title: Chemical-genetic induction of Malonyl-CoA decarboxylase in skeletal muscle.
abstract: BACKGROUND
  Defects in skeletal muscle fatty acid oxidation have been implicated in the etiology of insulin resistance. Malonyl-CoA decarboxylase (MCD) has been a target of investigation because it reduces the concentration of malonyl-CoA, a metabolite that inhibits fatty acid oxidation. The in vivo role of muscle MCD expression in the development of insulin resistance remains unclear.
  
  
  RESULTS
  To determine the role of MCD in skeletal muscle of diet induced obese and insulin resistant mouse models we generated mice expressing a muscle specific transgene for MCD (Tg-fMCD(Skel)) stabilized posttranslationally by the small molecule, Shield-1. Tg-fMCD(Skel) and control mice were placed on either a high fat or low fat diet for 3.5 months. Obese and glucose intolerant as well as lean control Tg-fMCD(Skel) and nontransgenic control mice were treated with Shield-1 and changes in their body weight and insulin sensitivity were determined upon induction of MCD. Inducing MCD activity >5-fold in skeletal muscle over two weeks did not alter body weight or glucose intolerance of obese mice. MCD induction further potentiated the defects in insulin signaling of obese mice. In addition, key enzymes in fatty acid oxidation were suppressed following MCD induction.
  
  
  CONCLUSIONS
  Acute induction of MCD in the skeletal muscle of obese and glucose intolerant mice did not improve body weight and decreased insulin sensitivity compared to obese nontransgenic controls. Induction of MCD in skeletal muscle resulted in a suppression of mitochondrial oxidative genes suggesting a redundant and metabolite driven regulation of gene expression.
authors.forename: Susana
authors.initials: S
authors.lastname: Rodriguez
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Ellis
authors.affiliation: Department of Biological Chemistry, Center for Metabolism and Obesity Research, Johns Hopkins University School of Medicine, 725 N, Wolfe St,, 475 Rangos Building, Baltimore, Maryland 21205, USA. mwolfga1@jhmi.edu.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Wolfgang
mesh_terms: D000818:Animals; D001483:Base Sequence; D002262:Carboxy-Lyases / Q000378:metabolism*; D017931:DNA Primers; D005951:Glucose Tolerance Test; D007328:Insulin / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000201:enzymology*; D010084:Oxidation-Reduction; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction
chemical_list: D017931:DNA Primers; D007328:Insulin; D002262:Carboxy-Lyases; C021532:malonyl-CoA decarboxylase