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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 (PGC1?) to maintain energy supply for locomotion and survival. At the whole-body level, these adaptations result in resistance to obesity.

SUBMITTER: Wicks SE 

PROVIDER: S-EPMC4485116 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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Impaired mitochondrial fat oxidation induces adaptive remodeling of muscle metabolism.

Wicks Shawna E SE   Vandanmagsar Bolormaa B   Haynie Kimberly R KR   Fuller Scott E SE   Warfel Jaycob D JD   Stephens Jacqueline M JM   Wang Miao M   Han Xianlin X   Zhang Jingying J   Noland Robert C RC   Mynatt Randall L RL  

Proceedings of the National Academy of Sciences of the United States of America 20150608 25


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 nonest  ...[more]

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