title: Sexual dimorphism of lipid metabolism in very long-chain acyl-CoA dehydrogenase deficient (VLCAD-/-) mice in response to medium-chain triglycerides (MCT).
abstract: Medium-chain triglycerides (MCT) are widely applied in the treatment of long-chain fatty acid oxidation disorders. Previously it was shown that long-term MCT supplementation strongly affects lipid metabolism in mice. We here investigate sex-specific effects in mice with very-long-chain-acyl-CoA dehydrogenase (VLCAD) deficiency in response to a long-term MCT modified diet. We quantified blood lipids, acylcarnitines, glucose, insulin and free fatty acids, as well as tissue triglycerides in the liver and skeletal muscle under a control and an MCT diet over 1 year. In addition, visceral and hepatic fat content and muscular intramyocellular lipids (IMCL) were assessed by in vivo(1)H magnetic resonance spectroscopy (MRS) techniques. The long-term application of an MCT diet induced a marked alteration of glucose homeostasis. However, only VLCAD-/- female mice developed a severe metabolic syndrome characterized by marked insulin resistance, dyslipidemia, severe hepatic and visceral steatosis, whereas VLCAD-/- males seemed to be protected and only presented with milder insulin resistance. Moreover, the highly saturated MCT diet is associated with a decreased hepatic stearoyl-CoA desaturase 1 (SCD1) activity in females aggravating the harmful effects of a saturated MCT diet. Long-term MCT supplementation deeply affects lipid metabolism in a sexual dimorphic manner resulting in a severe metabolic syndrome only in female mice. These findings are striking since the first signs of insulin resistance already occur in female VLCAD-/- mice during their reproductive period. How these metabolic adaptations are finally regulated needs to be determined. More important, the relevance of these findings for humans under these dietary modifications needs to be investigated.
authors.affiliation: Department of General Pediatrics, Center for Pediatrics and Adolescent Medicine, University Hospital Freiburg, 79106 Freiburg, Germany. Electronic address: sara.tucci@uniklinik-freiburg.de.
authors.forename: Sara
authors.initials: S
authors.lastname: Tucci
authors.affiliation: Department of Molecular Cardiology, Heinrich-Heine-University Duesseldorf, 40225 Düsseldorf, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Flögel
authors.affiliation: Department of General Pediatrics, Center for Pediatrics and Adolescent Medicine, University Hospital Freiburg, 79106 Freiburg, Germany.
authors.forename: Ute
authors.initials: U
authors.lastname: Spiekerkoetter
mesh_terms: D044942:Acyl-CoA Dehydrogenase, Long-Chain / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D059305:Diet, High-Fat / Q000009:adverse effects*; D005260:Female; D050356:Lipid Metabolism; D008297:Male; D024821:Metabolic Syndrome / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D012737:Sex Factors; D013230:Stearoyl-CoA Desaturase / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism
chemical_list: D014280:Triglycerides; C490333:Scd1 protein, mouse; D013230:Stearoyl-CoA Desaturase; D044942:Acyl-CoA Dehydrogenase, Long-Chain
keywords: MCT supplementation; Metabolic syndrome; Sexual dimorphism; VLCAD-deficiency