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

Abstract

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...

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

“…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. This in turn may underlie the phenotype we observed in the MGL Ϫ / Ϫ mice.…”

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

“…Intestinal MGAT2 is likely a major contributor. Its expression levels determine the rate of MAG uptake and esterifi cation in enterocytes ( 8,10 ). Defi ciency of MGAT2 in the intestine leads to changes in temporal and spatial distribution of fat absorption, which may result in blunted postprandial triglyceridemia as seen in both Mogat2…”

“…The primer sequences of the Cypb gene were 5 ′ TGCCGGAGTCGACAATGAT-3 ′ (forward) and 5 ′ -TGGAAGAGCACCAAGACAGACA-3 ′ (reverse). The primers to differences in body weight ( 8,10 ), suggesting complex mechanisms underlying the role of MGAT2 in the regulation of systemic energy balance.…”

“…MGAT activity assays were performed with total tissue homogenates as previously described ( 10 ). Reactions were started by adding total tissue homogenates to the assay mixture and were stopped by adding chloroform-methanol (2:1, v/v).…”

Usefulness of Obese Animal Models in Antiobesity Drug Development

“…MGAT2 deficient mice are protected from HF diet-induced obesity and glucose intolerance [106]. Moreover, MGAT2 deficiency results in increased metabolic rates, decreased food consumption, and protection from obesity in genetically obese Agouti mice, suggesting that MGAT2 regulates energy balance [106,107]. The intestinal function of MGAT2 and the effect of this function on obesity are also investigated using intestine-specific MGAT2 KO mice [108].…”