title: Paradoxical coupling of triglyceride synthesis and fatty acid oxidation in skeletal muscle overexpressing DGAT1.
abstract: OBJECTIVE
  Transgenic expression of diacylglycerol acyltransferase-1 (DGAT1) in skeletal muscle leads to protection against fat-induced insulin resistance despite accumulation of intramuscular triglyceride, a phenomenon similar to what is known as the "athlete paradox." The primary objective of this study is to determine how DGAT1 affects muscle fatty acid oxidation in relation to whole-body energy metabolism and insulin sensitivity.
  
  
  METHODS
  We first quantified insulin sensitivity and the relative tissue contributions to the improved whole-body insulin sensitivity in muscle creatine kisase (MCK)-DGAT1 transgenic mice by hyperinsulinemic-euglycemic clamps. Metabolic consequences of DGAT1 overexpression in skeletal muscles were determined by quantifying triglyceride synthesis/storage (anabolic) and fatty acid oxidation (catabolic), in conjunction with gene expression levels of representative marker genes in fatty acid metabolism. Whole-body energy metabolism including food consumption, body weights, oxygen consumption, locomotor activity, and respiration exchange ratios were determined at steady states.
  
  
  RESULTS
  MCK-DGAT1 mice were protected against muscle lipoptoxicity, although they remain susceptible to hepatic lipotoxicity. While augmenting triglyceride synthesis, DGAT1 overexpression also led to increased muscle mitochondrial fatty acid oxidation efficiency, as compared with wild-type muscles. On a high-fat diet, MCK-DGAT1 mice displayed higher basal metabolic rates and 5-10% lower body weights compared with wild-type littermates, whereas food consumption was not different.
  
  
  CONCLUSIONS
  DGAT1 overexpression in skeletal muscle led to parallel increases in triglyceride synthesis and fatty acid oxidation. Seemingly paradoxical, this phenomenon is characteristic of insulin-sensitive myofibers and suggests that DGAT1 plays an active role in metabolic "remodeling" of skeletal muscle coupled with insulin sensitization.
authors.affiliation: Department of Medicine, Preventive Medicine and Nutrition, Columbia University, New York, New York, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Shi
authors.forename: Cheol Soo
authors.initials: CS
authors.lastname: Choi
authors.forename: Gerald I
authors.initials: GI
authors.lastname: Shulman
authors.forename: Katherine
authors.initials: K
authors.lastname: Klaus
authors.forename: K Sreekumaran
authors.initials: KS
authors.lastname: Nair
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Schwartz
authors.forename: Yiying
authors.initials: Y
authors.lastname: Zhang
authors.forename: Ira J
authors.initials: IJ
authors.lastname: Goldberg
authors.forename: Yi-Hao
authors.initials: YH
authors.lastname: Yu
mesh_terms: D015094:3-Hydroxyacyl CoA Dehydrogenases / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002334:Carnitine O-Palmitoyltransferase / Q000378:metabolism; D002950:Citrate (si)-Synthase / Q000378:metabolism; D052283:Creatine Kinase, MM Form / Q000235:genetics / Q000378:metabolism; D004272:DNA, Mitochondrial / Q000235:genetics; D051048:Diacylglycerol O-Acyltransferase / Q000235:genetics* / Q000378:metabolism; D004041:Dietary Fats / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism*; D005786:Gene Expression Regulation; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D010084:Oxidation-Reduction; D010101:Oxygen Consumption; D015656:Respiratory Mechanics / Q000502:physiology; D014280:Triglycerides / Q000096:biosynthesis* / Q000378:metabolism
chemical_list: D004272:DNA, Mitochondrial; D004041:Dietary Fats; D005227:Fatty Acids; D014280:Triglycerides; D000255:Adenosine Triphosphate; D015094:3-Hydroxyacyl CoA Dehydrogenases; C494882:Dgat1 protein, mouse; D051048:Diacylglycerol O-Acyltransferase; D002334:Carnitine O-Palmitoyltransferase; D002950:Citrate (si)-Synthase; D052283:Creatine Kinase, MM Form
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