Adropin inhibited tilapia hepatic glucose output and triglyceride accumulation via AMPK activation

in Journal of Endocrinology
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  • Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, China

Correspondence should be addressed to Q Jiang; jiangqua@gmail.com
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Adropin plays a role in the maintenance of energy homeostasis, insulin resistance prevention, and impaired glucose tolerance. However, the molecular mechanisms by which adropin affects hepatic glucose and lipid metabolism in vitro are not entirely understood. This study intended to examine the roles and underlying mechanisms of adropin in glucose and lipid metabolism in Nile tilapia. In primary cultured tilapia hepatocytes, adropin significantly attenuated oleic acid (OA)-induced glucose output and reduced the activities and mRNA expression of cytosolic phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase), which are involved in gluconeogenesis. In contrast, adropin facilitated glucose uptake activity via glucose transporter 1 (Glut1) upregulation in OA-treated hepatocytes. One-week of adropin treatment reduced the hepatic total lipid accumulation in OA-fed tilapia without changes in body weight. Subsequent studies revealed that adropin suppressed OA-induced intracellular triglyceride accumulation and decreased the expression of genes and proteins involved in lipid metabolisms such as sterol regulatory element-binding protein-1c (SREBP-1c), acetyl-CoA carboxylase α (ACCα) and CD36, but upregulated peroxisome proliferator-activated receptor α (PPARα) levels. In parallel studies, however, adropin had no detectable effects on fatty acid-binding protein 4 (Fabp4) and carnitine palmitoyltransferase 1α (Cpt1α) mRNA expression. Furthermore, adropin treatment dose-dependently increased the phosphorylation level of AMP-activated protein kinase (AMPK). Suppression of AMPK by compound C or AMPKα1 siRNA blocked adropin-induced decreases in the mature form of SREBP-1c expression, glucose output, and intracellular triglyceride content in OA-treated hepatocytes. These findings suggest that teleost adropin could suppress hepatic gluconeogenesis and triglyceride accumulation via a mechanism dependent on AMPK signalling.

Supplementary Materials

    • sFig.1 Effects of 0.1% DMSO on srebp-1c gene expression in tilapia hepatocytes. Hepatocytes were incubated for 24 h in the presence or absence of the 0.1% DMSO. Data presented for srebp-1c mRNA are expressed as means±SEM (N=3) and groups denoted by the same letter represent a similar magnitude of srebp-1c gene expression (Student’s t-test).

 

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  • Akcilar R, Emel Kocak F, Simsek H, Akcilar A, Bayat Z, Ece E & Kokdasgil H 2016 The effect of adropin on lipid and glucose metabolism in rats with hyperlipidemia. Iranian Journal of Basic Medical Sciences 19 245251.

    • Search Google Scholar
    • Export Citation
  • Alegre M, Ciudad CJ, Fillat C & Guinovart JJ 1988 Determination of glucose-6-phosphatase activity using the glucose dehydrogenase-coupled reaction. Analytical Biochemistry 173 185189. (https://doi.org/10.1016/0003-2697(88)90176-5)

    • Search Google Scholar
    • Export Citation
  • Altamimi TR, Gao S, Karwi QG, Fukushima A, Rawat S, Wagg CS, Zhang L & Lopaschuk GD 2019 Adropin regulates cardiac energy metabolism and improves cardiac function and efficiency. Metabolism: Clinical and Experimental 98 3748. (https://doi.org/10.1016/j.metabol.2019.06.005)

    • Search Google Scholar
    • Export Citation
  • Bentle LA & Lardy HA 1976 Interaction of anions and divalent metal ions with phosphoenolpyruvate carboxykinase. Journal of Biological Chemistry 251 29162921.

    • Search Google Scholar
    • Export Citation
  • Bonnefont JP, Djouadi F, Prip-Buus C, Gobin S, Munnich A & Bastin J 2004 Carnitine palmitoyltransferases 1 and 2: biochemical, molecular and medical aspects. Molecular Aspects of Medicine 25 495520. (https://doi.org/10.1016/j.mam.2004.06.004)

    • Search Google Scholar
    • Export Citation
  • Bougarne N, Weyers B, Desmet SJ, Deckers J, Ray DW, Staels B & De Bosscher K 2018 Molecular actions of PPARalpha in lipid metabolism and inflammation. Endocrine Reviews 39 760802. (https://doi.org/10.1210/er.2018-00064)

    • Search Google Scholar
    • Export Citation
  • Butler AA, Tam CS, Stanhope KL, Wolfe BM, Ali MR, O’Keeffe M, St-Onge MP, Ravussin E & Havel PJ 2012 Low circulating adropin concentrations with obesity and aging correlate with risk factors for metabolic disease and increase after gastric bypass surgery in humans. Journal of Clinical Endocrinology and Metabolism 97 37833791. (https://doi.org/10.1210/jc.2012-2194)

    • Search Google Scholar
    • Export Citation
  • Ceddia RB 2013 The role of AMP-activated protein kinase in regulating white adipose tissue metabolism. Molecular and Cellular Endocrinology 366 194203. (https://doi.org/10.1016/j.mce.2012.06.014)

    • Search Google Scholar
    • Export Citation
  • Chen YJ, Zhang TY, Chen HY, Lin SM, Luo L & Wang DS 2017 An evaluation of hepatic glucose metabolism at the transcription level for the omnivorous GIFT tilapia, Oreochromis niloticus during postprandial nutritional status transition from anabolism to catabolism. Aquaculture 473 375382. (https://doi.org/10.1016/j.aquaculture.2017.03.009)

    • Search Google Scholar
    • Export Citation
  • Chen L, Duan Y, Wei H, Ning H, Bi C, Zhao Y, Qin Y & Li Y 2019 Acetyl-CoA carboxylase (ACC) as a therapeutic target for metabolic syndrome and recent developments in ACC1/2 inhibitors. Expert Opinion on Investigational Drugs 28 917930. (https://doi.org/10.1080/13543784.2019.1657825)

    • Search Google Scholar
    • Export Citation
  • Chow BK, Moon TW, Hoo RL, Yeung CM, Muller M, Christos PJ & Mojsov S 2004 Identification and characterization of a glucagon receptor from the goldfish Carassius auratus: implications for the evolution of the ligand specificity of glucagon receptors in vertebrates. Endocrinology 145 32733288. (https://doi.org/10.1210/en.2003-0597)

    • Search Google Scholar
    • Export Citation
  • Du J, Jia R, Cao LP, Ding W, Xu P & Yin G 2018 Effects of rhizoma Alismatis extract on biochemical indices and adipose gene expression in oleic acid-induced hepatocyte injury in Jian carp (Cyprinus carpio var. Jian). Fish Physiology and Biochemistry 44 747768. (https://doi.org/10.1007/s10695-017-0428-2)

    • Search Google Scholar
    • Export Citation
  • Folch J, Lees M & Sloane Stanley GH 1957 A simple method for the isolation and purification of total lipides from animal tissues. Journal of Biological Chemistry 226 497509.

    • Search Google Scholar
    • Export Citation
  • Foretz M, Pacot C, Dugail I, Lemarchand P, Guichard C, Le Liepvre X, Berthelier-Lubrano C, Spiegelman B, Kim JB, Ferre P, et al. 1999 ADD1/SREBP-1c is required in the activation of hepatic lipogenic gene expression by glucose. Molecular and Cellular Biology 19 37603768. (https://doi.org/10.1128/mcb.19.5.3760)

    • Search Google Scholar
    • Export Citation
  • Fujii T, Ha H, Yokoyama H, Hamamoto H, Yoon SH & Hori H 1995 Applications of MTT assay to primary cultured rat hepatocytes. Biological and Pharmaceutical Bulletin 18 14461449. (https://doi.org/10.1248/bpb.18.1446)

    • Search Google Scholar
    • Export Citation
  • Ganesh Kumar K, Zhang J, Gao S, Rossi J, McGuinness OP, Halem HH, Culler MD, Mynatt RL & Butler AA 2012 Adropin deficiency is associated with increased adiposity and insulin resistance. Obesity 20 13941402. (https://doi.org/10.1038/oby.2012.31)

    • Search Google Scholar
    • Export Citation
  • Gao S, McMillan RP, Zhu Q, Lopaschuk GD, Hulver MW & Butler AA 2015 Therapeutic effects of adropin on glucose tolerance and substrate utilization in diet-induced obese mice with insulin resistance. Molecular Metabolism 4 310324. (https://doi.org/10.1016/j.molmet.2015.01.005)

    • Search Google Scholar
    • Export Citation
  • Gao S, Ghoshal S, Zhang L, Stevens JR, McCommis KS, Finck BN, Lopaschuk GD & Butler AA 2019 The peptide hormone adropin regulates signal transduction pathways controlling hepatic glucose metabolism in a mouse model of diet-induced obesity. Journal of Biological Chemistry 294 1336613377. (https://doi.org/10.1074/jbc.RA119.008967)

    • Search Google Scholar
    • Export Citation
  • Garcia D & Shaw RJ 2017 AMPK: mechanisms of cellular energy sensing and restoration of metabolic balance. Molecular Cell 66 789800. (https://doi.org/10.1016/j.molcel.2017.05.032)

    • Search Google Scholar
    • Export Citation
  • Garcia NA, Gonzalez-King H, Grueso E, Sanchez R, Martinez-Romero A, Javega B, O’Connor JE, Simons PJ, Handberg A & Sepulveda P 2019 Circulating exosomes deliver free fatty acids from the bloodstream to cardiac cells: possible role of CD36. PLoS ONE 14 e0217546. (https://doi.org/10.1371/journal.pone.0217546)

    • Search Google Scholar
    • Export Citation
  • Ghoshal S, Stevens JR, Billon C, Girardet C, Sitaula S, Leon AS, Rao DC, Skinner JS, Rankinen T, Bouchard C, et al. 2018 Adropin: an endocrine link between the biological clock and cholesterol homeostasis. Molecular Metabolism 8 5164. (https://doi.org/10.1016/j.molmet.2017.12.002)

    • Search Google Scholar
    • Export Citation
  • Hayashi T, Hirshman MF, Kurth EJ, Winder WW & Goodyear LJ 1998 Evidence for 5′ AMP-activated protein kinase mediation of the effect of muscle contraction on glucose transport. Diabetes 47 13691373. (https://doi.org/10.2337/diab.47.8.1369)

    • Search Google Scholar
    • Export Citation
  • He AY, Ning LJ, Chen LQ, Chen YL, Xing Q, Li JM, Qiao F, Li DL, Zhang ML & Du ZY 2015 Systemic adaptation of lipid metabolism in response to low- and high-fat diet in Nile tilapia (Oreochromis niloticus). Physiological Reports 3 e12485. (https://doi.org/10.14814/phy2.12485)

    • Search Google Scholar
    • Export Citation
  • Horton JD, Goldstein JL & Brown MS 2002 SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. Journal of Clinical Investigation 109 11251131. (https://doi.org/10.1172/JCI15593)

    • Search Google Scholar
    • Export Citation
  • Jasaszwili M, Billert M, Strowski MZ, Nowak KW & Skrzypski M 2020 Adropin as A fat-burning hormone with multiple functions-review of a decade of research. Molecules 25 549. (https://doi.org/10.3390/molecules25030549)

    • Search Google Scholar
    • Export Citation
  • Jiang Q & Wong AO 2013 Signal transduction mechanisms for autocrine/paracrine regulation of somatolactin-alpha secretion and synthesis in carp pituitary cells by somatolactin-alpha and -beta. American Journal of Physiology: Endocrinology and Metabolism 304 E176E186. (https://doi.org/10.1152/ajpendo.00455.2012)

    • Search Google Scholar
    • Export Citation
  • Kahn BB, Alquier T, Carling D & Hardie DG 2005 AMP-activated protein kinase: ancient energy gauge provides clues to modern understanding of metabolism. Cell Metabolism 1 1525. (https://doi.org/10.1016/j.cmet.2004.12.003)

    • Search Google Scholar
    • Export Citation
  • Karim S, Adams DH & Lalor PF 2012 Hepatic expression and cellular distribution of the glucose transporter family. World Journal of Gastroenterology 18 67716781. (https://doi.org/10.3748/wjg.v18.i46.6771)

    • Search Google Scholar
    • Export Citation
  • Kumar KG, Trevaskis JL, Lam DD, Sutton GM, Koza RA, Chouljenko VN, Kousoulas KG, Rogers PM, Kesterson RA, Thearle M, et al. 2008 Identification of adropin as a secreted factor linking dietary macronutrient intake with energy homeostasis and lipid metabolism. Cell Metabolism 8 468481. (https://doi.org/10.1016/j.cmet.2008.10.011)

    • Search Google Scholar
    • Export Citation
  • Lian A, Wu K, Liu T, Jiang N & Jiang Q 2016 Adropin induction of lipoprotein lipase expression in tilapia hepatocytes. Journal of Molecular Endocrinology 56 1122. (https://doi.org/10.1530/JME-15-0207)

    • Search Google Scholar
    • Export Citation
  • Liu HY, Collins QF, Xiong Y, Moukdar F, Lupo EG Jr, Liu Z & Cao W 2007 Prolonged treatment of primary hepatocytes with oleate induces insulin resistance through p38 mitogen-activated protein kinase. Journal of Biological Chemistry 282 1420514212. (https://doi.org/10.1074/jbc.M609701200)

    • Search Google Scholar
    • Export Citation
  • Liu H, Xu Y, Wang Y, Zhong S, Wang M, Lin P, Li H & Liu Z 2017 CD36 is a candidate lipid sensor involved in the sensory detection of fatty acid in zebrafish. Physiology and Behavior 182 3439. (https://doi.org/10.1016/j.physbeh.2017.09.015)

    • Search Google Scholar
    • Export Citation
  • Liu L, Wang Q, Wang Q, Zhao X, Zhao P, Geng T & Gong D 2018 Role of miR29c in goose fatty liver is mediated by its target genes that are involved in energy homeostasis and cell growth. BMC Veterinary Research 14 325. (https://doi.org/10.1186/s12917-018-1653-3)

    • Search Google Scholar
    • Export Citation
  • Logie L, Lees Z, Allwood JW, McDougall G, Beall C & Rena G 2018 Regulation of hepatic glucose production and AMPK by AICAR but not by metformin depends on drug uptake through the equilibrative nucleoside transporter 1 (ENT1). Diabetes, Obesity and Metabolism 20 27482758. (https://doi.org/10.1111/dom.13455)

    • Search Google Scholar
    • Export Citation
  • Malhi H, Bronk SF, Werneburg NW & Gores GJ 2006 Free fatty acids induce JNK-dependent hepatocyte lipoapoptosis. Journal of Biological Chemistry 281 1209312101. (https://doi.org/10.1074/jbc.M510660200)

    • Search Google Scholar
    • Export Citation
  • Mao J, DeMayo FJ, Li H, Abu-Elheiga L, Gu Z, Shaikenov TE, Kordari P, Chirala SS, Heird WC & Wakil SJ 2006 Liver-specific deletion of acetyl-CoA carboxylase 1 reduces hepatic triglyceride accumulation without affecting glucose homeostasis. PNAS 103 85528557. (https://doi.org/10.1073/pnas.0603115103)

    • Search Google Scholar
    • Export Citation
  • Mencarelli A, Cipriani S, Renga B, Francisci D, Palladino G, Distrutti E, Baldelli F & Fiorucci S 2010 The bile acid sensor FXR protects against dyslipidemia and aortic plaques development induced by the HIV protease inhibitor ritonavir in mice. PLoS ONE 5 e13238. (https://doi.org/10.1371/journal.pone.0013238)

    • Search Google Scholar
    • Export Citation
  • Miquilena-Colina ME, Lima-Cabello E, Sanchez-Campos S, Garcia-Mediavilla MV, Fernandez-Bermejo M, Lozano-Rodriguez T, Vargas-Castrillon J, Buque X, Ochoa B, Aspichueta P, et al. 2011 Hepatic fatty acid translocase CD36 upregulation is associated with insulin resistance, hyperinsulinaemia and increased steatosis in non-alcoholic steatohepatitis and chronic hepatitis C. Gut 60 13941402. (https://doi.org/10.1136/gut.2010.222844)

    • Search Google Scholar
    • Export Citation
  • Ning LJ, He AY, Lu DL, Li JM, Qiao F, Li DL, Zhang ML, Chen LQ & Du ZY 2017 Nutritional background changes the hypolipidemic effects of fenofibrate in Nile tilapia (Oreochromis niloticus). Scientific Reports 7 41706. (https://doi.org/10.1038/srep41706)

    • Search Google Scholar
    • Export Citation
  • Ochs RS & Harris RA 1986 Mechanism for the oleate stimulation of gluconeogenesis from dihydroxyacetone by hepatocytes from fasted rats. Biochimica et Biophysica Acta 886 4047. (https://doi.org/10.1016/0167-4889(86)90209-0)

    • Search Google Scholar
    • Export Citation
  • Oliveira AF, Cunha DA, Ladriere L, Igoillo-Esteve M, Bugliani M, Marchetti P & Cnop M 2015 In vitro use of free fatty acids bound to albumin: a comparison of protocols. BioTechniques 58 228233. (https://doi.org/10.2144/000114285)

    • Search Google Scholar
    • Export Citation
  • Pawlak M, Lefebvre P & Staels B 2015 Molecular mechanism of PPARalpha action and its impact on lipid metabolism, inflammation and fibrosis in non-alcoholic fatty liver disease. Journal of Hepatology 62 720733. (https://doi.org/10.1016/j.jhep.2014.10.039)

    • Search Google Scholar
    • Export Citation
  • Rao A & Herr DR 2017 G Protein-coupled receptor GPR19 regulates E-cadherin expression and invasion of breast cancer cells. Biochimica et Biophysica Acta: Molecular Cell Research 1864 13181327. (https://doi.org/10.1016/j.bbamcr.2017.05.001)

    • Search Google Scholar
    • Export Citation
  • Rui L 2014 Energy metabolism in the liver. Comprehensive Physiology 4 177197. (https://doi.org/10.1002/cphy.c130024)

  • Sharma S, Mells JE, Fu PP, Saxena NK & Anania FA 2011 GLP-1 analogs reduce hepatocyte steatosis and improve survival by enhancing the unfolded protein response and promoting macroautophagy. PLoS ONE 6 e25269. (https://doi.org/10.1371/journal.pone.0025269)

    • Search Google Scholar
    • Export Citation
  • Shi HJ, Xu C, Liu MY, Wang BK, Liu WB, Chen DH, Zhang L, Xu CY & Li XF 2018 Resveratrol improves the energy sensing and glycolipid metabolism of blunt snout bream megalobrama amblycephala fed high-carbohydrate diets by activating the AMPK-SIRT1-PGC-1alpha network. Frontiers in Physiology 9 1258. (https://doi.org/10.3389/fphys.2018.01258)

    • Search Google Scholar
    • Export Citation
  • Stein LM, Yosten GL & Samson WK 2016 Adropin acts in brain to inhibit water drinking: potential interaction with the orphan G protein-coupled receptor, GPR19. American Journal of Physiology: Regulatory, Integrative and Comparative Physiology 310 R476R480. (https://doi.org/10.1152/ajpregu.00511.2015)

    • Search Google Scholar
    • Export Citation
  • Stubhaug I, Tocher DR, Bell JG, Dick JR & Torstensen BE 2005 Fatty acid metabolism in Atlantic salmon (Salmo salar L.) hepatocytes and influence of dietary vegetable oil. Biochimica et Biophysica Acta 1734 277288. (https://doi.org/10.1016/j.bbalip.2005.04.003)

    • Search Google Scholar
    • Export Citation
  • Talukdar S & Hillgartner FB 2006 The mechanism mediating the activation of acetyl-coenzyme A carboxylase-alpha gene transcription by the liver X receptor agonist T0-901317. Journal of Lipid Research 47 24512461. (https://doi.org/10.1194/jlr.M600276-JLR200)

    • Search Google Scholar
    • Export Citation
  • Thapa D, Stoner MW, Zhang M, Xie B, Manning JR, Guimaraes D, Shiva S, Jurczak MJ & Scott I 2018 Adropin regulates pyruvate dehydrogenase in cardiac cells via a novel GPCR-MAPK-PDK4 signaling pathway. Redox Biology 18 2532. (https://doi.org/10.1016/j.redox.2018.06.003)

    • Search Google Scholar
    • Export Citation
  • Thapa D, Xie B, Manning JR, Zhang M, Stoner MW, Huckestein BR, Edmunds LR, Zhang X, Dedousis NL, O’Doherty RM, et al. 2019 Adropin reduces blood glucose levels in mice by limiting hepatic glucose production. Physiological Reports 7 e14043. (https://doi.org/10.14814/phy2.14043)

    • Search Google Scholar
    • Export Citation
  • Trepiana J, Milton-Laskibar I, Gomez-Zorita S, Eseberri I, Gonzalez M, Fernandez-Quintela A & Portillo MP 2018 Involvement of 5′-activated protein kinase (AMPK) in the effects of resveratrol on liver steatosis. International Journal of Molecular Sciences 19 3473. (https://doi.org/10.3390/ijms19113473)

    • Search Google Scholar
    • Export Citation
  • Wilson CG, Tran JL, Erion DM, Vera NB, Febbraio M & Weiss EJ 2016 Hepatocyte-specific disruption of CD36 attenuates fatty liver and improves insulin sensitivity in HFD-Fed Mice. Endocrinology 157 570585. (https://doi.org/10.1210/en.2015-1866)

    • Search Google Scholar
    • Export Citation
  • Wolf K 1963 Physiological salines for fresh-water teleosts. Progressive Fish-Culturist 25 135140. (https://doi.org/10.1577/1548-8659(1963)25[135:PSFFT]2.0.CO;2)

    • Search Google Scholar
    • Export Citation
  • Xu J, Xiao G, Trujillo C, Chang V, Blanco L, Joseph SB, Bassilian S, Saad MF, Tontonoz P, Lee WN, et al. 2002 Peroxisome proliferator-activated receptor alpha (PPARalpha) influences substrate utilization for hepatic glucose production. Journal of Biological Chemistry 277 5023750244. (https://doi.org/10.1074/jbc.M201208200)

    • Search Google Scholar
    • Export Citation
  • Yabaluri N & Bashyam MD 2010 Hormonal regulation of gluconeogenic gene transcription in the liver. Journal of Biosciences 35 473484. (https://doi.org/10.1007/s12038-010-0052-0)

    • Search Google Scholar
    • Export Citation
  • Yang F, Zhou L, Qian X, Wang D, He WJ, Tang ZW, Yin J & Huang QY 2017 Adropin is a key mediator of hypoxia induced anti-dipsogenic effects via TRPV4-CamKK-AMPK signaling in the circumventricular organs of rats. Frontiers in Molecular Neuroscience 10 105. (https://doi.org/10.3389/fnmol.2017.00105)

    • Search Google Scholar
    • Export Citation
  • Yanhong F, Chenghua H, Guofang L & Haibin Z 2008 Optimization of the isolation and cultivation of Cyprinus carpio primary hepatocytes. Cytotechnology 58 8592. (https://doi.org/10.1007/s10616-008-9169-5)

    • Search Google Scholar
    • Export Citation
  • Zimmerman AW & Veerkamp JH 2002 New insights into the structure and function of fatty acid-binding proteins. Cellular and Molecular Life Sciences 59 10961116. (https://doi.org/10.1007/s00018-002-8490-y)

    • Search Google Scholar
    • Export Citation