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

Su Gao, Ryan P. McMillan, Jordi Jacas, Qingzhang Zhu, Xuesen Li, Ganesh K. Kumar, Núria Casals, Fausto G. Hegardt, Paul D. Robbins, Gary D. Lopaschuk, Matthew W. Hulver, Andrew A. Butler

Research output: Contribution to journalArticle

41 Scopus citations

Abstract

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-1 B (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 (SIRT 1), a PGC1α 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.

Original languageEnglish (US)
Pages (from-to)3242-3252
Number of pages11
JournalDiabetes
Volume63
Issue number10
DOIs
StatePublished - Oct 1 2014
Externally publishedYes

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    Gao, S., McMillan, R. P., Jacas, J., Zhu, Q., Li, X., Kumar, G. K., Casals, N., Hegardt, F. G., Robbins, P. D., Lopaschuk, G. D., Hulver, M. W., & Butler, A. A. (2014). Regulation of substrate oxidation preferences in muscle by the peptide hormone adropin. Diabetes, 63(10), 3242-3252. https://doi.org/10.2337/db14-0388