it may induce the synthesis of the enzymes needed to cope with it.

- a chemical reaction will involve a change in the free energy of asystem (G)

thioester of Succinyl-CoA to drive synthesis of a high-energy ..

Multiple patents have been filed on DGAT inhibitors for the treatment of obesity and its related metabolic complications. For example, the DGAT1 inhibitor XP620 has recently been shown to reduce apoB secretion in Caco-2 cells, TAG and DAG synthesis in primary enterocytes, and dietary fat absorption in mice (). Recently, a highly potent DGAT1 inhibitor was shown to cause weight loss, reduction in liver TAG, and depletion of serum TAG following a lipid challenge in a dose-dependent manner, recapturing the major phenotype of DGAT1-knockout mice (). However, it remains unclear whether a pan-inhibitor for both DGAT enzymes is more beneficial than isoform-specific inhibitors. Although inhibition of DGAT2 in the liver would likely offer the advantages of the prevention of steatosis and/or dyslipidemia, inhibition of DGAT2 in skeletal muscle and skin could exacerbate insulin resistance associated with obesity (). On the other hand, it could be argued that an agent that inhibits both DGAT activities might be more desirable to achieve maximal effects on inhibition of TAG synthesis in all tissues. Practically, development of isoform-specific inhibitors may be beneficial due to the tissue- and intracellular compartment-specific distribution of DGAT1 and DGAT2 and the lack of sequence homology between these two isoforms. When targeting DGAT1 and/or DGAT2 in obesity treatments, one must also consider the potential side effects in skin, lactation, and teratogenic consequences as predicted from the pathophysiological conditions associated with DGAT1 and DGAT2 deficiency (, ). Whether these pharmacological approaches would succeed awaits definitive answers from clinical trials of DGAT1 and MGAT inhibitors that may be delivered soon by several pharmaceuticals.

Oxidative phosphorylation produces lots of energy, but requires hydrogen (NADH and FADH).

penicillin destroys an enzyme crucial to the synthesis of ..

DGAT1 polymorphisms have been linked with a certain type of human obesity (). In plants, a single amino acid polymorphism of the DGAT1 gene is linked with oil content in maize (). Likewise, a single nucleotide polymorphism of DGAT1 is associated with milk fat content in cattle (). DGAT1 protein levels increased sharply following differentiation of 3T3-L1 into mature adipocytes. Overexpression of DGAT1 and DGAT2 results in a significant increase in TAG synthesis in mature adipocytes (, ). Conversely, mice with DGAT1 deficiency demonstrated a reduction in adiposity and resistance to high-fat diet-induced obesity (), which is accompanied by increased energy expenditure and hyperlocomotive activity (). This metabolic phenotype is likely caused by changes in adipocyte lipid metabolism resulting from DGAT1 deficiency. Wild-type mice with adipose transplanted from the DGAT1-deficient mice demonstrated physiological features that are similar to the DGAT1-knockout mice, including resistance to diet-induced obesity and an improvement in insulin sensitivity ().

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Obesity is characterized by excessive accumulation of TAG in adipose tissue. As discussed in the previous sections, the MGAT and DGAT enzymes are implicated in various steps in energy homeostasis from dietary fat absorption and fat storage to regulation of energy expenditure. Therefore, inhibiting these enzymes may offer pharmacological strategies for antiobesity treatment (). Consumption of a Western diet rich in animal fat is considered to be one of the major factors contributing to the ongoing obesity epidemic. In industrialized countries, dietary fat intake provides >40% of the caloric content of daily food consumption (). Inhibitors of dietary fat absorption can be used to treat obesity, as exemplified by the development of pancreatic lipase inhibitors for the treatment of obesity. As one of the only two drugs currently marketed for obesity (), Orlistat, also known as Xenical, is a potent and specific inhibitor of both gastric and pancreatic lipases (, , , ) used in the clinic for the treatment of obesity. The drug acts nonsystemically and reduces fat absorption by ∼30%. However, Orlistat is not widely used by obese patients due to its major gastrointestinal side effects related to malabsorbed TAG, such as abdominal pain, urgency to defecate, increased flatus, steatorrhea, and diarrhea. Therefore, the MGAT and DGAT enzymes present an alternative drug target for dietary fat absorption due to their major role in fat absorption (). Furthermore, the three MGAT enzymes are expressed predominantly in gastrointestinal tract, which could possibly alleviate potential side effects of chemical inhibitors in other tissues. Discharge of MAG and free FA as an unabsorbed energy source in the stool may avoid the unwanted gastrointestinal side effects caused by Orlistat. This strategy is supported by the recent successful development of Slentrol, a microsomal triglyceride transfer protein (MTP) inhibitor developed specifically for the treatment of canine obesity (). Slentrol causes significant weight loss in canines by inhibiting dietary fat absorption and reducing food intake. Like MTP inhibitors, inhibition of MGAT enzymes may reduce food intake, since high concentration of MAG and free FA is expected to stimulate the secretion of norexigenic peptides, such as cholecystokinin, peptide YY, and glucagon-like peptide-1, that mimic the effects observed in gastrointestinal bypass patients (). One major concern for a potential MGAT inhibitor is the theoretical excessive accumulation of FA and MAG in enterocytes, which could be lipotoxic. However, this has not been a concern with MTP inhibitors, at least in canines, likely due to the high turnover rate of the gastrointestinal lining (). Detailed phenotypic characterization on MGAT-knockout mice is needed to better understand the pharmaceutical potentials of MGAT inhibitors for the treatment of obesity and its related metabolic complications.

These reactions, like all chemical reactions, involve making and breakingbonds between atoms, and this sometimes requires energy.

High energy molecules, such as ATP, ..

MGAT catalyzes the first step in TAG synthesis involved in dietary absorption by enterocytes. Three isoforms of MGAT enzymes, known as MGAT1, MGAT2, and MGAT3, have been identified so far. All three MGAT isoforms possess strong MGAT enzyme activity and are localized in the endoplasmic reticulum (ER) (, , , , ). However, they differ in tissue expression patterns and in catalytic properties. The MGAT1 mRNA has been detected mainly in stomach, kidney, and adipose tissue, whereas MGAT2 and MGAT3 exhibit highest expression in the small intestine (, , , ). Among the MGAT isoforms, MGAT3 possesses some unique features. The MGAT3 gene is found only in higher mammals and humans but not in rodents. Although named after its enzyme activity, MGAT3 shares higher sequence homology with DGAT2 than with the other MGAT isoforms. In addition, MGAT3 demonstrates significantly higher DGAT activity than MGAT1 and MGAT2 in the order MGAT3 > MGAT1 > MGAT2 when either MAG or DAG is used as substrate, suggesting that MGAT3 also functions as a TAG synthase (). The DGAT activity of MGAT3 is relative to the concentration of MAG substrate. When low concentrations of 2-MAG are used as a substrate, the major enzyme product of MGAT3 is TAG (). In contrast, DAG is the major enzymatic product when high concentrations of 2-MAG are used as a substrate (). It can be envisaged that MGATs and DGAT2 enzymes may be evolved from a common ancestral gene. This notion is supported by their similar subcellullar localization pattern () and the colocalization of DGAT2 gene with MGAT2 gene on the same region of human chromosome 11. Although MGAT3 enzyme exhibits strong DGAT activity, its catalytic properties are quite different from those of DGAT1. Whereas MGAT3 is very sensitive to treatment with 1% 3[(3-cholamidopropyl)dimethylammonio]-propanesulfonate, DGAT1 activity is stimulated by its application, indicating that they possess different catalytic mechanisms. Interestingly, MGAT3 activity is equally sensitive to detergent inactivation when either MAG or DAG is used as a substrate, suggesting that the DGAT and MGAT activities of the MGAT enzymes are inseparable ().

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DGAT catalyzes the final step in mammalian TAG synthesis that merges the MGAT and G-3-P pathways () (). In mammals, there are two isoforms of DGAT enzymes, DGAT1 and DGAT2. DGAT1 is a member of the mammalian ACAT gene family (, ), whereas DGAT2 belongs to a new family of acyltransferases that includes the three MGAT enzymes. In addition to DAG, both DGAT1 and DGAT2 also recognize MAG as a substrate in the synthesis of TAG (, ). Although both DGAT1 and DGAT2 enzymes catalyze the same reactions in TAG synthesis with DAG or MAG and acyl-CoA as substrates, they are functionally distinguished by their differences in catalytic properties (, ), subcellular localization (), physiological regulation (), and phenotypic consequences when rendered deficient in mice (, ). When MAG is used as a substrate, the major enzymatic product catalyzed by DGAT2 is TAG. In contrast, the enzymatic products catalyzed by DGAT1 depend on the concentration of MAG, but the TAG/MAG product and substrate relationship does not obey the classic Michaelis-Menten kinetics. At low concentrations of MAG, the major acylation product by DGAT1 is TAG. However, the DGAT activity of DGAT1 is dramatically inhibited when high concentration of MAG is used as a substrate, resulting in an increased production of DAG (). Overexpression of DGAT1 results in the accumulation of small lipid droplets around the cell periphery, whereas overexpression of DGAT2 leads to increases in large cytosolic lipid droplets (). This difference may be related to the previous reports on two proposed types of DGAT activities in liver microsomes, an overt activity that regulates the cytosolic TAG pools and another that is latent and plays a role in TAG secretion (, ). This is supported by studies in which inactivation of the yeast Dgat1 gene resulted in the reduction of DGAT activity on lipid particles, but without significant effect on DGAT activity in the ER (). Upon the treatment of oleate, DGAT2, but not DGAT1 and MGAT2, can also be detected in mitochondria-associated membranes and lipid droplets in addition to ER (). Furthermore, when DGAT1 is overexpressed in mouse liver via an adenoviral vector, the mice showed increased VLDL secretion and gonadal fat mass, whereas hepatic-specific DGAT2 overexpression increased liver TAG content but not VLDL secretion (). DGAT1 has also been shown to recognize wax alcohol and retinol as acyl acceptors in potential acyl-CoA:wax alcohol acyltransferase and acyl CoA:retinol acyltransferase reactions, implicating a role of DGAT1 in the synthesis of wax esters and retinyl esters, respectively (, ).