Impaired mitochondrial fat oxidation induces adaptive remodeling of muscle metabolism

• Published in: Proceedings of the National Academy of Sciences - PNAS 2015-06, Vol.112 (25), p.E3300-E3309
• Main Authors: Wicks, Shawna E, Bolormaa Vandanmagsar, Kimberly R. Haynie, Scott E. Fuller, Jaycob D. Warfel, Jacqueline M. Stephens, Miao Wang, Xianlin Han, Jingying Zhang, Robert C. Noland, Randall L. Mynatt
• Format: Article
• Language: English
• Subjects: Adaptation, Physiological; Animals; beta oxidation; biogenesis; Biological Sciences; carbohydrate; Carnitine O-Palmitoyltransferase - genetics; Carnitine O-Palmitoyltransferase - metabolism; carnitine palmitoyltransferase; energy conservation; energy expenditure; fatty acid; Fatty acids; Fatty Acids, Nonesterified - metabolism; Food and Agriculture Organization; fuels; Insulin resistance; lipid; Lipids; Metabolism; Mice; Mice, Knockout; mitochondria; Mitochondria, Muscle - metabolism; muscle; Muscle, Skeletal - metabolism; Muscle, Skeletal - physiology; muscles; Muscular system; obesity; Oxidation; Oxidation-Reduction; phenotype; PNAS Plus; skeletal muscle
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1418560112

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. Significance Many theories regarding the causes of insulin resistance in skeletal muscle center on the ability of muscle to oxidize fat, with evidence supporting either decreased or increased fatty acid oxidation (FAO) as causal to insulin resistance. Inhibition of fatty acid transport into mitochondria specifically in mouse muscle results in a rather remarkable phenotype. Despite an accumulation of lipids in muscle, insulin sensitivity is maintained. The muscle responds to decreased FAO by adapting muscle metabolism to use other fuel sources, and by an increased reliance upon peroxisomal fat oxidation. There is also an increase in mitochondrial biogenesis. At the whole-body level, the mice seem to enter an energy conservation mode with reduced activity, energy expenditure, and resistance to diet-induced obesity.