title: Impaired mitochondrial fat oxidation induces adaptive remodeling of muscle metabolism.
abstract: The correlations between intramyocellular lipid (IMCL), decreased fatty acid oxidation (FAO), and insulin resistance have led to the hypothesis that impaired FAO causes accumulation of lipotoxic intermediates that inhibit muscle insulin signaling. Using a skeletal muscle-specific carnitine palmitoyltransferase-1 KO model, we show that prolonged and severe mitochondrial FAO inhibition results in increased carbohydrate utilization, along with reduced physical activity; increased circulating nonesterified fatty acids; and increased IMCLs, diacylglycerols, and ceramides. Perhaps more importantly, inhibition of mitochondrial FAO also initiates a local, adaptive response in muscle that invokes mitochondrial biogenesis, compensatory peroxisomal fat oxidation, and amino acid catabolism. Loss of its major fuel source (lipid) induces an energy deprivation response in muscle coordinated by signaling through AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) to maintain energy supply for locomotion and survival. At the whole-body level, these adaptations result in resistance to obesity.
authors.affiliation: Gene Nutrient Interactions Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA 70808;
authors.forename: Shawna E
authors.initials: SE
authors.lastname: Wicks
authors.affiliation: Gene Nutrient Interactions Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA 70808;
authors.forename: Bolormaa
authors.initials: B
authors.lastname: Vandanmagsar
authors.affiliation: Gene Nutrient Interactions Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA 70808;
authors.forename: Kimberly R
authors.initials: KR
authors.lastname: Haynie
authors.affiliation: Adipocyte Biology Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA 70808;
authors.forename: Scott E
authors.initials: SE
authors.lastname: Fuller
authors.affiliation: Gene Nutrient Interactions Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA 70808;
authors.forename: Jaycob D
authors.initials: JD
authors.lastname: Warfel
authors.affiliation: Adipocyte Biology Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA 70808;
authors.forename: Jacqueline M
authors.initials: JM
authors.lastname: Stephens
authors.affiliation: Sanford-Burnham Medical Research Institute, Orlando, FL 32827;
authors.forename: Miao
authors.initials: M
authors.lastname: Wang
authors.affiliation: Sanford-Burnham Medical Research Institute, Orlando, FL 32827;
authors.forename: Xianlin
authors.initials: X
authors.lastname: Han
authors.affiliation: Transgenic Core Facility, Pennington Biomedical Research Center, Baton Rouge, LA 70808;
authors.forename: Jingying
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Skeletal Muscle Metabolism Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA 70808.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Noland
authors.affiliation: Gene Nutrient Interactions Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA 70808; Transgenic Core Facility, Pennington Biomedical Research Center, Baton Rouge, LA 70808; randall.mynatt@pbrc.edu.
authors.forename: Randall L
authors.initials: RL
authors.lastname: Mynatt
mesh_terms: D000222:Adaptation, Physiological; D000818:Animals; D002334:Carnitine O-Palmitoyltransferase / Q000235:genetics / Q000378:metabolism; D005230:Fatty Acids, Nonesterified / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008931:Mitochondria, Muscle / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000502:physiology; D010084:Oxidation-Reduction
chemical_list: D005230:Fatty Acids, Nonesterified; D002334:Carnitine O-Palmitoyltransferase
keywords: carbohydrate; carnitine palmitoyltransferase; fatty acid; lipid; muscle