title: Muscle expression of a malonyl-CoA-insensitive carnitine palmitoyltransferase-1 protects mice against high-fat/high-sucrose diet-induced insulin resistance.
abstract: Impaired skeletal muscle mitochondrial fatty acid oxidation (mFAO) has been implicated in the etiology of insulin resistance. Carnitine palmitoyltransferase-1 (CPT1) is a key regulatory enzyme of mFAO whose activity is inhibited by malonyl-CoA, a lipogenic intermediate. Whereas increasing CPT1 activity in vitro has been shown to exert a protective effect against lipid-induced insulin resistance in skeletal muscle cells, only a few studies have addressed this issue in vivo. We thus examined whether a direct modulation of muscle CPT1/malonyl-CoA partnership is detrimental or beneficial for insulin sensitivity in the context of diet-induced obesity. By using a Cre-LoxP recombination approach, we generated mice with skeletal muscle-specific and inducible expression of a mutated CPT1 form (CPT1mt) that is active but insensitive to malonyl-CoA inhibition. When fed control chow, homozygous CPT1mt transgenic (dbTg) mice exhibited decreased CPT1 sensitivity to malonyl-CoA inhibition in isolated muscle mitochondria, which was sufficient to substantially increase ex vivo muscle mFAO capacity and whole body fatty acid utilization in vivo. Moreover, dbTg mice were less prone to high-fat/high-sucrose (HFHS) diet-induced insulin resistance and muscle lipotoxicity despite similar body weight gain, adiposity, and muscle malonyl-CoA content. Interestingly, these CPT1mt-protective effects in dbTg-HFHS mice were associated with preserved muscle insulin signaling, increased muscle glycogen content, and upregulation of key genes involved in muscle glucose metabolism. These beneficial effects of muscle CPT1mt expression suggest that a direct modulation of the malonyl-CoA/CPT1 partnership in skeletal muscle could represent a potential strategy to prevent obesity-induced insulin resistance.
authors: Institut National de la Santé et de la Recherche Médicale, U1016, Institut Cochin, Paris, France; Centre National de la Recherche Scientifique, UMR8104, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Université Paris Diderot, Paris, France;
authors: Eliska
authors: E
authors: Vavrova
authors: Institut National de la Santé et de la Recherche Médicale, U1016, Institut Cochin, Paris, France; Centre National de la Recherche Scientifique, UMR8104, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France;
authors: Véronique
authors: V
authors: Lenoir
authors: Institut National de la Santé et de la Recherche Médicale, U1016, Institut Cochin, Paris, France; Centre National de la Recherche Scientifique, UMR8104, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France;
authors: Marie-Clotilde
authors: MC
authors: Alves-Guerra
authors: Université Paris Diderot, Sorbonne Paris Cité, Unité de Biologie Fonctionnelle et Adaptative, Centre National de la Recherche Scientifique UMR8251, Paris, France;
authors: Raphaël G
authors: RG
authors: Denis
authors: Université Paris Diderot, Sorbonne Paris Cité, Unité de Biologie Fonctionnelle et Adaptative, Centre National de la Recherche Scientifique UMR8251, Paris, France;
authors: Julien
authors: J
authors: Castel
authors: Institut National de la Santé et de la Recherche Médicale, U1016, Institut Cochin, Paris, France; Centre National de la Recherche Scientifique, UMR8104, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France;
authors: Catherine
authors: C
authors: Esnous
authors: Cardiovascular Research Centre, Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada;
authors: Jason R B
authors: JR
authors: Dyck
authors: Université Paris Diderot, Sorbonne Paris Cité, Unité de Biologie Fonctionnelle et Adaptative, Centre National de la Recherche Scientifique UMR8251, Paris, France;
authors: Serge
authors: S
authors: Luquet
authors: Institut de Génétique et de Biologie Moléculaire et Cellulaire, Institut National de la Santé et de la Recherche Médicale, U964, Centre National de la Recherche Scientifique, UMR7104, Université de Strasbourg, Illkirch, France.
authors: Daniel
authors: D
authors: Metzger
authors: Institut National de la Santé et de la Recherche Médicale, U1016, Institut Cochin, Paris, France; Centre National de la Recherche Scientifique, UMR8104, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France;
authors: Frédéric
authors: F
authors: Bouillaud
authors: Institut National de la Santé et de la Recherche Médicale, U1016, Institut Cochin, Paris, France; Centre National de la Recherche Scientifique, UMR8104, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France; carina.prip-buus@inserm.fr.
authors: Carina
authors: 0000-0002-2153-7857
authors: C
authors: Prip-Buus
mesh_terms: D000818:Animals; D002334:Carnitine O-Palmitoyltransferase / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D059305:Diet, High-Fat / Q000009:adverse effects*; D019422:Dietary Sucrose / Q000009:adverse effects*; D004734:Energy Metabolism / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D007333:Insulin Resistance; D008297:Male; D008316:Malonyl Coenzyme A / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008931:Mitochondria, Muscle / Q000187:drug effects / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D009765:Obesity / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D019422:Dietary Sucrose; D008316:Malonyl Coenzyme A; C558401:CPT1B protein, mouse; D002334:Carnitine O-Palmitoyltransferase; D005947:Glucose
keywords: fatty acid oxidation; glucose homeostasis; mitochondria; obesity