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.

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Naringenin reduces adiposity and ameliorates adipose tissue inflammation, with a moderate inhibitory effect on tumor growth in obese ovariectomized mice.

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...