Regulation of substrate oxidation preferences in muscle by the peptide hormone adropin.
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.
Department of Metabolism and Aging, Scripps Research Institute, Jupiter, FL.
Su
S
Gao
Department of Human Nutrition, Foods and Exercise, Virginia Polytechnic Institute and State University, Blacksburg, VA.
Ryan P
RP
McMillan
Basic Sciences Department, Faculty of Medicine and Health Sciences, Universitat Internacional de Catalunya, Barcelona, Spain.
Jordi
J
Jacas
Department of Metabolism and Aging, Scripps Research Institute, Jupiter, FL.
Qingzhang
Q
Zhu
Department of Metabolism and Aging, Scripps Research Institute, Jupiter, FL.
Xuesen
X
Li
Department of Metabolism and Aging, Scripps Research Institute, Jupiter, FL.
Ganesh K
GK
Kumar
Basic Sciences Department, Faculty of Medicine and Health Sciences, Universitat Internacional de Catalunya, Barcelona, Spain Department 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, Barcelona, Spain.
Núria
N
Casals
Department 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, Barcelona, Spain.
Fausto G
FG
Hegardt
Department of Metabolism and Aging, Scripps Research Institute, Jupiter, FL.
Paul D
PD
Robbins
Department of Pediatrics, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada.
Gary D
GD
Lopaschuk
Department of Human Nutrition, Foods and Exercise, Virginia Polytechnic Institute and State University, Blacksburg, VA.
Matthew W
MW
Hulver
Department of Metabolism and Aging, Scripps Research Institute, Jupiter, FL Department of Pharmacological & Physiological Science, Saint Louis University School of Medicine, St. Louis, MO butleraa@slu.edu.
Andrew A
AA
Butler
D000818:Animals; D002334:Carnitine O-Palmitoyltransferase / Q000235:genetics / Q000378:metabolism; D005215:Fasting / Q000378:metabolism*; D005227:Fatty Acids / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000378:metabolism*; D010084:Oxidation-Reduction; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010766:Phosphorylation; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
C534289:Enho protein, mouse; D005227:Fatty Acids; D036341:Intercellular Signaling Peptides and Proteins; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D011506:Proteins; D014157:Transcription Factors; D002334:Carnitine O-Palmitoyltransferase; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1