Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 109, Issue 17, Pages 6739-6744Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1121060109
Keywords
fat; mitochondria; myocyte; zinc finger
Categories
Funding
- NIH [HL086614, HL072952, HL084154, P30HL101294, HL094660, F32HL110538, T32HL105338, RC2AR058962-01, U24 DK059637, P60 DK020593]
- Missouri Life Sciences Research Board
- Australian Government National Health and Medical Research Council
- Genome and Transcriptome Sequencing Core at Case Western Reserve University
- Visconsi Research Scholar Fund
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The ability of skeletal muscle to enhance lipid utilization during exercise is a form of metabolic plasticity essential for survival. Conversely, metabolic inflexibility in muscle can cause organ dysfunction and disease. Although the transcription factor Kruppel-like factor 15 (KLF15) is an important regulator of glucose and amino acid metabolism, its endogenous role in lipid homeostasis and muscle physiology is unknown. Here we demonstrate that KLF15 is essential for skeletal muscle lipid utilization and physiologic performance. KLF15 directly regulates a broad transcriptional program spanning all major segments of the lipid-flux pathway in muscle. Consequently, Klf15-deficient mice have abnormal lipid and energy flux, excessive reliance on carbohydrate fuels, exaggerated muscle fatigue, and impaired endurance exercise capacity. Elucidation of this heretofore unrecognized role for KLF15 now implicates this factor as a central component of the transcriptional circuitry that coordinates physiologic flux of all three basic cellular nutrients: glucose, amino acids, and lipids.
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