Impaired de Novo Choline Synthesis Explains Why Phosphatidylethanolamine N-Methyltransferase-deficient Mice Are Protected from Diet-induced Obesity

• Published in: The Journal of biological chemistry 2010-07, Vol.285 (29), p.22403-22413
• Main Authors: Jacobs, René L., Zhao, Yang, Koonen, Debby P.Y., Sletten, Torunn, Su, Brian, Lingrell, Susanne, Cao, Guoqing, Peake, David A., Kuo, Ming-Shang, Proctor, Spencer D., Kennedy, Brian P., Dyck, Jason R.B., Vance, Dennis E.
• Format: Article
• Language: English
• Subjects: Adipose Tissue; Animals; Betaine - administration & dosage; Betaine - pharmacology; Choline; Choline - biosynthesis; Diabetes; Diet; Dietary Fats - administration & dosage; Dietary Fats - pharmacology; Dietary Supplements; Energy Metabolism - drug effects; Fatty Liver - chemically induced; Fatty Liver - complications; Fatty Liver - enzymology; Fatty Liver - pathology; Feeding Behavior - drug effects; Insulin Resistance; Lipids; Male; Metabolic Networks and Pathways - drug effects; Metabolism; Methylation; Mice; Mice, Inbred C57BL; Mitochondria - drug effects; Mitochondria - ultrastructure; Obesity - chemically induced; Obesity - complications; Obesity - enzymology; Obesity - prevention & control; Phenotype; Phosphatidylcholine; Phosphatidylcholines - biosynthesis; Phosphatidylethanolamine N-Methyltransferase - deficiency; Phosphatidylethanolamine N-Methyltransferase - metabolism; Phospholipid Metabolism; Weight Gain - drug effects
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M110.108514

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.