Regulation of Substrate Oxidation Preferences in Muscle by the Peptide Hormone Adropin

  1. Andrew A. Butler1,6
  1. 1Department of Metabolism and Aging, Scripps Research Institute, Jupiter, FL, USA.
  2. 2Department of Human Nutrition, Foods and Exercise; Virginia Polytechnic Institute and State University, Blacksburg VA, USA
  3. 3Basic Sciences Department, Faculty of Medicine and Health Sciences, Universitat Internacional de Catalunya, Barcelona, Spain
  4. 4Department of Biochemistry and Molecular Biology and Centro de Investigación Biomédica en Red de la Fisiopatología de la Obesidad y Nutrición, Facultat de Farmàcia, Universitat de Barcelona, E-08028 Barcelona, Spain
  5. 5Department of Pediatrics, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada.
  6. 6Department of Pharmacological & Physiological Science, Saint Louis University School of Medicine, Saint Louis, Missouri 63104, USA
  1. Corresponding authors: Dr. Andrew A. Butler, Butleraa{at}Slu.Edu


Rigorous control of substrate oxidation by humoral factors is essential for maintaining metabolic homeostasis. Carbohydrate and fat are two primary substrates in oxidative metabolism during feeding and fasting cycles. Here, we report a novel role for the peptide hormone adropin in regulating substrate oxidation. Plasma levels of adropin rapidly increase with feeding and decrease upon fasting. A comparison of whole body substrate preference and skeletal muscle substrate oxidation in adropin knockout and transgenic mice suggest that adropin promotes carbohydrate oxidation over fat oxidation. In muscle, adropin activates pyruvate dehydrogenase (PDH), which is rate-limiting for glucose oxidation, and suppresses carnitine palmitoyltransferase-1B (CPT1B), a key enzyme in fatty acid oxidation. Adropin down regulates PDH-kinase-4 (PDK4), which inhibits PDH, thereby increasing PDH activity. The molecular mechanisms of adropin’s effects involve acetylation (suggesting inhibition) of the transcriptional co-activator PGC1α, down regulating expression of Cpt1b and Pdk4. Increased PGC1α acetylation by adropin may be mediated by inhibiting Sirtuin-1 (SIRT1), a PGC-1α deacetylase. Altered SIRT1 and PGC1α activity appear to mediate aspects of adropin’s metabolic actions in muscle. Similar outcomes were observed in fasted mice treated with synthetic adropin. Together, these results suggest a role for adropin in regulating muscle substrate preference under different nutritional states.

  • Received March 11, 2014.
  • Accepted May 5, 2014.

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