Brain Acetylcholine: Control by Dietary Choline

Cohen, Edith L.; Wurtman, Richard J.

doi:10.1126/science.1251187

Cited by 371 publications

(95 citation statements)

References 21 publications

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“…However, when acetylcholine turnover is high, choline supply appears to become limiting for the production of acetylcholine (51). Furthermore, brain choline and acetylcholine levels are lower in rats fed a diet devoid of choline than in rats fed a choline-replete diet (52). The M 3 muscarinic acetylcholine subtype receptor is important in regulating energy metabolism (53).…”

Section: Discussionmentioning

confidence: 99%

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

Jacobs

Zhao

Koonen

et al. 2010

Journal of Biological Chemistry

183

197

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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.

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Section: Discussionmentioning

confidence: 99%

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

Jacobs

Zhao

Koonen

et al. 2010

Journal of Biological Chemistry

183

197

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“…As discussed above, choline accelerates the synthesis and release of acetylcholine in nerve cells (12,26,27,49,133,135). A specific carrier mechanism transports free choline across the blood-brain barrier at a rate that is proportional to serum choline concentration (29,100).…”

Section: Choline and Neuronal Function In Adultsmentioning

confidence: 99%

Choline: Critical Role During Fetal Development and Dietary Requirements in Adults

2006

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Choline is an essential nutrient needed for the structural integrity and signaling functions of cell membranes; for normal cholinergic neurotransmission; for normal muscle function; for lipid transport from liver; and it is the major source of methyl groups in the diet. Choline is critical during fetal development, when it influences stem cell proliferation and apoptosis, thereby altering brain and spinal cord structure and function and influencing risk for neural tube defects and lifelong memory function. Choline is derived not only from the diet, but from de novo synthesis as well. Though many foods contain choline, there is at least a twofold variation in dietary intake in humans. When deprived of dietary choline, most men and postmenopausal women developed signs of organ dysfunction (fatty liver or muscle damage), while less than half of premenopausal women developed such signs. Aside from gender differences, there is significant variation in the dietary requirement for choline that can be explained by very common genetic polymorphisms.

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“…Moreover, pharmacologic doses (grams) of choline and lecithin are administered to humans to treat some neurological diseases presumably arising from deficient central cholinergic tone (2). The basis for this therapy is the finding that plasma choline concentration directly influences acetylcholine synthesis and release in rat brain (3,4). The increases in plasma choline concentrations seen after oral (3-5) or intravenous (6-8) administration of a large choline dose are small and of short duration.…”

mentioning

confidence: 99%

Uptake of free choline by isolated perfused rat liver.

Zeisel¹,

Story²,

Wurtman³

et al. 1980

Proc. Natl. Acad. Sci. U.S.A.

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The uptake of free choline by isolated perfused rat liver was characterized. A saturable uptake mechanism [Ka = 0.17 ± 0.07 mM (SD); Vm.x = 0.84 i 0.16 gmol/min X g dry weight] and a nonsaturable mechanism (through which uptake is proportional to choline concentration in the perfusate) were identified. Most of the choline transported into hepatocytes was converted to betaine, phosphorylcholine, or lecithin. Free choline also accumulated within the intracellular space, suggesting that choline oxidase activity does not always limit choline's uptake by the liver. Choline, in the form of the phospholipid lecithin, is an integral component of all membranes and an important constituent of the diet. The intake of choline in the United States usually varies between 100 and 600 mg per day (1). Moreover, pharmacologic doses (grams) of choline and lecithin are administered to humans to treat some neurological diseases presumably arising from deficient central cholinergic tone (2). The basis for this therapy is the finding that plasma choline concentration directly influences acetylcholine synthesis and release in rat brain (3,4). The increases in plasma choline concentrations seen after oral (3-5) or intravenous (6-8) administration of a large choline dose are small and of short duration. This suggests that highcapacity mechanisms must exist for clearing choline from the blood. The characterization of such mechanisms should be useful in deciding how best to administer choline.The liver influences plasma choline concentration both by synthesizing choline radicals (in lecithin) via sequential methylation of phosphatidylethanolamine (9,10) and by removing dietary choline from the portal circulation (11,12). Choline uptake into the liver has been demonstrated both in vivo (6,8,13) and in the isolated perfused organ (14-16). In published perfusion studies, initial choline concentrations (1.25 and 2.50 mM) were much higher than physiological levels (0.01-0.02 mM) and no attempt was made to determine the kinetics of the uptake phenomenon. In the present study we have examined the kinetics of free choline uptake in isolated liver by using a wide range of perfusate concentrations (0.01-5 mM). We present evidence that free choline is rapidly taken up into the liver through both a saturable and a nonsaturable mechanism. METHODS Animals. Sprague-Dawley rats (Charles River Breeding Laboratories), 150-250 g, were housed in a controlled environment (240C; 12 hr of light from 0600 to 1800 daily). They were fed Purina chow from 0900 to 1200 hr for 2-3 weeks before being used as liver donors. Water was supplied ad lib.Closed-Circuit Perfusions. Livers were isolated and perfused by a method reported previously (17 (40,000 dpm/,umol) concentrations. When more than one concentration was used, the second and third were, respectively, 10 and 100 times the first. The initial amount of choline was added to the perfusate at 30 min, with subsequent amounts added at 30-min intervals. The peak choline concentrations achieved in this serie...

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Brain Acetylcholine: Control by Dietary Choline

Cited by 371 publications

References 21 publications

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

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

Choline: Critical Role During Fetal Development and Dietary Requirements in Adults

Uptake of free choline by isolated perfused rat liver.

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