Abstract
The peptide hormone adropin regulates energy metabolism in skeletal muscle and plays important roles in the regulation of metabolic homeostasis. Besides muscle, the liver has an essential role in regulating glucose homeostasis. Previous studies have reported that treatment of diet-induced obese (DIO) male mice with adropin34-76 (the putative secreted domain) reduces fasting blood glucose independently of body weight changes, suggesting that adropin suppresses glucose production in the liver. Here, we explored the molecular mechanisms underlying adropin's effects on hepatic glucose metabolism in DIO mice. Male DIO B6 mice maintained on a high-fat diet received five intraperitoneal injections of adropin34-76 (450 nmol/kg/injection) over a 48-h period. We found that adropin34-76 enhances major intracellular signaling activities in the liver that are involved in insulin-mediated regulation of glucose homeostasis. Moreover, treatment with adropin34-76 alleviated endoplasmic reticulum stress responses and reduced activity of c-Jun N-terminal kinase in the liver, explaining the enhanced activities of hepatic insulin signaling pathways observed with adropin34-76 treatment. Furthermore, adropin34-76 suppressed cAMP activated protein kinase A (PKA) activities, resulting in reduced phosphorylation of inositol trisphosphate receptor, which mediates endoplasmic reticulum calcium efflux, and of cAMP-responsive element-binding protein, a key transcription factor in hepatic regulation of glucose metabolism. Adropin34-76 directly affected liver metabolism, decreasing glucose production and reducing PKA-mediated phosphorylation in primary mouse hepatocytes in vitro Our findings indicate that major hepatic signaling pathways contribute to the improved glycemic control achieved with adropin34-76 treatment in situations of obesity.
Highlights
The peptide hormone adropin regulates energy metabolism in skeletal muscle and plays important roles in the regulation of metabolic homeostasis
We found that adropin[34–76] enhances major intracellular signaling activities in the liver that are involved in insulin-mediated regulation of glucose homeostasis
Increased Ser[307] phosphorylation of insulin receptor substrate 1 (IRS1) that is frequently observed in B6 mice fed high-fat diet (HFD) (Fig. S2A) (7, 16) was markedly reduced by adropin[34–76] treatment (Fig. 1A)
Summary
B6, C57BL/6J; PKA, protein kinase A; IP3R, inositol-1,4,5-triphosphate receptor; JNK, c-Jun N-terminal kinase; G6Pase, glucose-6-phosphatase; PEPCK, phosphoenolpyruvate carboxykinase; ER, endoplasmic reticulum; AdrKO, adropin knockout; HFD, high fat diet; DIO, diet-induced obese; GPCR, G protein– coupled receptor; IRS, insulin receptor substrate; GSK, glycogen synthase kinase; PC, pyruvate carboxylase; PERK, PKR-like ER kinase; IRE, inositol-requiring enzyme; ATF, activating transcription factor; eIF, eukaryotic initiation factor; BiP, binding immunoglobulin protein; IKK, inhibitor B kinase; TAG, triacylglycerol; SREBP, sterol regulatory element– binding protein; CREB, cAMP-responsive elementbinding protein; GK, glucokinase; CRTC, CREB-regulated transcription coactivator; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; XBP1s, spliced form of X-box– binding protein 1. Treatment of diet-induced obese (DIO) B6 mice with the putative secreted domain of adropin, adropin[34–76], improves glucose tolerance as well as wholebody insulin sensitivity (3, 6). These responses are accounted for at least in part by adropin’s enhancement of the insulin intracellular signaling pathway in skeletal muscle (6). We have reported that adropin[34–76] treatment reduced fasting hyperglycemia and hyperinsulinemia in diabetic DIO mice (3), indicating that adropin treatment improves hepatic glucose metabolism and may enhance insulin’s hepatic intracellular signaling actions in obesity. We explored the effect of adropin on cAMP-dependent signaling pathways in the liver
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