determine whether MGAT2 defi ciency protects against obesity in the absence of high-fat feeding, we crossed Mogat2 ؊ / ؊ mice with genetically obese Agouti mice. MGAT2 defi ciency increased energy expenditure and prevented these mice from gaining excess weight. Our results suggest that MGAT2 modulates energy expenditure through multiple mechanisms, including one independent of dietary fat; these fi ndings also raise the prospect of inhibiting MGAT2 as a strategy for combating obesity and related metabolic disorders resulting from excessive calorie intake. Abbreviations: DGAT, diacylglycerol acyltransferase; MGAT, monoacylglycerol acyltransferase; RER, respiratory exchange ratio.

Section: Discussionmentioning

confidence: 78%

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

Gao

Spencer

et al. 2011

“…DGAT1 is highly expressed in the intestine and other tissues, including the adipose tissues. Reintroduction of intestinal DGAT1 using the same villin promoter as used in our study restores the rate of fat absorption and susceptibility to diet-induced hepatic steatosis and obesity, highlighting the role of intestinal lipid metabolism in systemic energy balance ( 34 …”

Section: Expression Of Hmogat2 Partially Restores Metabolic Effi Cienmentioning

confidence: 99%

Intestine-specific expression of MOGAT2 partially restores metabolic efficiency in Mogat2-deficient mice

Gao

Banh

et al. 2013

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...

“…The topology of these two enzymes, with the active site of DGAT2 facing the cytosol and DGAT1 facing both the cytosol as well as the ER lumen, supports the model ( 80,83 ). However, the dichotomy is not supported by the observations that overexpression of either enzyme in cultured hepatocytes, livers, or intestines did not lead to increases in TAG-rich lipoproteins or cytosolic lipid droplets invariably (109)(110)(111)(112)(113)(114).…”

Section: Enzymes Catalyzing the G3p Pathway In The Intestinementioning

confidence: 37%

“…However, its role in intestinal TAG synthesis appears to be a major component. Reintroduction of DGAT1 into the intestine of Dgat1 Ϫ / Ϫ mice reverses many of the fat absorption and energy balance phenotypes ( 113 ). Intestine-specifi c expression of DGAT1 clears the excess TAG storage in the cytosolic lipid droplets of enterocytes and restores the increases in plasma TAG in response to an oil bolus.…”

Section: Specific Inhibitors Of the Mag Pathwaymentioning

confidence: 99%

Intestinal triacylglycerol synthesis in fat absorption and systemic energy metabolism

Yen

Yen

2015

122

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