Abstract
Biosynthesis of hepatic choline via phosphatidylethanolamine N-methyltransferase (PEMT) plays an important role in the development of type 2 diabetes and obesity. We investigated the mechanism(s) by which choline modulates insulin sensitivity. PEMT wild-type (Pemt(+/+)) and knock-out (Pemt(-/-)) mice received either a high fat diet (HF; 60% kcal of fat) or a high fat, high choline diet (HFHC; 4 g of choline/kg of HF diet) for 1 week. Hepatic insulin signaling and glucose and lipid homeostasis were investigated. Glucose and insulin intolerance occurred in Pemt(-/-) mice fed the HFHC diet, but not in their Pemt(-/-) littermates fed the HF diet. Plasma glucagon was elevated in Pemt(-/-) mice fed the HFHC diet compared with Pemt(-/-) mice fed the HF diet, concomitant with increased hepatic expression of glucagon receptor, phosphorylated AMP-activated protein kinase (AMPK), and phosphorylated insulin receptor substrate 1 at serine 307 (IRS1-s307). Gluconeogenesis and mitochondrial oxidative stress were markedly enhanced, whereas glucose oxidation and triacylglycerol biosynthesis were diminished in Pemt(-/-) mice fed the HFHC diet. A glucagon receptor antagonist (2-aminobenzimidazole) attenuated choline-induced hyperglycemia and insulin intolerance and blunted up-regulation of phosphorylated AMPK and IRS1-s307. Choline induces glucose and insulin intolerance in Pemt(-/-) mice through modulating plasma glucagon and its action in liver.
Highlights
Mice lacking phosphatidylethanolamine N-methyltransferase (PemtϪ/Ϫ) are glucose- and insulin-sensitive when fed a high fat diet
Systemic glucose clearance assessed by a glucose tolerance test (GTT) was significantly delayed in PemtϪ/Ϫ mice fed the HFHC diet compared with littermates on the high fat diet (HF) diet (Fig. 1A)
An intraperitoneal insulin tolerance test (ITT) showed that PemtϪ/Ϫ mice fed the HFHC diet were less insulin-sensitive compared with their littermates fed the HF diet (Fig. 1C), whereas the diet did not alter the ITT in Pemtϩ/ϩ mice (Fig. 1D)
Summary
Mice lacking phosphatidylethanolamine N-methyltransferase (PemtϪ/Ϫ) are glucose- and insulin-sensitive when fed a high fat diet. Results: Increased plasma glucagon and hepatic gluconeogenesis occurred in PemtϪ/Ϫ mice fed excess choline. Choline induces glucose and insulin intolerance in Pemt؊/؊ mice through modulating plasma glucagon and its action in liver. Despite the lack of PEMT, the levels of hepatic PC and phosphatidylethanolamine in PemtϪ/Ϫ mice remain unchanged when fed a chow diet [5]. We reported that PemtϪ/Ϫ mice are protected from high fat (HF) diet-induced obesity and insulin resistance [7] This protection was eliminated when excess choline was added to the HF diet, indicating a possible link between choline and obesity/ insulin resistance. We report that choline causes an increase in plasma glucagon which induces glucose and insulin intolerance in PemtϪ/Ϫ mice
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