title: Muscle-specific deletion of carnitine acetyltransferase compromises glucose tolerance and metabolic flexibility.
abstract: The concept of "metabolic inflexibility" was first introduced to describe the failure of insulin-resistant human subjects to appropriately adjust mitochondrial fuel selection in response to nutritional cues. This phenomenon has since gained increasing recognition as a core component of the metabolic syndrome, but the underlying mechanisms have remained elusive. Here, we identify an essential role for the mitochondrial matrix enzyme, carnitine acetyltransferase (CrAT), in regulating substrate switching and glucose tolerance. By converting acetyl-CoA to its membrane permeant acetylcarnitine ester, CrAT regulates mitochondrial and intracellular carbon trafficking. Studies in muscle-specific Crat knockout mice, primary human skeletal myocytes, and human subjects undergoing L-carnitine supplementation support a model wherein CrAT combats nutrient stress, promotes metabolic flexibility, and enhances insulin action by permitting mitochondrial efflux of excess acetyl moieties that otherwise inhibit key regulatory enzymes such as pyruvate dehydrogenase. These findings offer therapeutically relevant insights into the molecular basis of metabolic inflexibility.
authors.affiliation: Sarah W. Stedman Nutrition and Metabolism Center, Department of Medicine, Duke University, Durham, NC 27704, USA. muoio@duke.edu
authors.forename: Deborah M
authors.initials: DM
authors.lastname: Muoio
authors.forename: Robert C
authors.initials: RC
authors.lastname: Noland
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Kovalik
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Seiler
authors.forename: Michael N
authors.initials: MN
authors.lastname: Davies
authors.forename: Karen L
authors.initials: KL
authors.lastname: DeBalsi
authors.forename: Olga R
authors.initials: OR
authors.lastname: Ilkayeva
authors.forename: Robert D
authors.initials: RD
authors.lastname: Stevens
authors.forename: Indu
authors.initials: I
authors.lastname: Kheterpal
authors.forename: Jingying
authors.initials: J
authors.lastname: Zhang
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Covington
authors.forename: Sudip
authors.initials: S
authors.lastname: Bajpeyi
authors.forename: Eric
authors.initials: E
authors.lastname: Ravussin
authors.forename: William
authors.initials: W
authors.lastname: Kraus
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Koves
authors.forename: Randall L
authors.initials: RL
authors.lastname: Mynatt
mesh_terms: D000105:Acetyl Coenzyme A / Q000378:metabolism; D000108:Acetylcarnitine / Q000378:metabolism; D000818:Animals; D002244:Carbon / Q000378:metabolism; D002331:Carnitine / Q000031:analogs & derivatives / Q000378:metabolism; D002332:Carnitine O-Acetyltransferase / Q000172:deficiency* / Q000378:metabolism*; D002478:Cells, Cultured; D004734:Energy Metabolism; D005227:Fatty Acids / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D005951:Glucose Tolerance Test; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D018485:Muscle Fibers, Skeletal / Q000378:metabolism*
chemical_list: D005227:Fatty Acids; D007328:Insulin; C116917:acylcarnitine; D000108:Acetylcarnitine; D000105:Acetyl Coenzyme A; D002244:Carbon; D002332:Carnitine O-Acetyltransferase; D005947:Glucose; D002331:Carnitine