Adaptations to excess choline in insulin resistant andPcyt2deficient skeletal muscle

Abstract

It was hypothesized that choline supplementation in insulin resistant (IR) CTP:phosphoethanolamine cytidylyltransferase deficient (Pcyt2) mice would ameliorate muscle function by remodeling glucose and fatty acid (FA) metabolism. Pcyt2 mice either received no treatment or were allowed access to 2 mg/mL choline in drinking water for 4 weeks. Skeletal muscle was harvested from choline treated and untreated mice. Lipid analysis and metabolic gene expression and signaling pathways were compared between untreated Pcyt2 mice, treated Pcyt2 mice, and Pcyt2 mice. The major positive effect of choline supplementation on IR muscle was the reduction of glucose utilization for FA and triglyceride (TAG) synthesis and increased muscle glucose storage as glycogen. Choline reduced the expression of genes for FA and TAG formation (Scd1, Fas, Srebp1c, Dgat1/2), upregulated the genes for FA oxidation (Cpt1, Pparα, Pgc1α), and had minor effects on phospholipid and lipolysis genes. Pcyt2 muscle had reduced insulin signaling (IRS1), autophagy (LC3), and choline transport (CTL1) proteins that were restored by choline treatment. Additionally, choline activated AMPK and Akt while inhibiting mTORC1 phosphorylation. These data established that choline supplementation could restore muscle glucose metabolism by reducing lipogenesis and improving mitochondrial and intracellular signaling for protein and energy metabolism in insulin resistant Pcyt2 deficient mice.

Choline transport for phospholipid synthesis: An emerging role of choline transporter-like protein 1

“…47 In mice lacking one allele of CTP: phosphoethanolamine cytidylyl transferase (Pcyt2 þ/À mice), choline supplementation was able to restore lipid metabolism and therefore alleviate the disturbances in glucose metabolism in the skeletal muscle of these mice. 48 Choline reduced triglyceride accumulation by decreasing fatty acid synthesis and lipogenesis in the muscle of these mice, increased fatty acid oxidation, and improved insulin signaling. In summary, these recent data show that choline is not only important for lipid metabolism in the liver, but that choline deficiency may alter phosphatidylcholine metabolism and in consequence all glycerolipid metabolism in muscle cells.…”

Betaine and Choline Improve Lipid Homeostasis in Obesity by Participation in Mitochondrial Oxidative Demethylation

“…This mouse is unable to efficiently synthesize PE from ethanolamine and diacylglycerol, which causes a homeostatic shift toward increased fatty acid/TAG synthesis and inhibited lipolysis/ fatty acid (FA) oxidation, resulting in NAFLD, insulin resistance, hypertriglyceridemia, and obesity ( 12 ). Cho administration to HET mice stimulates lipolysis and FA oxidation via PPARα and PGC-1α activation, thereby preventing disease development and weight gain ( 13 , 14 ). Cho increases PC remodeling but does not modify the PC and PE content or expression of liver and adipocyte phospholipid genes ( 13 ).…”

“…Cho increases PC remodeling but does not modify the PC and PE content or expression of liver and adipocyte phospholipid genes ( 13 ). Similarly, the positive effect of Cho on muscle FA/TAG metabolism is accompanied by the activation of AMPK and PI3K/Akt insulin signaling pathway and improvements in glucose stores in HET muscle ( 14 ).…”

Untitled

“…Methyl cinnamate is a safe antibacterial and flavouring agent used in food industry, and was shown to inhibit the gastrointestinal contractility [50], PPARγ activity and adipocyte differentiation in part, by the CaMKK2-AMPK signalling pathway [51]. Phenethylamine is widely used in weight-loss type of dietary supplements [52].…”

“…It has been demonstrated that choline supplementation in insulin resistant (IR) mice would ameliorate muscle function by remodelling glucose and fatty acid (FA) metabolism [52]. This will be achieved by the reduction of glucose utilization for FA and triglyceride (TAG) synthesis, and increased muscle storage of glucose as glycogen.…”