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

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-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.

First and third trimester serum concentrations of adropin and copeptin in gestational diabetes mellitus and normal pregnancy

“…Recently, a novel role for ADR was reported in promoting carbohydrate oxidation over fat oxidation in skeletal muscles [7]. Moreover, adropine's influence on expression of an inducible nitric oxide synthase was discovered [8], which can explain ADRs' potential role in prediction of endothelial dysfunction in patients with diabetes mellitus [9].…”

PGC-1α, glucose metabolism and type 2 diabetes mellitus

“…As described previously, PGC-1α activity is regulated by a variety of posttranslational modifications, especially by phosphorylation and acetylation. PGC-1α is involved in many signaling pathways that are critical to glucose storage and utilization, including AMPK , p38 MAPK (Hong et al 2011), and SIRT1 pathways (Gao et al 2014). Furthermore, a series of studies have shed light on the role of posttranslational modifications of PGC-1α in glucose metabolism.…”

Adropin induction of lipoprotein lipase expression in tilapia hepatocytes

“…In mammals, several observations suggest that adropin has a role in the regulation of energy homeostasis. In mice muscle, adropin has a significant role in regulating substrate oxidation during feeding and fasting cycles (Gao et al 2014). In dietinduced obese mice, transgenic overexpression adropin exhibit inhibition LPL genes expression in adipose tissue (Kumar et al 2008).…”