title: Impaired de novo choline synthesis explains why phosphatidylethanolamine N-methyltransferase-deficient mice are protected from diet-induced obesity.
abstract: Phosphatidylcholine (PC) is synthesized from choline via the CDP-choline pathway. Liver cells can also synthesize PC via the sequential methylation of phosphatidylethanolamine, catalyzed by phosphatidylethanolamine N-methyltransferase (PEMT). The current study investigates whether or not hepatic PC biosynthesis is linked to diet-induced obesity. Pemt(+/+) mice fed a high fat diet for 10 weeks increased in body mass by 60% and displayed insulin resistance, whereas Pemt(-/-) mice did not. Compared with Pemt(+/+) mice, Pemt(-/-) mice had increased energy expenditure and maintained normal peripheral insulin sensitivity; however, they developed hepatomegaly and steatosis. In contrast, mice with impaired biosynthesis of PC via the CDP-choline pathway in liver became obese when fed a high fat diet. We, therefore, hypothesized that insufficient choline, rather than decreased hepatic phosphatidylcholine, was responsible for the lack of weight gain in Pemt(-/-) mice despite the presence of 1.3 g of choline/kg high fat diet. Supplementation with an additional 2.7 g of choline (but not betaine)/kg of diet normalized energy metabolism, weight gain, and insulin resistance in high fat diet-fed Pemt(-/-) mice. Furthermore, Pemt(+/+) mice that were fed a choline-deficient diet had increased oxygen consumption, had improved glucose tolerance, and gained less weight. Thus, de novo synthesis of choline via PEMT has a previously unappreciated role in regulating whole body energy metabolism.
authors.affiliation: Group on the Molecular and Cell Biology of Lipids and Department of Biochemistry, University of Alberta, Edmonton, Alberta T6G 2S2, Canada.
authors.forename: René L
authors.initials: RL
authors.lastname: Jacobs
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhao
authors.forename: Debby P Y
authors.initials: DP
authors.lastname: Koonen
authors.forename: Torunn
authors.initials: T
authors.lastname: Sletten
authors.forename: Brian
authors.initials: B
authors.lastname: Su
authors.forename: Susanne
authors.initials: S
authors.lastname: Lingrell
authors.forename: Guoqing
authors.initials: G
authors.lastname: Cao
authors.forename: David A
authors.initials: DA
authors.lastname: Peake
authors.forename: Ming-Shang
authors.initials: MS
authors.lastname: Kuo
authors.forename: Spencer D
authors.initials: SD
authors.lastname: Proctor
authors.forename: Brian P
authors.initials: BP
authors.lastname: Kennedy
authors.forename: Jason R B
authors.initials: JR
authors.lastname: Dyck
authors.forename: Dennis E
authors.initials: DE
authors.lastname: Vance
mesh_terms: D000818:Animals; D001622:Betaine / Q000008:administration & dosage / Q000494:pharmacology; D002794:Choline / Q000096:biosynthesis*; D004032:Diet; D004041:Dietary Fats / Q000008:administration & dosage / Q000494:pharmacology; D019587:Dietary Supplements; D004734:Energy Metabolism / Q000187:drug effects; D005234:Fatty Liver / Q000139:chemically induced / Q000150:complications / Q000201:enzymology / Q000473:pathology; D005247:Feeding Behavior / Q000187:drug effects; D007333:Insulin Resistance; D008297:Male; D053858:Metabolic Networks and Pathways / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000648:ultrastructure; D009765:Obesity / Q000139:chemically induced / Q000150:complications / Q000201:enzymology* / Q000517:prevention & control*; D010641:Phenotype; D010713:Phosphatidylcholines / Q000096:biosynthesis; D050918:Phosphatidylethanolamine N-Methyltransferase / Q000172:deficiency* / Q000378:metabolism; D015430:Weight Gain / Q000187:drug effects
chemical_list: D004041:Dietary Fats; D010713:Phosphatidylcholines; D001622:Betaine; D050918:Phosphatidylethanolamine N-Methyltransferase; D002794:Choline
references.citation: Circ Res. 2004 May 14;94(9):e78-84
references.pmid: 15105298
references.citation: FASEB J. 2005 Aug;19(10):1266-71
references.pmid: 16051693
references.citation: Atherosclerosis. 2007 Dec;195(2):e100-7
references.pmid: 17689540
references.citation: J Nutr. 2008 May;138(5):914-20
references.pmid: 18424601
references.citation: J Lipid Res. 2006 Oct;47(10):2280-90
references.pmid: 16829692
references.citation: Diabetes. 2009 Apr;58(4):855-66
references.pmid: 19136649
references.citation: Hepatology. 1995 Nov;22(5):1399-403
references.pmid: 7590654
references.citation: Eur J Pharmacol. 2008 Jul 28;589(1-3):315-22
references.pmid: 18561911
references.citation: Lab Invest. 2007 Jan;87(1):56-65
references.pmid: 17075577
references.citation: Eur J Biochem. 2003 Mar;270(5):991-9
references.pmid: 12603332
references.citation: Biochem Biophys Res Commun. 2008 Apr 18;368(4):893-8
references.pmid: 18267108
references.citation: J Biol Chem. 2008 Dec 19;283(51):35496-506
references.pmid: 18842588
references.citation: Gastroenterology. 2006 Apr;130(4):1259-69
references.pmid: 16618417
references.citation: Science. 2002 Jul 12;297(5579):240-3
references.pmid: 12114623
references.citation: Am J Gastroenterol. 2001 Sep;96(9):2711-7
references.pmid: 11569700
references.citation: Clin Chem Lab Med. 2005;43(10):1069-75
references.pmid: 16197300
references.citation: J Gastroenterol Hepatol. 2007 Sep;22(9):1526-33
references.pmid: 17716355
references.citation: J Biol Chem. 2008 Apr 11;283(15):10048-57
references.pmid: 18238778
references.citation: Cell Metab. 2005 Apr;1(4):231-44
references.pmid: 16054068
references.citation: Neurochem Int. 1998 May-Jun;32(5-6):479-85
references.pmid: 9676747
references.citation: Biochem J. 1981 Apr 15;196(1):261-7
references.pmid: 6272753
references.citation: J Lipid Res. 2008 May;49(5):1068-76
references.pmid: 18227531
references.citation: FASEB J. 1991 Apr;5(7):2093-8
references.pmid: 2010061
references.citation: J Biol Chem. 2004 Nov 5;279(45):47402-10
references.pmid: 15331603
references.citation: Arterioscler Thromb Vasc Biol. 2009 Sep;29(9):1349-55
references.pmid: 19520976
references.citation: Adv Chromatogr. 1989;28:267-332
references.pmid: 2646858
references.citation: J Pharmacol Exp Ther. 1997 Sep;282(3):1139-45
references.pmid: 9316819
references.citation: J Biol Chem. 2007 Nov 16;282(46):33237-41
references.pmid: 17881348
references.citation: Cell Metab. 2006 Nov;4(5):363-75
references.pmid: 17084710
references.citation: Biochim Biophys Acta. 2007 Sep;1771(9):1186-94
references.pmid: 17616479
references.citation: J Biol Chem. 2002 Nov 1;277(44):42358-65
references.pmid: 12193594
references.citation: J Biol Chem. 2003 Jun 13;278(24):21851-9
references.pmid: 12668679
references.citation: Nat Med. 2004 Mar;10(3):268-74
references.pmid: 14770177
references.citation: Hepatology. 1999 Sep;30(3):725-9
references.pmid: 10462379
references.citation: FASEB J. 2006 Jul;20(9):1336-44
references.pmid: 16816108
references.citation: J Biol Chem. 2005 Mar 18;280(11):9887-94
references.pmid: 15632182
references.citation: Am J Physiol Regul Integr Comp Physiol. 2005 Jan;288(1):R182-7
references.pmid: 15331385
references.citation: J Biol Chem. 2005 Aug 5;280(31):28299-305
references.pmid: 15958390
references.citation: Proc Natl Acad Sci U S A. 2008 Jan 29;105(4):1297-302
references.pmid: 18216263
references.citation: Am J Physiol Gastrointest Liver Physiol. 2007 Oct;293(4):G894-902
references.pmid: 17702954
references.citation: Science. 1976 Feb 13;191(4227):561-2
references.pmid: 1251187
references.citation: J Biol Chem. 2008 Jan 25;283(4):2147-55
references.pmid: 18042552
references.citation: J Biol Chem. 1999 Oct 15;274(42):29683-8
references.pmid: 10514439
references.citation: Cell Metab. 2007 Jul;6(1):69-78
references.pmid: 17618857
references.citation: Proc Natl Acad Sci U S A. 1997 Nov 25;94(24):12880-5
references.pmid: 9371769
references.citation: Biochim Biophys Acta. 2003 Jul 4;1633(1):1-12
references.pmid: 12842190
references.citation: Diabetes. 2006 Jul;55(7):2015-20
references.pmid: 16804070
references.citation: Neurochem Int. 2008 May;52(6):972-8
references.pmid: 18023504
references.citation: J Biol Chem. 1997 May 16;272(20):13146-51
references.pmid: 9148929
references.citation: J Biol Chem. 2005 Jun 17;280(24):23356-62
references.pmid: 15829484
references.citation: J Hepatol. 2004 Jan;40(1):47-51
references.pmid: 14672613
references.citation: Cell. 2007 Nov 2;131(3):476-91
references.pmid: 17981116
references.citation: J Biol Chem. 1988 Feb 25;263(6):2998-3004
references.pmid: 3343237
references.citation: Biochim Biophys Acta. 2004 Nov 8;1686(1-2):108-17
references.pmid: 15522827
references.citation: Cell Metab. 2007 Feb;5(2):91-102
references.pmid: 17276352
references.citation: J Lipid Res. 2007 Sep;48(9):2058-64
references.pmid: 17595447
references.citation: Science. 2006 Jun 16;312(5780):1656-9
references.pmid: 16778057
references.citation: Annu Rev Biochem. 2006;75:367-401
references.pmid: 16756496
references.citation: Hepatology. 2005 Aug;42(2):362-71
references.pmid: 16001399