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DOI: 10.1055/s-0033-1351321
Hypothalamic Actions of Apelin on Energy Metabolism: New Insight on Glucose Homeostasis and Metabolic Disorders
Publikationsverlauf
received 26. April 2013
accepted 08. Juli 2013
Publikationsdatum:
15. August 2013 (online)
![](https://www.thieme-connect.de/media/hmr/201313/lookinside/thumbnails/10.1055-s-0033-1351321-1.jpg)
Abstract
Hypothalamus is key area implicated in control of glucose homeostasis. This structure integrates nervous and peripheral informations to adapt a response modifying peripheral glucose utilization and maintaining energetic balance. Among peripheral signals, adipokines such as adiponectin and leptin are of special importance since deregulations of their actions are closely associated to metabolic disorders such as obesity and type 2 diabetes. During the past ten years, we have identified a new adipokine named apelin which has emerging role in the control of metabolism. The originality of the apelinergic system is to be largely represented in peripheral tissues (adipose tissue, intestine, etc.) and in the brain. Then, apelin is released by adipose tissue as all adipokines, but also present another crucial role as neurotransmitter in hypothalamic neurons. By acting in the whole body, apelin exerts pleiotropic actions and is now considered as a major determinant of physiological functions. Besides its general beneficial effects on peripheral targets, central action of apelin remains still a matter of debate. In this review, we have made a parallel between peripheral vs. central actions of apelin in term of signalization and effects. Then, we have focused our attention on hypothalamic apelin and its potential role in glucose metabolism and associated pathologies.
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References
- 1 Tatemoto K, Hosoya M, Habata Y, Fujii R, Kakegawa T, Zou MX, Kawamata Y, Fukusumi S, Hinuma S, Kitada C, Kurokawa T, Onda H, Fujino M. Isolation and characterization of a novel endogenous peptide ligand for the human APJ receptor. Biochem Biophys Res Commun 1998; 251: 471-476
- 2 O’Dowd BF, Heiber M, Chan A, Heng HH, Tsui LC, Kennedy JL, Shi X, Petronis A, George SR, Nguyen T. A human gene that shows identity with the gene encoding the angiotensin receptor is located on chromosome 11. Gene 1993; 136: 355-360
- 3 De Mota N, Lenkei Z, Llorens-Cortes C. Cloning, pharmacological characterization and brain distribution of the rat apelin receptor. Neuroendocrinology 2000; 72: 400-407
- 4 Pope GR, Roberts EM, Lolait SJ, O’Carroll AM. Central and peripheral apelin receptor distribution in the mouse: species differences with rat. Peptides 2012; 33: 139-148
- 5 Hosoya M, Kawamata Y, Fukusumi S, Fujii R, Habata Y, Hinuma S, Kitada C, Honda S, Kurokawa T, Onda H, Nishimura O, Fujino M. Molecular and functional characteristics of APJ. Tissue distribution of mRNA and interaction with the endogenous ligand apelin. J Biol Chem 2000; 275: 21061-21067
- 6 Kawamata Y, Habata Y, Fukusumi S, Hosoya M, Fujii R, Hinuma S, Nishizawa N, Kitada C, Onda H, Nishimura O, Fujino M. Molecular properties of apelin: tissue distribution and receptor binding. Biochim Biophys Acta 2001; 1538: 162-171
- 7 Lee DK, Cheng R, Nguyen T, Fan T, Kariyawasam AP, Liu Y, Osmond DH, George SR, O’Dowd BF. Characterization of apelin, the ligand for the APJ receptor. J Neurochem 2000; 74: 34-41
- 8 Boucher J, Masri B, Daviaud D, Gesta S, Guigne C, Mazzucotelli A, Castan-Laurell I, Tack I, Knibiehler B, Carpene C, Audigier Y, Saulnier-Blache JS, Valet P. Apelin, a newly identified adipokine up-regulated by insulin and obesity. Endocrinology 2005; 146: 1764-1771
- 9 De Mota N, Reaux-Le Goazigo A, El Messari S, Chartrel N, Roesch D, Dujardin C, Kordon C, Vaudry H, Moos F, Llorens-Cortes C. Apelin, a potent diuretic neuropeptide counteracting vasopressin actions through inhibition of vasopressin neuron activity and vasopressin release. Proc Natl Acad Sci USA 2004; 101: 10464-10469
- 10 Castan-Laurell I, Dray C, Knauf C, Kunduzova O, Valet P. Apelin, a promising target for type 2 diabetes treatment?. Trends Endocrinol Metab 2012; 23: 234-241
- 11 Maguire JJ, Kleinz MJ, Pitkin SL, Davenport AP. [Pyr1]apelin-13 identified as the predominant apelin isoform in the human heart: vasoactive mechanisms and inotropic action in disease. Hypertension 2009; 54: 598-604
- 12 Bo Y, Yuan LP. Glomerular expression of apelin and its association with proteinuria. Indian J Pediatr 2012; 79: 1028-1032
- 13 Kleinz MJ, Davenport AP. Emerging roles of apelin in biology and medicine. Pharmacol Ther 2005; 107: 198-211
- 14 Vickers C, Hales P, Kaushik V, Dick L, Gavin J, Tang J, Godbout K, Parsons T, Baronas E, Hsieh F, Acton S, Patane M, Nichols A, Tummino P. Hydrolysis of biological peptides by human angiotensin-converting enzyme-related carboxypeptidase. J Biol Chem 2002; 277: 14838-14843
- 15 Lee DK, Ferguson SS, George SR, O’Dowd BF. The fate of the internalized apelin receptor is determined by different isoforms of apelin mediating differential interaction with beta-arrestin. Biochem Biophys Res Commun 2010; 395: 185-189
- 16 Reaux A, De Mota N, Skultetyova I, Lenkei Z, El Messari S, Gallatz K, Corvol P, Palkovits M, Llorens-Cortes C. Physiological role of a novel neuropeptide, apelin, and its receptor in the rat brain. J Neurochem 2001; 77: 1085-1096
- 17 Masri B, Lahlou H, Mazarguil H, Knibiehler B, Audigier Y. Apelin (65-77) activates extracellular signal-regulated kinases via a PTX-sensitive G protein. Biochem Biophys Res Commun 2002; 290: 539-545
- 18 Masri B, Morin N, Cornu M, Knibiehler B, Audigier Y. Apelin (65-77) activates p70 S6 kinase and is mitogenic for umbilical endothelial cells. FASEB J 2004; 18: 1909-1911
- 19 Zhong JC, Yu XY, Huang Y, Yung LM, Lau CW, Lin SG. Apelin modulates aortic vascular tone via endothelial nitric oxide synthase phosphorylation pathway in diabetic mice. Cardiovasc Res 2007; 74: 388-395
- 20 Dray C, Knauf C, Daviaud D, Waget A, Boucher J, Buleon M, Cani PD, Attane C, Guigne C, Carpene C, Burcelin R, Castan-Laurell I, Valet P. Apelin stimulates glucose utilization in normal and obese insulin-resistant mice. Cell Metab 2008; 8: 437-445
- 21 Liu C, Su T, Li F, Li L, Qin X, Pan W, Feng F, Chen F, Liao D, Chen L. PI3K/Akt signaling transduction pathway is involved in rat vascular smooth muscle cell proliferation induced by apelin-13. Acta Bioch Biophy Sinica 2010; 42: 396-402
- 22 Kidoya H, Kunii N, Naito H, Muramatsu F, Okamoto Y, Nakayama T, Takakura N. The apelin/APJ system induces maturation of the tumor vasculature and improves the efficiency of immune therapy. Oncogene 2012; 31: 3254-3264
- 23 Eyries M, Siegfried G, Ciumas M, Montagne K, Agrapart M, Lebrin F, Soubrier F. Hypoxia-induced apelin expression regulates endothelial cell proliferation and regenerative angiogenesis. Circ Res 2008; 103: 432-440
- 24 Kasai A, Shintani N, Kato H, Matsuda S, Gomi F, Haba R, Hashimoto H, Kakuda M, Tano Y, Baba A. Retardation of retinal vascular development in apelin-deficient mice. Arterioscler Thromb Vasc Biol 2008; 28: 1717-1722
- 25 Rayalam S, Della-Fera MA, Kasser T, Warren W, Baile CA. Emerging role of apelin as a therapeutic target in cancer: a patent review. Recent Patents Anticancer Drug Discov 2011; 6: 367-372
- 26 Tatemoto K, Takayama K, Zou MX, Kumaki I, Zhang W, Kumano K, Fujimiya M. The novel peptide apelin lowers blood pressure via a nitric oxide-dependent mechanism. Regul Pept 2001; 99: 87-92
- 27 Szokodi I, Tavi P, Foldes G, Voutilainen-Myllyla S, Ilves M, Tokola H, Pikkarainen S, Piuhola J, Rysa J, Toth M, Ruskoaho H. Apelin, the novel endogenous ligand of the orphan receptor APJ, regulates cardiac contractility. Circ Res 2002; 91: 434-440
- 28 Zhang Z, Yu B, Tao GZ. Apelin protects against cardiomyocyte apoptosis induced by glucose deprivation. Chin Med J (Engl) 2009; 122: 2360-2365
- 29 Foussal C, Lairez O, Calise D, Pathak A, Guilbeau-Frugier C, Valet P, Parini A, Kunduzova O. Activation of catalase by apelin prevents oxidative stress-linked cardiac hypertrophy. FEBS Lett 2010; 584: 2363-2370
- 30 Chong KS, Gardner RS, Morton JJ, Ashley EA, McDonagh TA. Plasma concentrations of the novel peptide apelin are decreased in patients with chronic heart failure. Eur J Heart Fail 2006; 8: 355-360
- 31 Wang G, Anini Y, Wei W, Qi X, AM OC, Mochizuki T, Wang HQ, Hellmich MR, Englander EW, Greeley Jr GH. Apelin, a new enteric peptide: localization in the gastrointestinal tract, ontogeny, and stimulation of gastric cell proliferation and of cholecystokinin secretion. Endocrinology 2004; 145: 1342-1348
- 32 Flemstrom G, Makela K, Purhonen AK, Sjoblom M, Jedstedt G, Walkowiak J, Herzig KH. Apelin stimulation of duodenal bicarbonate secretion: feeding-dependent and mediated via apelin-induced release of enteric cholecystokinin. Acta Physiologica 2011; 201: 141-150
- 33 Ohno S, Yakabi K, Ro S, Ochiai M, Onouchi T, Sakurada T, Takabayashi H, Ishida S, Takayama K. Apelin-12 stimulates acid secretion through an increase of histamine release in rat stomachs. Regul Pept 2012; 174: 71-78
- 34 Dray C, Sakar Y, Vinel C, Daviaud D, Masri B, Garrigues L, Wanecq E, Galvani S, Negre-Salvayre A, Barak LS, Monsarrat B, Burlet-Schiltz O, Valet P, Castan-Laurell I, Ducroc R. The intestinal glucose-apelin cycle controls carbohydrate absorption in mice. Gastroenterology 2013; 144: 771-780
- 35 Biddinger SB, Kahn CR. From mice to men: insights into the insulin resistance syndromes. Annu Rev Physiol 2006; 68: 123-158
- 36 Harwood Jr HJ. The adipocyte as an endocrine organ in the regulation of metabolic homeostasis. Neuropharmacology 2012; 63: 57-75
- 37 Sorhede Winzell M, Magnusson C, Ahren B. The apj receptor is expressed in pancreatic islets and its ligand, apelin, inhibits insulin secretion in mice. Regul Pept 2005; 131: 12-17
- 38 Boucher J, Castan-Laurell I, Daviaud D, Guigne C, Buleon M, Carpene C, Saulnier-Blache JS, Valet P. Adipokine expression profile in adipocytes of different mouse models of obesity. Horm Metab Res 2005; 37: 761-767
- 39 Yue P, Jin H, Aillaud M, Deng AC, Azuma J, Asagami T, Kundu RK, Reaven GM, Quertermous T, Tsao PS. Apelin is necessary for the maintenance of insulin sensitivity. Am J Physiol Endocrinol Metab 2010; 298: E59-E67
- 40 Higuchi K, Masaki T, Gotoh K, Chiba S, Katsuragi I, Tanaka K, Kakuma T, Yoshimatsu H. Apelin, an APJ receptor ligand, regulates body adiposity and favors the messenger ribonucleic acid expression of uncoupling proteins in mice. Endocrinology 2007; 148: 2690-2697
- 41 Attane C, Foussal C, Le Gonidec S, Benani A, Daviaud D, Wanecq E, Guzman-Ruiz R, Dray C, Bezaire V, Rancoule C, Kuba K, Ruiz-Gayo M, Levade T, Penninger J, Burcelin R, Penicaud L, Valet P, Castan-Laurell I. Apelin treatment increases complete Fatty Acid oxidation, mitochondrial oxidative capacity, and biogenesis in muscle of insulin-resistant mice. Diabetes 2012; 61: 310-320
- 42 Cani PD, Amar J, Iglesias MA, Poggi M, Knauf C, Bastelica D, Neyrinck AM, Fava F, Tuohy KM, Chabo C, Waget A, Delmee E, Cousin B, Sulpice T, Chamontin B, Ferrieres J, Tanti JF, Gibson GR, Casteilla L, Delzenne NM, Alessi MC, Burcelin R. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes 2007; 56: 1761-1772
- 43 Delzenne NM, Neyrinck AM, Cani PD. Gut microbiota and metabolic disorders: How prebiotic can work?. Br J Nutr 2013; 109 (Suppl. 02) S81-S85
- 44 Geurts L, Lazarevic V, Derrien M, Everard A, Van Roye M, Knauf C, Valet P, Girard M, Muccioli GG, Francois P, de Vos WM, Schrenzel J, Delzenne NM, Cani PD. Altered gut microbiota and endocannabinoid system tone in obese and diabetic leptin-resistant mice: impact on apelin regulation in adipose tissue. Front Microbiol 2011; 2: 149
- 45 Soriguer F, Garrido-Sanchez L, Garcia-Serrano S, Garcia-Almeida JM, Garcia-Arnes J, Tinahones FJ, Garcia-Fuentes E. Apelin levels are increased in morbidly obese subjects with type 2 diabetes mellitus. Obes Surg 2009; 19: 1574-1580
- 46 Reaux-Le Goazigo A, Bodineau L, De Mota N, Jeandel L, Chartrel N, Knauf C, Raad C, Valet P, Llorens-Cortes C. Apelin and the proopiomelanocortin system: a new regulatory pathway of hypothalamic alpha-MSH release. Am J Physiol Endocrinol Metab 2011; 301: E955-E966
- 47 Choe W, Albright A, Sulcove J, Jaffer S, Hesselgesser J, Lavi E, Crino P, Kolson DL. Functional expression of the seven-transmembrane HIV-1 co-receptor APJ in neural cells. J Neurovirol 2000; 6 (Suppl. 01) S61-S69
- 48 Kasai A, Kinjo T, Ishihara R, Sakai I, Ishimaru Y, Yoshioka Y, Yamamuro A, Ishige K, Ito Y, Maeda S. Apelin deficiency accelerates the progression of amyotrophic lateral sclerosis. PLoS One 2011; 6: e23968
- 49 Lv SY, Qin YJ, Wang NB, Yang YJ, Chen Q. Supraspinal antinociceptive effect of apelin-13 in a mouse visceral pain model. Peptides 2012; 37: 165-170
- 50 Telegdy G, Adamik A, Jaszberenyi M. Involvement of neurotransmitters in the action of apelin-13 on passive avoidance learning in mice. Peptides 2013; 39: 171-174
- 51 Zeng XJ, Yu SP, Zhang L, Wei L. Neuroprotective effect of the endogenous neural peptide apelin in cultured mouse cortical neurons. Exp Cell Res 2010; 316: 1773-1783
- 52 O’Carroll AM, Lolait SJ. Regulation of rat APJ receptor messenger ribonucleic acid expression in magnocellular neurones of the paraventricular and supraopric nuclei by osmotic stimuli. J Neuroendocrinol 2003; 15: 661-666
- 53 Newson MJ, Pope GR, Roberts EM, Lolait SJ, O’Carroll AM. Stress-dependent and gender-specific neuroregulatory roles of the apelin receptor in the hypothalamic-pituitary-adrenal axis response to acute stress. J Endocrinol 2013; 216: 99-109
- 54 Roberts EM, Pope GR, Newson MJ, Landgraf R, Lolait SJ, O’Carroll AM. Stimulus-specific neuroendocrine responses to osmotic challenges in apelin receptor knockout mice. J Neuroendocrinol 2010; 22: 301-308
- 55 Schwartz MW, Woods SC, Porte Jr D, Seeley RJ, Baskin DG. Central nervous system control of food intake. Nature 2000; 404: 661-671
- 56 Sunter D, Hewson AK, Dickson SL. Intracerebroventricular injection of apelin-13 reduces food intake in the rat. Neurosci Lett 2003; 353: 1-4
- 57 Clarke KJ, Whitaker KW, Reyes TM. Diminished metabolic responses to centrally-administered apelin-13 in diet-induced obese rats fed a high-fat diet. J Neuroendocrinol 2009; 21: 83-89
- 58 Taheri S, Murphy K, Cohen M, Sujkovic E, Kennedy A, Dhillo W, Dakin C, Sajedi A, Ghatei M, Bloom S. The effects of centrally administered apelin-13 on food intake, water intake and pituitary hormone release in rats. Biochem Biophys Res Commun 2002; 291: 1208-1212
- 59 O’Donnell LA, Agrawal A, Sabnekar P, Dichter MA, Lynch DR, Kolson DL. Apelin, an endogenous neuronal peptide, protects hippocampal neurons against excitotoxic injury. J Neurochem 2007; 102: 1905-1917
- 60 Tang SY, Xie H, Yuan LQ, Luo XH, Huang J, Cui RR, Zhou HD, Wu XP, Liao EY. Apelin stimulates proliferation and suppresses apoptosis of mouse osteoblastic cell line MC3T3-E1 via JNK and PI3-K/Akt signaling pathways. Peptides 2007; 28: 708-718
- 61 Duparc T, Colom A, Cani PD, Massaly N, Rastrelli S, Drougard A, Le Gonidec S, Mouledous L, Frances B, Leclercq I, Llorens-Cortes C, Pospisilik JA, Delzenne NM, Valet P, Castan-Laurell I, Knauf C. Central apelin controls glucose homeostasis via a nitric oxide-dependent pathway in mice. Antioxid Redox Signal 2011; 15: 1477-1496
- 62 Yao F, Modgil A, Zhang Q, Pingili A, Singh N, O’Rourke ST, Sun C. Pressor effect of apelin-13 in the rostral ventrolateral medulla: role of NAD(P)H oxidase-derived superoxide. J Pharmacol Exp Ther 2011; 336: 372-380
- 63 Leloup C, Tourrel-Cuzin C, Magnan C, Karaca M, Castel J, Carneiro L, Colombani AL, Ktorza A, Casteilla L, Penicaud L. Mitochondrial reactive oxygen species are obligatory signals for glucose-induced insulin secretion. Diabetes 2009; 58: 673-681
- 64 Leloup C, Casteilla L, Carriere A, Galinier A, Benani A, Carneiro L, Penicaud L. Balancing mitochondrial redox signaling: a key point in metabolic regulation. Antioxid Redox Signal 2011; 14: 519-530
- 65 Jaillard T, Roger M, Galinier A, Guillou P, Benani A, Leloup C, Casteilla L, Penicaud L, Lorsignol A. Hypothalamic reactive oxygen species are required for insulin-induced food intake inhibition: an NADPH oxidase-dependent mechanism. Diabetes 2009; 58: 1544-1549
- 66 Rodriguez EM, Blazquez JL, Guerra M. The design of barriers in the hypothalamus allows the median eminence and the arcuate nucleus to enjoy private milieus: the former opens to the portal blood and the latter to the cerebrospinal fluid. Peptides 2010; 31: 757-776
- 67 Takayama K, Iwazaki H, Hirabayashi M, Yakabi K, Ro S. Distribution of c-Fos immunoreactive neurons in the brain after intraperitoneal injection of apelin-12 in Wistar rats. Neurosci Lett 2008; 431: 247-250
- 68 Cabou C, Cani PD, Campistron G, Knauf C, Mathieu C, Sartori C, Amar J, Scherrer U, Burcelin R. Central insulin regulates heart rate and arterial blood flow: an endothelial nitric oxide synthase-dependent mechanism altered during diabetes. Diabetes 2007; 56: 2872-2877
- 69 Drougard A, Duparc T, Brenachot X, Carneiro L, Gouazé A, Fournel A, Geurts L, Cadoudal T, Prats AC, Pénicaud L, Vieau D, Lesage J, Leloup C, Benani A, Cani PD, Valet P, Knauf C. Hypothalamic apelin/ROS signaling controls hepatic glucose metabolism in the onset of diabetes. Antioxid Redox Signal 2013; in press
- 70 Kalsbeek A, Yi CX, La Fleur SE, Fliers E. The hypothalamic clock and its control of glucose homeostasis. Trends Endocrinol Metab 2010; 21: 402-410
- 71 Penicaud L, Cousin B, Leloup C, Lorsignol A, Casteilla L. The autonomic nervous system, adipose tissue plasticity, and energy balance. Nutrition 2000; 16: 903-908
- 72 Masaki T, Yasuda T, Yoshimatsu H. Apelin-13 microinjection into the paraventricular nucleus increased sympathetic nerve activity innervating brown adipose tissue in rats. Brain Res Bull 2012; 87: 540-543
- 73 Yang YJ, Lv SY, Xiu MH, Xu N, Chen Q. Intracerebroventricular administration of apelin-13 inhibits distal colonic transit in mice. Peptides 2010; 31: 2241-2246
- 74 Lv SY, Yang YJ, Qin YJ, Xiong W, Chen Q. Effect of centrally administered apelin-13 on gastric emptying and gastrointestinal transit in mice. Peptides 2011; 32: 978-982