title: Genetic and Pharmacological Inhibition of Malonyl CoA Decarboxylase Does Not Exacerbate Age-Related Insulin Resistance in Mice.
abstract: Aging is associated with the development of chronic diseases such as insulin resistance and type 2 diabetes. A reduction in mitochondrial fat oxidation is postulated to be a key factor contributing to the progression of these diseases. Our aim was to investigate the contribution of impaired mitochondrial fat oxidation toward age-related disease. Mice deficient for malonyl CoA decarboxylase (MCD(-/-)), a mouse model of reduced fat oxidation, were allowed to age while life span and a number of physiological parameters (glucose tolerance, insulin tolerance, indirect calorimetry) were assessed. Decreased fat oxidation in MCD(-/-) mice resulted in the accumulation of lipid intermediates in peripheral tissues, but this was not associated with a worsening of age-associated insulin resistance and, conversely, improved longevity. This improvement was associated with reduced oxidative stress and reduced acetylation of the antioxidant enzyme superoxide dismutase 2 in muscle but not the liver of MCD(-/-) mice. These findings were recapitulated in aged mice treated with an MCD inhibitor (CBM-3001106), and these mice also demonstrated improvements in glucose and insulin tolerance. Therefore, our results demonstrate that in addition to decreasing fat oxidation, MCD inhibition also has novel effects on protein acetylation. These combined effects protect against age-related metabolic dysfunction, demonstrating that MCD inhibitors may have utility in the battle against chronic disease in the elderly.
authors.affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Canada Alberta Diabetes Institute, University of Alberta, Edmonton, Canada.
authors.forename: John R
authors.initials: JR
authors.lastname: Ussher
authors.affiliation: Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Canada Alberta Diabetes Institute, University of Alberta, Edmonton, Canada.
authors.forename: Natasha
authors.initials: N
authors.lastname: Fillmore
authors.affiliation: Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Canada Alberta Diabetes Institute, University of Alberta, Edmonton, Canada.
authors.forename: Wendy
authors.initials: W
authors.lastname: Keung
authors.affiliation: Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Canada Alberta Diabetes Institute, University of Alberta, Edmonton, Canada.
authors.forename: Liyan
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Canada Alberta Diabetes Institute, University of Alberta, Edmonton, Canada.
authors.forename: Jun
authors.initials: J
authors.lastname: Mori
authors.affiliation: Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Canada Alberta Diabetes Institute, University of Alberta, Edmonton, Canada.
authors.forename: Vaninder K
authors.initials: VK
authors.lastname: Sidhu
authors.affiliation: Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Canada Alberta Diabetes Institute, University of Alberta, Edmonton, Canada.
authors.forename: Arata
authors.initials: A
authors.lastname: Fukushima
authors.affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Canada Alberta Diabetes Institute, University of Alberta, Edmonton, Canada.
authors.forename: Keshav
authors.initials: K
authors.lastname: Gopal
authors.affiliation: Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Canada Alberta Diabetes Institute, University of Alberta, Edmonton, Canada.
authors.forename: David G
authors.initials: DG
authors.lastname: Lopaschuk
authors.affiliation: Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Canada Alberta Diabetes Institute, University of Alberta, Edmonton, Canada.
authors.forename: Cory S
authors.initials: CS
authors.lastname: Wagg
authors.affiliation: Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Canada Alberta Diabetes Institute, University of Alberta, Edmonton, Canada.
authors.forename: Jagdip S
authors.initials: JS
authors.lastname: Jaswal
authors.affiliation: Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Canada Alberta Diabetes Institute, University of Alberta, Edmonton, Canada.
authors.forename: Jason R B
authors.initials: JR
authors.lastname: Dyck
authors.affiliation: Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Canada Alberta Diabetes Institute, University of Alberta, Edmonton, Canada gary.lopaschuk@ualberta.ca.
authors.forename: Gary D
authors.initials: GD
authors.lastname: Lopaschuk
mesh_terms: D000375:Aging / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002153:Calorimetry, Indirect; D002262:Carboxy-Lyases / Q000037:antagonists & inhibitors / Q000235:genetics*; D004075:Diglycerides / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D018149:Glucose Intolerance / Q000235:genetics* / Q000378:metabolism; D005951:Glucose Tolerance Test; D007333:Insulin Resistance / Q000235:genetics*; D015227:Lipid Peroxidation / Q000187:drug effects / Q000235:genetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008136:Longevity / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics*; D010101:Oxygen Consumption / Q000235:genetics*; D010671:Phenylurea Compounds / Q000494:pharmacology; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism; D000099156:Superoxide Dismutase 2
chemical_list: D002262:Carboxy-Lyases; D004075:Diglycerides; D005947:Glucose; D010671:Phenylurea Compounds; D013482:Superoxide Dismutase; D014280:Triglycerides; D000099156:Superoxide Dismutase 2; C509702:methyl 5-(N-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl)morpholine-4-carboxamido)pentanoate; C021532:malonyl-CoA decarboxylase