Impaired de novo choline synthesis explains why phosphatidylethanolamine N-methyltransferase-deficient mice are protected from diet-induced obesity.
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.
Jacobs
René L
RL
Group on the Molecular and Cell Biology of Lipids and Department of Biochemistry, University of Alberta, Edmonton, Alberta T6G 2S2, Canada.
Zhao
Yang
Y
Koonen
Debby P Y
DP
Sletten
Torunn
T
Su
Brian
B
Lingrell
Susanne
S
Cao
Guoqing
G
Peake
David A
DA
Kuo
Ming-Shang
MS
Proctor
Spencer D
SD
Kennedy
Brian P
BP
Dyck
Jason R B
JR
Vance
Dennis E
DE
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
D004041:Dietary Fats; D010713:Phosphatidylcholines; D001622:Betaine; D050918:Phosphatidylethanolamine N-Methyltransferase; D002794:Choline
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