title: Choline supplementation promotes hepatic insulin resistance in phosphatidylethanolamine N-methyltransferase-deficient mice via increased glucagon action.
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.
authors.affiliation: Group on the Molecular and Cell Biology of Lipids and Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada T6G 2S2.
authors.forename: Gengshu
authors.initials: G
authors.lastname: Wu
authors.forename: Liyan
authors.initials: L
authors.lastname: Zhang
authors.forename: Tete
authors.initials: T
authors.lastname: Li
authors.forename: Azeret
authors.initials: A
authors.lastname: Zuniga
authors.forename: Gary D
authors.initials: GD
authors.lastname: Lopaschuk
authors.forename: Liang
authors.initials: L
authors.lastname: Li
authors.forename: René L
authors.initials: RL
authors.lastname: Jacobs
authors.forename: Dennis E
authors.initials: DE
authors.lastname: Vance
mesh_terms: D000818:Animals; D001483:Base Sequence; D002794:Choline / Q000008:administration & dosage* / Q000494:pharmacology; D017931:DNA Primers; D005934:Glucagon / Q000502:physiology*; D005943:Gluconeogenesis / Q000187:drug effects; D005951:Glucose Tolerance Test; D007333:Insulin Resistance; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D050918:Phosphatidylethanolamine N-Methyltransferase / Q000235:genetics / Q000378:metabolism*
chemical_list: D017931:DNA Primers; D005934:Glucagon; D050918:Phosphatidylethanolamine N-Methyltransferase; D002794:Choline