title: Skeletal Muscle Phospholipid Metabolism Regulates Insulin Sensitivity and Contractile Function.
abstract: Skeletal muscle insulin resistance is an early defect in the development of type 2 diabetes. Lipid overload induces insulin resistance in muscle and alters the composition of the sarcoplasmic reticulum (SR). To test the hypothesis that skeletal muscle phospholipid metabolism regulates systemic glucose metabolism, we perturbed choline/ethanolamine phosphotransferase 1 (CEPT1), the terminal enzyme in the Kennedy pathway of phospholipid synthesis. In C2C12 cells, CEPT1 knockdown altered SR phospholipid composition and calcium flux. In mice, diet-induced obesity, which decreases insulin sensitivity, increased muscle CEPT1 expression. In high-fat diet-fed mice with skeletal muscle-specific knockout of CEPT1, systemic and muscle-based approaches demonstrated increased muscle insulin sensitivity. In CEPT1-deficient muscles, an altered SR phospholipid milieu decreased sarco/endoplasmic reticulum Ca(2+) ATPase-dependent calcium uptake, activating calcium-signaling pathways known to improve insulin sensitivity. Altered muscle SR calcium handling also rendered these mice exercise intolerant. In obese humans, surgery-induced weight loss increased insulin sensitivity and decreased skeletal muscle CEPT1 protein. In obese humans spanning a spectrum of metabolic health, muscle CEPT1 mRNA was inversely correlated with insulin sensitivity. These results suggest that high-fat feeding and obesity induce CEPT1, which remodels the SR to preserve contractile function at the expense of insulin sensitivity.
authors.affiliation: Division of Endocrinology, Metabolism and Lipid Research, Washington University in St. Louis School of Medicine, St. Louis, MO Departments of Kinesiology and Physiology, East Carolina University, Greenville, NC.
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Funai
authors.affiliation: Division of Endocrinology, Metabolism and Lipid Research, Washington University in St. Louis School of Medicine, St. Louis, MO.
authors.forename: Irfan J
authors.initials: IJ
authors.lastname: Lodhi
authors.affiliation: Division of Endocrinology, Metabolism and Lipid Research, Washington University in St. Louis School of Medicine, St. Louis, MO.
authors.forename: Larry D
authors.initials: LD
authors.lastname: Spears
authors.affiliation: Division of Endocrinology, Metabolism and Lipid Research, Washington University in St. Louis School of Medicine, St. Louis, MO.
authors.forename: Li
authors.initials: L
authors.lastname: Yin
authors.affiliation: Division of Endocrinology, Metabolism and Lipid Research, Washington University in St. Louis School of Medicine, St. Louis, MO.
authors.forename: Haowei
authors.initials: H
authors.lastname: Song
authors.affiliation: Division of Geriatrics and Nutritional Science, Washington University in St. Louis School of Medicine, St. Louis, MO.
authors.forename: Samuel
authors.initials: S
authors.lastname: Klein
authors.affiliation: Division of Endocrinology, Metabolism and Lipid Research, Washington University in St. Louis School of Medicine, St. Louis, MO Department of Cell Biology and Physiology, Washington University in St. Louis School of Medicine, St. Louis, MO csemenko@dom.wustl.edu.
authors.forename: Clay F
authors.initials: CF
authors.lastname: Semenkovich
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000503:physiopathology*; D055785:Gene Knockdown Techniques; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007333:Insulin Resistance / Q000502:physiology*; D050155:Lipogenesis; D051379:Mice; D008810:Mice, Inbred C57BL; D009119:Muscle Contraction / Q000187:drug effects*; D018482:Muscle, Skeletal / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism; D010743:Phospholipids / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000187:drug effects; D017855:Transferases (Other Substituted Phosphate Groups) / Q000235:genetics / Q000378:metabolism*
chemical_list: D010743:Phospholipids; D012333:RNA, Messenger; D017855:Transferases (Other Substituted Phosphate Groups); C119514:choline-ethanolaminephosphotransferase; D005947:Glucose; D002118:Calcium