MGAT2 deficiency ameliorates high-fat diet-induced obesity and insulin resistance by inhibiting intestinal fat absorption in mice.
BACKGROUND
Resynthesis of triglycerides in enterocytes of the small intestine plays a critical role in the absorption of dietary fat. Acyl-CoA:monoacylglycerol acyltransferase-2 (MGAT2) is highly expressed in the small intestine and catalyzes the synthesis of diacylglycerol from monoacylglycerol and acyl-CoA. To determine the physiological importance of MGAT2 in metabolic disorders and lipid metabolism in the small intestine, we constructed and analyzed Mgat2-deficient mice.


RESULTS
In oral fat tolerance test (OFTT), Mgat2-deficient mice absorbed less fat into the circulation. When maintained on a high-fat diet (HFD), Mgat2-deficient mice were protected from HFD-induced obesity and insulin resistance. Heterozygote (Mgat2+/-) mice had an intermediate phenotype between Mgat2+/+ and Mgat2-/- and were partially protected from metabolic disorders. Despite of a decrease in fat absorption in the Mgat2-deficient mice, lipid levels in the feces and small intestine were comparable among the genotypes. Oxygen consumption was increased in the Mgat2-deficient mice when maintained on an HFD. A prominent upregulation of the genes involved in fatty acid oxidation was observed in the duodenum but not in the liver of the Mgat2-deficient mice.


CONCLUSIONS
These results suggest that MGAT2 has a pivotal role in lipid metabolism in the small intestine, and the inhibition of MGAT2 activity may be a promising strategy for the treatment of obesity-related metabolic disorders.
Department I, Pharmacology Research Laboratories II, Research Division, Mitsubishi Tanabe Pharma Corporation, 2-2-50, Kawagishi, Toda-shi, Saitama, 335-8505, Japan. tsuchida.takuma@mx.mt-pharma.co.jp
Takuma
T
Tsuchida
Sayaka
S
Fukuda
Hisanori
H
Aoyama
Nobuhiko
N
Taniuchi
Tomomi
T
Ishihara
Noriko
N
Ohashi
Hiroko
H
Sato
Koji
K
Wakimoto
Masaharu
M
Shiotani
Akira
A
Oku
D000818:Animals; D001823:Body Composition / Q000235:genetics / Q000502:physiology; D059305:Diet, High-Fat / Q000009:adverse effects*; D005223:Fats / Q000378:metabolism*; D005951:Glucose Tolerance Test; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology*; D007408:Intestinal Absorption / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D017351:N-Acetylglucosaminyltransferases; D009765:Obesity / Q000235:genetics / Q000378:metabolism*; D016133:Polymerase Chain Reaction
D005223:Fats; D017351:N-Acetylglucosaminyltransferases; C063313:alpha-1,6-mannosyl-glycoprotein beta-1,2-N-acetylglucosaminyltransferase