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.

Endocrine role of bone: recent and emerging perspectives beyond osteocalcin

“…Choline supplementation by others results in hepatic insulin resistance . Moreover, the impairment of de novo synthesis of choline via phosphatidylethanolamine N-methyltransferase, which catalyses the methylation of phosphatidylethanolamine in the liver, protects mice from diet-induced obesity (Jacobs et al 2010). However, in contradiction to the results of these studies, it has recently been reported that choline can promote liver health by maintaining cholesterol homoeostasis (Al Rajabi et al 2014).…”

The Concentration of Phosphatidylethanolamine in Mitochondria Can Modulate ATP Production and Glucose Metabolism in Mice

“…The PEMT pathway is responsible for ;30% of hepatic PC synthesis; the remaining 70% is generated via the cytidine diphosphate-choline pathway (10). Unexpectedly, we reported that mice lacking PEMT are protected against high-fat diet (HFD)-induced obesity and IR (7). This protection was completely blunted when the diet was supplemented with choline, leading to the conclusion that PEMT provides an endogenous source of choline that supports normal weight gain (7).…”

“…Therefore, abnormal lipid and glucose metabolism associated with IR and type 2 diabetes may be related to abnormalities in mitochondria. Hepatic phosphatidylcholine (PC) synthesis also has a role in the development of IR (7). PC is synthesized via the cytidine diphosphate-choline pathway (8).…”

Phosphatidylcholine functional foods and nutraceuticals: A potential approach to prevent non‐alcoholic fatty liver disease

“…In the rat [24], hamster [25], dog [19] and monkey [26], choline deficiency results in liver dysfunction owing to accumulation of TG [27][28][29][30] and DAGs [31] within the hepatocyte. In rats, fatty liver begins within hours to days after initiation of a choline-deficient diet [32]. Also, fatty liver induced by a high fat diet in rats could be reversed by daily administration of choline for only 12 days [33].…”