Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 112, Issue 25, Pages E3300-E3309Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1418560112
Keywords
carnitine palmitoyltransferase; muscle; fatty acid; lipid; carbohydrate
Categories
Funding
- Center of Biomedical Research Excellence (COBRE) (NIH Grant) [8P20-GM103528]
- Nutrition Obesity Research Center (NORC) (NIH) center grants from the National Institutes of Health [2P30-DK072476]
- American Diabetes Association [1-10-BS-129]
- NIH Grant [R01DK089641, R01DK103860]
- NORC (NIH Grant) [2P30-DK072476]
- COBRE grant (NIH) [9P20-GM103528]
- [T32 AT004094]
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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 alpha) to maintain energy supply for locomotion and survival. At the whole-body level, these adaptations result in resistance to obesity.
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