Regulation of substrate oxidation preferences in muscle by the peptide hormone adropin

Diabetes. 2014 Oct;63(10):3242-52. doi: 10.2337/db14-0388. Epub 2014 May 21.


Rigorous control of substrate oxidation by humoral factors is essential for maintaining metabolic homeostasis. During feeding and fasting cycles, carbohydrates and fatty acids are the two primary substrates in oxidative metabolism. Here, we report a novel role for the peptide hormone adropin in regulating substrate oxidation preferences. Plasma levels of adropin 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 suggests 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 (CPT-1B), a key enzyme in fatty acid oxidation. Adropin downregulates PDH kinase-4 (PDK4) that inhibits PDH, thereby increasing PDH activity. The molecular mechanisms of adropin's effects involve acetylation (suggesting inhibition) of the transcriptional coactivator PGC-1α, downregulating expression of Cpt1b and Pdk4. Increased PGC-1α acetylation by adropin may be mediated by inhibiting Sirtuin-1 (SIRT1), a PGC-1α deacetylase. Altered SIRT1 and PGC-1α 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 various nutritional states.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carnitine O-Palmitoyltransferase / genetics
  • Carnitine O-Palmitoyltransferase / metabolism
  • Fasting / metabolism*
  • Fatty Acids / metabolism*
  • Intercellular Signaling Peptides and Proteins
  • Male
  • Mice
  • Mice, Knockout
  • Muscle, Skeletal / metabolism*
  • Oxidation-Reduction
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Phosphorylation
  • Proteins / genetics
  • Proteins / metabolism*
  • Sirtuin 1 / genetics
  • Sirtuin 1 / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism


  • Enho protein, mouse
  • Fatty Acids
  • Intercellular Signaling Peptides and Proteins
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Ppargc1a protein, mouse
  • Proteins
  • Transcription Factors
  • Carnitine O-Palmitoyltransferase
  • Sirt1 protein, mouse
  • Sirtuin 1