title: Abrogating monoacylglycerol acyltransferase activity in liver improves glucose tolerance and hepatic insulin signaling in obese mice.
abstract: Monoacylglycerol acyltransferase (MGAT) enzymes convert monoacylglycerol to diacylglycerol (DAG), a lipid that has been linked to the development of hepatic insulin resistance through activation of protein kinase C (PKC). The expression of genes that encode MGAT enzymes is induced in the livers of insulin-resistant human subjects with nonalcoholic fatty liver disease, but whether MGAT activation is causal of hepatic steatosis or insulin resistance is unknown. We show that the expression of Mogat1, which encodes MGAT1, and MGAT activity are also increased in diet-induced obese (DIO) and ob/obmice. To probe the metabolic effects of MGAT1 in the livers of obese mice, we administered antisense oligonucleotides (ASOs) against Mogat1 to DIO and ob/ob mice for 3 weeks. Knockdown of Mogat1 in liver, which reduced hepatic MGAT activity, did not affect hepatic triacylglycerol content and unexpectedly increased total DAG content. Mogat1 inhibition also increased both membrane and cytosolic compartment DAG levels. However, Mogat1 ASO treatment significantly improved glucose tolerance and hepatic insulin signaling in obese mice. In summary, inactivation of hepatic MGAT activity, which is markedly increased in obese mice, improved glucose tolerance and hepatic insulin signaling independent of changes in body weight, intrahepatic DAG and TAG content, and PKC signaling.
authors.affiliation: Center for Human Nutrition, Washington University School of Medicine, St. Louis, MO ahall@dom.wustl.edu.
authors.forename: Angela M
authors.initials: AM
authors.lastname: Hall
authors.affiliation: Center for Human Nutrition, Washington University School of Medicine, St. Louis, MO.
authors.forename: Nisreen
authors.initials: N
authors.lastname: Soufi
authors.affiliation: Center for Human Nutrition, Washington University School of Medicine, St. Louis, MO.
authors.forename: Kari T
authors.initials: KT
authors.lastname: Chambers
authors.affiliation: Center for Human Nutrition, Washington University School of Medicine, St. Louis, MO.
authors.forename: Zhouji
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Center for Human Nutrition, Washington University School of Medicine, St. Louis, MO.
authors.forename: George G
authors.initials: GG
authors.lastname: Schweitzer
authors.affiliation: Center for Human Nutrition, Washington University School of Medicine, St. Louis, MO.
authors.forename: Kyle S
authors.initials: KS
authors.lastname: McCommis
authors.affiliation: Cardiovascular, Metabolic, and Endocrine Diseases Research Unit, Pfizer Global Research and Development, Cambridge, MA.
authors.forename: Derek M
authors.initials: DM
authors.lastname: Erion
authors.affiliation: ISIS Pharmaceuticals, Inc., Carlsbad, CA.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Graham
authors.affiliation: Center for Human Nutrition, Washington University School of Medicine, St. Louis, MODepartment of Biochemistry and Molecular Biology, Medical College of Soochow University, Suzhou, China.
authors.forename: Xiong
authors.initials: X
authors.lastname: Su
authors.affiliation: Center for Human Nutrition, Washington University School of Medicine, St. Louis, MO.
authors.forename: Brian N
authors.initials: BN
authors.lastname: Finck
mesh_terms: D000217:Acyltransferases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D059305:Diet, High-Fat; D004075:Diglycerides / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D005947:Glucose / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D008822:Mice, Transgenic; D009765:Obesity / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D016376:Oligonucleotides, Antisense / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014280:Triglycerides / Q000378:metabolism
chemical_list: C011439:1,2-diacylglycerol; D004075:Diglycerides; D007328:Insulin; D016376:Oligonucleotides, Antisense; D014280:Triglycerides; D000217:Acyltransferases; C021802:2-acylglycerol O-acyltransferase; D005947:Glucose