Keywords: article scientifique, formation, groupe bibliographique, recherche infirmière, soin infirmier

L'avènement des recherches à l'initiative des infirmières impacte de plus en plus la prise en soins des patients. Ce constat encourageant peut pourtant paraître éloigné du quotidien sous tension de nombreux soignants. Dès lors, il semble intéressant de questionner les initiatives permettant de rapprocher les savoirs issus de la recherche de la pratique quotidienne des soignants encore trop peu sensibilisés. Une équipe lyonnaise relate son expérience, décrit les objectifs initiaux, la mise en place et l'organisation d'un groupe de lecture bibliographique pour des soignants non médicaux.

Dochead Fiches Sous-dochead Recherche

Fédérer une culture recherche par un groupe de bibliographie Benoît Chalancon a, * ,b Infirmier de recherche clinique, chercheur associé Florian Magny c Formateur en institut de formation en soins infirmiers, conseiller scientifique paramédical a Service hospitalo-universitaire, CH Le Vinatier, 95, boulevard Pinel, 69678 Bron, France b Laboratoire ICAR (UMR 5191), ENS de Lyon, Site Descartes, 15, parvis René-Descartes, 69342 Lyon cedex 7, France c École santé social Sud-Est, 20, rue de la Claire, 69009 Lyon, France T1 Idée rapportée d'un congrès À l'occasion de congrès spécialisés sur la recherche en soins, nous avons découvert l'existence de groupes bibliographiques pour les soignants non médicaux et d'une méthodologie propre à l'animation de ces temps de regroupement professionnel. TEG1 Lors d'un congrès organisé à Bordeaux, nous apprenons ainsi que "les groupes biblio" n'étaient pas exclusivement réservés aux internes ou à nos collègues psychiatres, grâce à l'intervention de Valérie Berger, docteur en philosophie, cadre supérieure de santé, coordinatrice de la recherche paramédicale au CHU de Bordeaux, qui présentait le groupe qu'elle avait initié [START_REF]3 e rencontre sur la recherche en soins en psychiatrie[END_REF]. Parmi les documents partagés lors de ce congrès, une bibliographie ayant pour thème "La recherche en soin" et notamment sa section réservée aux groupes bibliographiques retiendra notre attention. TEG1 Sur le trajet du retour, nous décidons de nous partager les articles proposés en lecture sur le sujet, dans l'idée de constituer un argumentaire à soumettre à nos cadres de santé pour la création d'un tel groupe. TEG1 Quelques semaines plus tard, alors qu'éclôt l'ambition d'un déploiement d'une culture recherche parmi les soignants non médicaux au sein de notre établissement, nous débutons la rédaction d'une fiche technique de ce groupe bibliographique décrivant ses objectifs et l'organisation proposée en nous appuyant sur les articles cités.

T1 Objectifs

L'objectif opérationnel fondateur pourrait ainsi se résumer à l'assertion suivante : fédérer autour d'un groupe les acteurs paramédicaux de la recherche en soins en activité sur l'hôpital. TEG1 Ce regroupement aura pour vocation d'initier prioritairement une culture recherche en soulignant l'aspect pragmatique et concret des travaux de recherche avant, nous l'espérons, de faire émerger de nouveaux parcours de recherche. Pour le dire autrement, nous souhaitons instaurer une dynamique de réflexion sur les pratiques soignantes, qui pourrait agir comme un traitement prophylactique de l'obsolescence des soins. TEG1 Le premier objectif est de regrouper les infirmiers, intra-et extrahospitaliers, impliqués dans la recherche sur un pôle de psychiatrie adulte générale (en l'occurrence, le pôle ouest de notre établissement) afin de mieux connaître les projets en cours, tout en favorisant la création d'un réseau intrapôle. L'inclusion des professionnels intéressés par la recherche, mais non pratiquants, leur permettrait de bénéficier du partage d'expérience de ceux qui ont pu obtenir un premier financement. TEG1 Le second objectif est de faire émerger et d'entretenir une réflexion dynamique sur la recherche paramédicale s'intéressant aux pratiques du quotidien au sein du pôle, favorisant ainsi la mise en commun des connaissances et des compétences. TEG1 Enfin, des bénéfices sont attendus : créer des liens entre chercheurs, faciliter le partage de connaissances et intéresser les agents souhaitant aller plus loin pour rendre accessible la recherche et en souligner l'aspect concret, au plus proche de la pratique clinique au quotidien.

T1 Constitution du groupe

Ce groupe est ouvert aux infirmiers comme aux cadres de proximité et aux cadres supérieurs, qui sont des promoteurs possibles prévus par les dispositifs de recherche (PHRIP [START_REF]Programme hospitalier de recherche infirmière et paramédicale (PHRIP)[END_REF] en premier lieu). TEG1 Avouons que la présence des cadres ne fut pas une évidence de prime abord. La crainte du regard de nos responsables hiérarchiques nous faisait redouter une mise en péril du groupe. Mais, à bien y réfléchir, ce sont les qualités de chercheur qui fondent la création de ce groupe, et non une position de cadre ou d'infirmier. Ce sont donc, d'abord, des personnes exerçant en qualité de soignants intéressés par la recherche qui assisteront à ce groupe, peu importe leur statut. Dans cet esprit, la participation des aides-soignants nous semble également envisageable aujourd'hui. TEG1 Si dans un premier temps il s'agira d'échanger sur les travaux en cours, et notamment sur l'origine de leur interrogation et les effets attendus sur les pratiques professionnelles du quotidien ; dans un second temps il sera question de proposer des lectures critiques d'articles. Pour cela, un outil conçu par Valérie Berger (chercheuse, et évaluatrice PHRIP) s'inspirant de la lecture critique d'article de Louis Rachid Salmi [START_REF] Salmi | Lecture critique et communication médicale scientifique. 3 e éd. Issy[END_REF] pourrait par exemple être utilisé. Ces lectures critiques interrogent des articles scientifiques en lien avec notre pratique, les agents pouvant librement se proposer d'en réaliser une pour la prochaine réunion. TEG1 Toutefois dans le souci constant de rendre ce groupe accessible, les lectures d'articles ne sont pas restreintes à la littérature scientifique, mais ouvertes à la littérature professionnelle, plus facile d'accès. La seule ligne directrice est de choisir un seul et unique article et de le traiter en profondeur. Puis, progressivement, sous l'impulsion des infirmiers éclairés à la recherche, et en s'appuyant sur un principe de formation entre pairs, il est question de ne plus traiter que des articles issus de la recherche.

T1 Organisation

Il est dans l'ordre des choses de pouvoir collaborer avec le centre de documentation de l'institut de formation en soins infirmiers (Ifsi), bénéficiant ainsi de toute l'expérience de ce lieu de ressources. Leur expertise sera convoquée afin de faciliter l'accès aux recherches documentaires, notamment en familiarisant le groupe aux différents outils de recherche en ligne. Quelques mois après l'ouverture du groupe, les participants ont d'une voix unanime sollicité un approfondissement de leur compétence en recherche documentaire. Un temps formatif de deux heures a pu être effectué, posant des bases simples pour la recherche d'article. Un accompagnement au long cours est d'ores et déjà engagé avec le centre de documentation. TEG1 Une salle de réunion occupant une place centrale dans l'hôpital et facile d'accès est mise à notre disposition. TEG1 Les rencontres sont programmées tous les quarante-cinq jours environ, hors vacances scolaires, sur des jours de semaine (plus favorablement le lundi ou le vendredi), de 12 heures à 14 heures. Le choix de cet horaire semble faciliter la soustraction d'un agent à l'activité du service. TEG1 La disponibilité des agents, sur leur temps de travail, montre ici que la recherche s'intègre au plus proche de l'activité quotidienne du soin et appartient à chacun des professionnels soignants. À cet intérêt professionnel se superpose, de fait, un engagement institutionnel prégnant un déploiement de la culture recherche, matérialisé par le soutien managérial disposé à intégrer ce groupe lecture dans l'organisation des soins. TEG1 Nous envisageons 12 places disponibles dédiées aux professionnels non médicaux auxquels s'ajoutent deux places réservées pour des étudiants en troisième année de formation en soins infirmiers au CH Le Vinatier, en situation de stage, afin qu'ils puissent venir accompagnés par leur tuteur. TEG1 La gestion des inscriptions à ce groupe est réalisée par le coordinateur du groupe bibliographique, simplement par un mail du soignant après que celui-ci a reçu l'accord verbal de son cadre de santé.

T1 Bilan provisoire À ce jour (fin 2019), 30 personnes sont venues au moins une fois au groupe de bibliographie, tous y ont assisté au moins deux fois ; signe probable qu'ils semblent y trouver des lectures intéressantes. Les nouveaux inscrits, tout comme la fréquentation, connaissent un pic de croissance en début de deuxième trimestre 2019, moment où le groupe a reçu le soutien de l'institution (figures 1 et 2). TEG1 Les thèmes abordés recoupent l'actualité hospitalière, comme la question de la réhospitalisation, de la transition générationnelle à l'hôpital psychiatrique, de l'intervention précoce auprès des personnes souffrant de psychose débutante, ou encore de l'évaluation de la complexité des interventions au domicile.

T1 Perspectives

Chaque fin d'année est l'occasion de réaliser un bilan, mais aussi de prévoir les perspectives, en prenant en compte les axes du groupe et les volontés de chacun. TEG1 L'année 2018 avait plébiscité d'une part une formation aux outils de la recherche par le centre de documentation de l'Ifsi, mais aussi une rencontre avec un infirmier ayant publié des résultats de recherches. TEG1 La fin d'année 2019 fut l'occasion d'intéresser les équipes de nuit à ce groupe, en ouvrant une section dédiée à ces équipes, respectant ici un des axes du projet qui inscrit ce temps de bibliographie dans l'exercice du soin. La coordination de ce groupe sera assurée spécifiquement par un des leurs, qui sera accompagné par le coordonnateur du groupe de jour sur le temps de la mise en place. En 2020, l'activité du groupe se poursuit, et si la crise sanitaire est venue freiner le rythme des rencontres, elle en fut également le sujet principal. Des rencontres en visioconférences étaient proposées pour faciliter l'accès au groupe au plus grand nombre à l'intérieur même de l'hôpital.

T1 Conclusion

Parti d'une initiative singulière de deux infirmiers, ce groupe de bibliographie soutenu par son institution semble réussir à intéresser une poignée de soignants aux réflexes, à la culture et à la pensée recherche. La collaboration du centre de documentation simplifie la démarche d'accès aux articles et ce groupe constitué se fédère autour de préoccupations communes, avec le souci permanent de l'amélioration des soins au bénéfice du patient. L'intégration des étudiants en soins infirmiers de tous les Ifsi confondus à l'échelle territoriale continuerait d'initier une culture recherche dès la formation initiale, trouvant dans ce groupe un continuum dans l'exercice pratique des sciences infirmières.

Déclaration de liens d'intérêts

Les auteurs déclarent ne pas avoir de liens d'intérêts.

  Fig1_Chalancon.eps © B. Chalancon/Elsevier Masson SAS Figure 1. Évolution du nombre d'inscrits depuis l'ouverture du groupe bibliographie.

Figure 2 .

 2 Fig2_Chalancon.eps © B. Chalancon/Elsevier Masson SAS Figure 2. Évolution du nombre de primo-arrivants dans le groupe bibliographie.


Anthony Estienne

Alice Bongrani

Pascal Froment

Joëlle Dupont
email: joelle.dupont@inrae.fr

Apelin and chemerin receptors are G protein-coupled receptors involved in metabolic as well as reproductive functions: Potential therapeutic implications?

Keywords: Apelin/APJ system, Chemerin, CMKLR1, GPR1, CCRL2, Metabolism, Reproduction. Akt

de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Introduction

Due to its ability to synthesize and secrete several cytokines and chemokines, as well as a large group of polypeptide hormones, named adipokines [START_REF] Knebel | Novel Insights into the Adipokinome of Obese and Obese/Diabetic Mouse Models[END_REF], white adipose tissue (WAT) is nowadays considered an active endocrine organ. Notably, adipokines are involved in the regulation of many physiological functions, as inflammatory processes [START_REF] Singh | Inflammatory processes in obesity: focus on endothelial dysfunction and the role of adipokines as inflammatory mediators[END_REF], energy expenditure, glucose and lipid metabolism [START_REF] Chait | Adipose Tissue Distribution, Inflammation and Its Metabolic Consequences, Including Diabetes and Cardiovascular Disease[END_REF], and reproduction [START_REF] Estienne | Involvement of Novel Adipokines, Chemerin, Visfatin, Resistin and Apelin in Reproductive Functions in Normal and Pathological Conditions in Humans and Animal Models[END_REF]. Their effects are mediated through different types of receptors, including G protein-coupled receptors (GPCRs) [START_REF] Kennedy | International Union of Basic and Clinical Pharmacology CIII: Chemerin Receptors CMKLR1 (Chemerin(1)) and GPR1 (Chemerin(2)) Nomenclature, Pharmacology, and Function[END_REF][START_REF] Read | International Union of Basic and Clinical Pharmacology. CVII. Structure and Pharmacology of the Apelin Receptor with a Recommendation that Elabela/Toddler Is a Second Endogenous Peptide Ligand[END_REF]. Here, we will review in detail the current knowledge about the role of chemerin and apelin GPCRs in both physiological and pathological metabolic and reproductive functions. Indeed, understanding of the functional and mechanistic role of these receptors is of high clinical importance, as it may significantly contribute to develop novel potential therapeutic strategies. Thus, in the last section, we will further discuss about their possible implication as innovative targets for pharmacological interventions.

Apelin and chemerin systems Apelin

Apelin is a peptide originally isolated from the bovine stomach tissue [START_REF] Tatemoto | Isolation and characterization of a novel endogenous peptide ligand for the human APJ receptor[END_REF]. In humans, it derives from the C-terminal processing of the 77 amino acids pre-proapelin, followed by several post-translational modifications that lead to the production of three main apelin fragments, apelin-36, apelin-17 and apelin-13 [START_REF] Huang | Apelin/APJ system: A novel potential therapy target for kidney disease[END_REF][START_REF] Luo | Apelin/APJ system: A critical regulator of vascular smooth muscle cell[END_REF] (Figure 1). The latter can further undergo cyclization of glutamine in its N-terminal to produce pyroglutamated-modified apelin-13 ((Pyr1)-apelin-13, Figure 1), characterised by increased stability and plasma halflife [START_REF] Read | International Union of Basic and Clinical Pharmacology. CVII. Structure and Pharmacology of the Apelin Receptor with a Recommendation that Elabela/Toddler Is a Second Endogenous Peptide Ligand[END_REF].

Recently, Apelin Receptor Early Endogenous Ligand (APELA, also named ELABELA or Toddler) was identified as a new endogenous ligand for apelin receptor, APJ [START_REF] Chng | ELABELA: a hormone essential for heart development signals via the apelin receptor[END_REF]. Similarly to apelin, human ELABELA derives from a 54 amino acids precursor, processed into several isoforms named ELABELA-32, ELABELA-21 and ELABELA-11 [START_REF] Zhang | Elabela, a newly discovered APJ ligand: Similarities and differences with Apelin[END_REF]. All apelin and ELABELA isoforms are able to bind to APJ, but they present variable receptor affinities and determine different intracellular trafficking pathways [START_REF] Read | International Union of Basic and Clinical Pharmacology. CVII. Structure and Pharmacology of the Apelin Receptor with a Recommendation that Elabela/Toddler Is a Second Endogenous Peptide Ligand[END_REF]. Anyway, as ELABELA is not described as an adipokine, in the present review we will not further discuss about it.

APJ is a typical 380 amino acids GPCR [START_REF] Read | International Union of Basic and Clinical Pharmacology. CVII. Structure and Pharmacology of the Apelin Receptor with a Recommendation that Elabela/Toddler Is a Second Endogenous Peptide Ligand[END_REF]. It was firstly identified in 1993 as a class A (rhodopsin-like) orphan GPCR that shares 54% sequence homology with the angiotensin II type 1 receptor [START_REF] O'dowd | A human gene that shows identity with the gene encoding the angiotensin receptor is located on chromosome 11[END_REF]. Apelin/APJ system is able to activate several signalling pathways through different types of G proteins (Figure 1). While apelin-36 induces stable βarrestin binding to APJ leading to its degradation, apelin-13 allows the dissociation of APJ from β-arrestin and its subsequent rapid recycling after internalisation [START_REF] Shin | Apelinergic System Structure and Function[END_REF]. Recent increasing evidence shows that APJ may form heterodimers with other GPCRs [START_REF] Cai | Apelin receptor homodimer-oligomers revealed by single-molecule imaging and novel G protein-dependent signaling[END_REF].

Chemerin

Chemerin, also known as Retinoic Acid Receptor Responder protein 2 (RARRES2), Tazarotene-Induced Gene 2 protein (TIG2), or RAR-responsive protein TIG2, is a small chemotactic protein derived from an initial precursor named pre-prochemerin [START_REF] Zabel | Chemerin activation by serine proteases of the coagulation, fibrinolytic, and inflammatory cascades[END_REF]. This requires the N-terminal cleavage of a 19 amino acids signalling domain to be secreted into the extracellular media as an inactive precursor of 163 amino acids, known as prochemerin or chemerin-S163 [START_REF] Henau | Signaling Properties of Chemerin Receptors CMKLR1, GPR1 and CCRL2[END_REF][START_REF] Helfer | Chemerin: a multifaceted adipokine involved in metabolic disorders[END_REF]. In humans, the subsequent extracellular proteolytic C-terminal processing by serine and cysteine proteases generates different active isoforms of chemerin, chemerin-F156, -S157 and -K158, all of which have been detected in biological fluids including plasma (Figure 1). Extracellular proteolytic events may further convert chemerin active isoforms to shorter deactivated proteins, like chemerin-F154 [START_REF] Gao | Resolvin E1 and chemokine-like receptor 1 mediate bone preservation[END_REF].

The biological effects of chemerin are mainly mediated by two GPCRs, chemokinelike receptor 1 (CMKLR1) and G protein-coupled receptor 1 (GPR1) [START_REF] Goralski | More Than an Adipokine: The Complex Roles of Chemerin Signaling in Cancer[END_REF][START_REF] Helfer | Chemerin: a multifaceted adipokine involved in metabolic disorders[END_REF][START_REF] Kennedy | International Union of Basic and Clinical Pharmacology CIII: Chemerin Receptors CMKLR1 (Chemerin(1)) and GPR1 (Chemerin(2)) Nomenclature, Pharmacology, and Function[END_REF]. Chemerin binds and activates both receptors, each triggering different intracellular signalling pathways (Figure 1). CMKLR1 is widely expressed in several organs, such as haematopoietic tissues, adipocytes, endothelial cells, osteoclasts and ovarian cells [START_REF] Kennedy | International Union of Basic and Clinical Pharmacology CIII: Chemerin Receptors CMKLR1 (Chemerin(1)) and GPR1 (Chemerin(2)) Nomenclature, Pharmacology, and Function[END_REF], while GPR1 expression, absent in immune cells, has been predominantly reported in central nervous system cells, murine brown adipose tissue, vascular cells of WAT, gonads and skeletal muscle [START_REF] Kennedy | International Union of Basic and Clinical Pharmacology CIII: Chemerin Receptors CMKLR1 (Chemerin(1)) and GPR1 (Chemerin(2)) Nomenclature, Pharmacology, and Function[END_REF]. The third receptor of chemerin, C-C motif chemokine receptor like 2 (CCRL2), shows limited homology with CMKLR1 and GPR1 and probably it does not mediate chemerin signalling. Indeed, it is thought to function rather as a membrane anchoring protein that increases local chemerin concentration and presents its ligand to cells expressing CMKLR1 and GPR1 [START_REF] Kennedy | International Union of Basic and Clinical Pharmacology CIII: Chemerin Receptors CMKLR1 (Chemerin(1)) and GPR1 (Chemerin(2)) Nomenclature, Pharmacology, and Function[END_REF][START_REF] Yoshimura | Chemokine-like receptor 1 (CMKLR1) and chemokine (C-C motif) receptor-like 2 (CCRL2); Two multifunctional receptors with unusual properties[END_REF]. Supporting this hypothesis, CCRL2 expression was detected in macrophages, mast cells, lung epithelial cells and the ovary.

Role of APJ and chemerin receptors in metabolism and reproduction

All isoforms of chemerin and apelin have been detected in many biological fluids, including serum, cerebrospinal fluid, colostrum and mature milk [START_REF] Helfer | Chemerin: a multifaceted adipokine involved in metabolic disorders[END_REF][START_REF] Huang | Apelin/APJ system: A novel potential therapy target for kidney disease[END_REF][START_REF] Kennedy | International Union of Basic and Clinical Pharmacology CIII: Chemerin Receptors CMKLR1 (Chemerin(1)) and GPR1 (Chemerin(2)) Nomenclature, Pharmacology, and Function[END_REF][START_REF] Kurowska | Apelin in Reproductive Physiology and Pathology of Different Species: A Critical Review[END_REF][START_REF] Luo | Apelin/APJ system: A critical regulator of vascular smooth muscle cell[END_REF][START_REF] Lv | Apelin/APJ system: A key therapeutic target for liver disease[END_REF][START_REF] Read | International Union of Basic and Clinical Pharmacology. CVII. Structure and Pharmacology of the Apelin Receptor with a Recommendation that Elabela/Toddler Is a Second Endogenous Peptide Ligand[END_REF].

Notably, apelin/APJ and chemerin systems are expressed in several regions of nervous and metabolic tissues implicated in regulating physiological processes as food and water intake, insulin secretion, glucose and lipid metabolism and adipogenesis, and their involvement in some metabolic disorders, including obesity, type 2 diabetes mellitus (T2DM) and hepatic cirrhosis, is supported by a growing body of evidence (Figure 2). Although less studied within the reproductive tract, apelin and chemerin expression has also been reported in male and female gonads, uterus and placenta, where these adipokines have been suggested to contribute to the development of some frequent diseases, like polycystic ovary syndrome (PCOS), endometriosis, preeclampsia (PE) and varicocele (Figure 3).

Metabolic effects of APJ and chemerin receptors in physiological and pathological conditions

Brain and food/water intake

The activation of chemerin signalling pathway in neuroendocrine axis seems to play a crucial role in appetite regulation, as suggested by a study conducted on photoperiodicsensitive F344 rats, where continuous intracerebral infusion of chemerin promoted food intake, whereas chemokine-like receptor 1 deficiency resulted in reduced food intake and body weight [START_REF] Helfer | A neuroendocrine role for chemerin in hypothalamic remodelling and photoperiodic control of energy balance[END_REF]. Although several studies have suggested a possible involvement of apelin system in feeding behaviour, to date, in mammals, results about its physiological effect on food intake are not consistent [START_REF] Yang | Role of apelin/APJ system in hypothalamic-pituitary axis[END_REF]. At the opposite, apelin seems to play a prominent role in the regulation of body fluid homeostasis in humans and rodents [START_REF] Flahault | Role of the vasopressin/Apelin Balance and Potential Use of Metabolically Stable Apelin Analogs in water Metabolism Disorders[END_REF]. Indeed, plasma apelin concentration is lower in patients with polyuria-polydipsia syndrome and intracerebroventricular injection of apelin into lactating rats inhibits the phasic electrical activity of arginine vasopressin (AVP) neurons, resulting in reduced plasma AVP levels and increased diuresis [START_REF] Flahault | Role of the vasopressin/Apelin Balance and Potential Use of Metabolically Stable Apelin Analogs in water Metabolism Disorders[END_REF]. Thus, as regards their effect on neuroendocrine axis, apelin appears to be mainly involved in fluid homeostasis, while chemerin would rather act as a potential regulator of food intake.

Liver and glucose metabolism

The association of chemerin and apelin with obesity and metabolic syndrome, as well as their involvement in insulin and glucose metabolism have been repeatedly reported [START_REF] Buechler | Chemerin Isoforms and Activity in Obesity[END_REF][START_REF] Lv | Apelin/APJ system: A key therapeutic target for liver disease[END_REF].

However, although hepatocytes are the main cell type producing chemerin, the effects of this adipokine in liver, particularly on gluconeogenesis, are still unclear [START_REF] Helfer | Chemerin: a multifaceted adipokine involved in metabolic disorders[END_REF]. Concerning apelin system, APJ expression has been shown in primary hepatocytes, HepG2 cells, murine hepatic tissue, rat liver [START_REF] O'carroll | Distribution of mRNA encoding B78/apj, the rat homologue of the human APJ receptor, and its endogenous ligand apelin in brain and peripheral tissues[END_REF] and human hepatic stellate cells [START_REF] Lv | Apelin/APJ system: A key therapeutic target for liver disease[END_REF]. This latter cell type expresses also apelin peptide, but apelin hepatic expression appears lower than that of APJ [START_REF] Lv | Apelin/APJ system: A key therapeutic target for liver disease[END_REF]. Confirming the relevant role of apelin in glucose homeostasis, in mice, intraventricular injection of this adipokine stimulates liver glycogenolysis and gluconeogenesis via the activation of sympathetic nervous system, resulting in peripheral hyperglycemia [START_REF] Lv | Apelin/APJ system: A key therapeutic target for liver disease[END_REF]. However, apelin effects on liver seems to be indirect since some studies demonstrated that insulin resistant mice treated by apelin decreased steatosis without directly targeting hepatocytes but by enhancing global sensitivity to insulin [START_REF] Bertrand | Chronic apelin treatment improves hepatic lipid metabolism in obese and insulin-resistant mice by an indirect mechanism[END_REF]. Some studies also suggest the involvement of chemerin and apelin in human hepatic pathology. Indeed, circulating chemerin has been shown to be increased in non-alcoholic fatty liver disease (NAFLD) [START_REF] Boutari | Association of Adipokines with Development and Progression of Nonalcoholic Fatty Liver Disease[END_REF], and plasma/liver expression of apelin would be higher in patients with hepatic fibrosis and cirrhosis [START_REF] Lv | Apelin/APJ system: A key therapeutic target for liver disease[END_REF][START_REF] Wang | Apelin promotes hepatic fibrosis through ERK signaling in LX-2 cells[END_REF]. Interestingly, in a mouse model of liver tumour, mimicking fibrosis associated to hepatocellular carcinoma, chemerin seems to present a tumour inhibitory potential, delaying early carcinogenesis [START_REF] Haberl | Overexpression of Hepatocyte Chemerin-156 Lowers Tumor Burden in a Murine Model of Diethylnitrosamine-Induced Hepatocellular Carcinoma[END_REF].

Pancreas and insulin secretion

Both apelin and chemerin, as well as their receptors, are expressed in pancreatic islets, notably in β-cells, strongly supporting their role in insulin sensitivity and glucose uptake regulation. Notably, in mice intravenous injection of apelin resulted in insulin secretion inhibition, decreased glucose levels and reduced insulin-resistance (IR) [START_REF] Read | International Union of Basic and Clinical Pharmacology. CVII. Structure and Pharmacology of the Apelin Receptor with a Recommendation that Elabela/Toddler Is a Second Endogenous Peptide Ligand[END_REF]. Conversely, apelin deficient mice developed a state of IR, that was reversed by exogenous apelin administration. In humans, circulating apelin seems to be increased in T2DM and obesity [START_REF] Read | International Union of Basic and Clinical Pharmacology. CVII. Structure and Pharmacology of the Apelin Receptor with a Recommendation that Elabela/Toddler Is a Second Endogenous Peptide Ligand[END_REF], and to play a protective role in the diabetes related complications, suggesting this adipokine as a potential metabolic biomarker [START_REF] Wysocka | The Role of Apelin in Cardiovascular Diseases, Obesity and Cancer[END_REF]. However, to date, the relationship between apelin, glucose metabolism and IR is still unclear and requires further investigations [START_REF] Wysocka | The Role of Apelin in Cardiovascular Diseases, Obesity and Cancer[END_REF].

Likewise, chemerin, CMKLR1 and GPR1 are expressed in human and rodent pancreatic β-cells [START_REF] Helfer | Chemerin: a multifaceted adipokine involved in metabolic disorders[END_REF] and systemic and local chemerin levels seem to be upregulated in T2DM patients and to represent a significant factor for metabolic syndrome [START_REF] Helfer | Chemerin: a multifaceted adipokine involved in metabolic disorders[END_REF].

Nevertheless, contrarily to apelin, chemerin would rather promote insulin secretion, as suggested by studies in knockout and overexpressing transgenic mice for chemerin and CMKLR1 [START_REF] Helfer | Chemerin: a multifaceted adipokine involved in metabolic disorders[END_REF].

Adipose tissue and adipogenesis/lipid metabolism

Although literature is still poor and data are often conflicting, increasing evidence highlights an important role of apelin in obesity and its related metabolic disorders [START_REF] Read | International Union of Basic and Clinical Pharmacology. CVII. Structure and Pharmacology of the Apelin Receptor with a Recommendation that Elabela/Toddler Is a Second Endogenous Peptide Ligand[END_REF]. Apelin/APJ system is expressed in white and brown preadipocytes and adipocytes [START_REF] Read | International Union of Basic and Clinical Pharmacology. CVII. Structure and Pharmacology of the Apelin Receptor with a Recommendation that Elabela/Toddler Is a Second Endogenous Peptide Ligand[END_REF], where it promotes insulin sensitivity and glucose utilisation [START_REF] Read | International Union of Basic and Clinical Pharmacology. CVII. Structure and Pharmacology of the Apelin Receptor with a Recommendation that Elabela/Toddler Is a Second Endogenous Peptide Ligand[END_REF]. Furthermore, apelin seems to be involved in angiogenesis of WAT and to inhibit white adipocytes differentiation, lipolysis and reactive oxygen species release [START_REF] Read | International Union of Basic and Clinical Pharmacology. CVII. Structure and Pharmacology of the Apelin Receptor with a Recommendation that Elabela/Toddler Is a Second Endogenous Peptide Ligand[END_REF]. Moreover, apelin, by blocking the increase in vascular permeability to fatty acids, would prevent their accumulation in WAT. Consequently, apelin could have an anti-obesogenic effect [START_REF] Sawane | Apelin inhibits dietinduced obesity by enhancing lymphatic and blood vessel integrity[END_REF]. It has also a dilatator effect on blood vessels in an endothelium-dependent manner [START_REF] Liu | Apelin/Elabela-APJ: a novel therapeutic target in the cardiovascular system[END_REF].

Visceral white AT appears as the fat major contributor of systemic chemerin, while brown AT participation would be significantly lower. The activation of chemerin-CMKLR1 pathway stimulates adipocytes differentiation and lipolysis in 3T3-L1 cells and bovine mature adipocytes [START_REF] Ferland | Chemerin contributes to in vivo adipogenesis in a location-specific manner[END_REF][START_REF] Fu | Chemerin induces lipolysis through ERK1/2 pathway in intramuscular mature adipocytes of dairy bull calves[END_REF], and in chemerin/CMKLR-1 knockout in 3T3-L1 cells adipogenesis was impaired [START_REF] Helfer | Chemerin: a multifaceted adipokine involved in metabolic disorders[END_REF]. In rats, a recent study showed that chemerin contributes significantly to adipocyte development, but in a location-specific manner, as its effect was limited to mesenteric AT [START_REF] Ferland | Chemerin contributes to in vivo adipogenesis in a location-specific manner[END_REF]. In humans and mice, plasma chemerin levels and its mRNA expression in subcutaneous and omental AT are clearly increased in obesity, decreased upon weight loss and positively correlated with BMI, waist-hip ratio and visceral adipose mass, confirming a strong relationship between chemerin and obesity (reviewed by [START_REF] Buechler | Chemerin Isoforms and Activity in Obesity[END_REF]).

Interestingly, apelin seems to be able to increase thermogenic brown-like characteristics of white adipocytes [START_REF] Than | Apelin Enhances Brown Adipogenesis and Browning of White Adipocytes[END_REF] and CMKLR1 deficiency results in suppression of thermogenesis-related genes expression in both white and brown AT, suggesting that chemerin and apelin could represent a novel potential target for therapeutic strategy in obesity [START_REF] Buechler | Chemerin Isoforms and Activity in Obesity[END_REF].

Skeletal and smooth muscle tissues

Apelin/APJ expression has been detected in skeletal and vascular smooth muscle cells, endothelial cells and cardiomyocytes [START_REF] Huang | Apelin/APJ system: A novel potential therapy target for kidney disease[END_REF]. Most of the studies investigating apelin effects on skeletal muscle have been performed in obesity and T2DM conditions. Concerning glucose metabolism, it have been also shown that apelin intravenous injections in mice lead to a powerful glucose-lowering effect associated with enhanced glucose uptake and utilization in skeletal muscle through AMPK signaling pathway [START_REF] Dray | Apelin stimulates glucose utilization in normal and obese insulin-resistant mice[END_REF]. A similar effect on AMPK by apelin has also been described in cultured C2C12 myotubes [START_REF] Yue | Apelin is necessary for the maintenance of insulin sensitivity[END_REF]. In skeletal muscle, apelin improves muscle function by triggering mitochondriogenesis, autophagy and anti-inflammatory pathways in myofibers, as well as enhancing muscle regenerative capacity by targeting stem cells [START_REF] Vinel | The exerkine apelin reverses age-associated sarcopenia[END_REF]. Indeed, deficient mice for apelin or APJ present dramatic alterations in muscle function with increasing age. In the light of these data, apelin was proposed as a promising therapeutic target to treat sarcopenia [START_REF] Vinel | The exerkine apelin reverses age-associated sarcopenia[END_REF].

Chemerin and its receptors are also expressed in skeletal and smooth muscle tissues [START_REF] Helfer | Chemerin: a multifaceted adipokine involved in metabolic disorders[END_REF]. However, in skeletal muscle cells, chemerin impairs insulin signalling and glucose uptake [START_REF] Helfer | Chemerin: a multifaceted adipokine involved in metabolic disorders[END_REF]. In addition, in rats, chemerin stimulates smooth muscle cells proliferation and migration via autophagy, that may contribute to vascular structural remodelling at the origin of blood hypertension [START_REF] Wen | Chemerin stimulates aortic smooth muscle cell proliferation and migration via activation of autophagy in VSMCs of metabolic hypertension rats[END_REF].

Thus, as regards muscle function, apelin and chemerin would exert opposite effects.

While apelin would have a protective role, improving insulin sensitivity and muscle function via mitochondriogenesis, chemerin seems impair muscle glucose uptake and participate to the development of obesity-related cardiovascular complications.

APJ and chemerin receptors effects on reproduction in physiological and pathological conditions

Ovary

Apelin, APJ, chemerin, CMKLR1, GPR1 and CCRL2 expression are found in human ovarian follicles, granulosa and theca cells, and oocytes and in vitro studies suggest a potential role of apelin and chemerin system in the control of several aspects of ovarian functions [START_REF] Bongrani | Ovarian Expression of Adipokines in Polycystic Ovary Syndrome: A Role for Chemerin, Omentin, and Apelin in Follicular Growth Arrest and Ovulatory Dysfunction[END_REF][START_REF] Estienne | Involvement of Novel Adipokines, Chemerin, Visfatin, Resistin and Apelin in Reproductive Functions in Normal and Pathological Conditions in Humans and Animal Models[END_REF]. Indeed, apelin enhances progesterone and estradiol secretion in primary human granulosa cells whereas chemerin inhibits it [START_REF] Kurowska | Apelin in Reproductive Physiology and Pathology of Different Species: A Critical Review[END_REF]. Apelin improves rat, bovine, and porcine in vitro granulosa cell proliferation whereas chemerin inhibits IGF-1-induced thymidine incorporation in human granulosa cells [START_REF] Kurowska | Apelin in Reproductive Physiology and Pathology of Different Species: A Critical Review[END_REF]. Both chemerin and apelin decrease in vitro bovine oocyte maturation [START_REF] Estienne | Involvement of Novel Adipokines, Chemerin, Visfatin, Resistin and Apelin in Reproductive Functions in Normal and Pathological Conditions in Humans and Animal Models[END_REF]. In corpus luteum, apelin and chemerin regulate the luteolysis process. The apelinergic axis plays a role in the transient luteal stage after ovulation. Chemerin through GPR1 signaling may suppress progesterone secretion and promote PGF2α-induced luteolysis in mice [START_REF] Yang | The role of GPR1 signaling in mice corpus luteum[END_REF]. In human, the concentrations of apelin and APJ are significantly increased in PCOS patients with a positive correlation between follicle count and APLN levels [START_REF] Bongrani | Ovarian Expression of Adipokines in Polycystic Ovary Syndrome: A Role for Chemerin, Omentin, and Apelin in Follicular Growth Arrest and Ovulatory Dysfunction[END_REF]. Chemerin follicular fluid concentration and chemerin and CMKLR1 mRNA levels in granulosa cells are also predominant in women with PCOS [START_REF] Bongrani | Ovarian Expression of Adipokines in Polycystic Ovary Syndrome: A Role for Chemerin, Omentin, and Apelin in Follicular Growth Arrest and Ovulatory Dysfunction[END_REF].

PCOS is is a common gynecological endocrinopathy disorder characterized by over-expressed LH triggered hyperandrogenism, chronic oligo/anovulation and polycystic ovaries morphology, with clinical manifestations described as "hirsutism, acne, irregular menstruation and subfertility". In mice, CMKLR1 gene deletion protects against the damage caused by chronic dihydrostestosterone treatment on ovarian function suggesting that androgen-induced polycystic ovary syndrome might be prevented through therapeutic targeting of CMKLR1 (reviewed in [START_REF] Estienne | Involvement of Novel Adipokines, Chemerin, Visfatin, Resistin and Apelin in Reproductive Functions in Normal and Pathological Conditions in Humans and Animal Models[END_REF]). In addition, Li et al., 2019 recently showed that elevated chemerin induces insulin resistance in human granulosa-lutein cells from PCOS patients suggesting that chemerin and its receptor could be further implicated as potential therapeutic targets in the future treatment of PCOS [START_REF] Li | Elevated chemerin induces insulin resistance in human granulosa-lutein cells from polycystic ovary syndrome patients[END_REF].

Thus, apelin and chemerin could be involved in the PCOS disorder that is is a common gynecological endocrinopathy affecting 6% to 13% of women of reproductive age and one of the leading causes of female poor fertility.

Uterus

In rat, plasma apelin levels are increased at the end of pregnancy, and the hormone induced the uterus contractions [START_REF] Kacar | The effects of apelin on myometrium contractions in pregnant rats[END_REF]. An in vitro study showed a vasodilator role of apelin in suppressing both spontaneous and oxytocin-induced contraction in human myometrial fibers.

Similar expression patterns of apelin was seen in both eutopic and ectopic endometrium during the menstrual cycle indicated that the ectopic endometrial lesion could share some characteristics with eutopic cellular processes in endometrium regeneration. Additionally, the angiogenesis and vasodilation effects of apelin could potentially be one of the causes in triggering the symptoms of endometriosis [START_REF] Kurowska | Apelin in Reproductive Physiology and Pathology of Different Species: A Critical Review[END_REF].

In the uterus, chemerin is up-regulated during decidualization, and it could play a crucial role in vascular remodelling during early pregnancy of women. Injection of CMKLR1

receptor antagonist (α-NETA) in the uterus of mice induces an increase in embryo resorption rate suggesting that chemerin/CMKLR1 system plays an important role in the maintenance of early pregnancy [START_REF] Yang | Role of chemerin/CMKLR1 in the maintenance of early pregnancy[END_REF]. Chemerin concentrations are higher in peritoneal fluid from women with endometriosis than that in that from controls [START_REF] Jin | Chemerin Expression in the Peritoneal Fluid, Serum, and Ovarian Endometrioma of Women with Endometriosis[END_REF]. In addition, mRNA and protein of chemerin and its receptor are significantly increased in the ovarian endometrioma tissue compared with eutopic endometrium of controls suggesting that chemerin plays a role in endometriosis-related pelvic inflammation [START_REF] Jin | Chemerin Expression in the Peritoneal Fluid, Serum, and Ovarian Endometrioma of Women with Endometriosis[END_REF]. Thus, both apelin and chemerin could be involved in the endometriosis that affects 10-15% of all women of reproductive age.

Placenta

Apelin and APJ is detected in numerous placental cells [START_REF] Mlyczynska | Apelin and apelin receptor in human placenta: Expression, signalling pathway and regulation of trophoblast JEG3 and BeWo cells proliferation and cell cycle[END_REF]. A drop in circulating apelin level observed in newborns rapidly after birth, suggests that the placenta could be a source of blood apelin for the fetus [START_REF] Mlyczynska | Apelin and apelin receptor in human placenta: Expression, signalling pathway and regulation of trophoblast JEG3 and BeWo cells proliferation and cell cycle[END_REF]. Apelin is strongly expressed in the cytoplasm of human cytotrophoblasts during the first two trimester of pregnancy, and then decreased at the third trimester. Based on this broad distribution and its known vasodilatory function in the periphery, apelin could be implicated in placental vascular tone and influences subsequent maternal-fetal exchange of oxygen and nutrients [START_REF] Mlyczynska | Apelin and apelin receptor in human placenta: Expression, signalling pathway and regulation of trophoblast JEG3 and BeWo cells proliferation and cell cycle[END_REF]. Preeclampsia (PE) is a serious disorder of pregnancy characterized by hypertension beginning after 20 weeks of pregnancy, often accompanied by proteinuria and multi-organ dysfunctions. Apelin sub-cutaneous administration in a rat model of PE (reduced uterine perfusion) reduces maternal hypertension and proteinuria, and ameliorates fetal growth suggesting that apelin could be a potential drug target for PE treatment [START_REF] Wang | Apelin as a novel drug for treating preeclampsia[END_REF].

Chemerin and its receptors are expressed in placenta trophoblastic cells. In rat, serum chemerin levels significantly decrease as gestation progresses (cited by [START_REF] Estienne | Involvement of Novel Adipokines, Chemerin, Visfatin, Resistin and Apelin in Reproductive Functions in Normal and Pathological Conditions in Humans and Animal Models[END_REF]). Chemerin plays a role in placentation by regulating NK cell accumulation and endothelial cell morphogenesis during early pregnancy (cited by [START_REF] Estienne | Involvement of Novel Adipokines, Chemerin, Visfatin, Resistin and Apelin in Reproductive Functions in Normal and Pathological Conditions in Humans and Animal Models[END_REF]). In mice and human, the chemerin/GPR1 could regulate the carbohydrate balance during pregnancy (reviewed by [START_REF] Estienne | Involvement of Novel Adipokines, Chemerin, Visfatin, Resistin and Apelin in Reproductive Functions in Normal and Pathological Conditions in Humans and Animal Models[END_REF][START_REF] Kurowska | Apelin in Reproductive Physiology and Pathology of Different Species: A Critical Review[END_REF]) . In women, PE is linked to increased plasma levels of chemerin [START_REF] Daskalakis | The role of serum adipokine levels in preeclampsia: A systematic review[END_REF]. In rat, a recent study shows that vitamin D supplementation would protect against development of preeclampsia through plasma chemerin reduction [START_REF] Nassar | Protective effect of vitamin D supplementation in a rat modal of preeclampsia: a possible implication of chemerin[END_REF].

Thus, the apelin and chemerin system might play an important role in the PE pathogenesis that is one of the main contributor to foetal, neonatal and maternal morbidity and mortality.

Testis

Apelin, APJ, chemerin and its three receptors CMKLR1, GPR1 and CCRL2 are expressed in rat and human male reproductive tracts (cited by [START_REF] Estienne | Involvement of Novel Adipokines, Chemerin, Visfatin, Resistin and Apelin in Reproductive Functions in Normal and Pathological Conditions in Humans and Animal Models[END_REF]). Intracerebroventricular infusion of Apelin-13 has been shown to reduce serum testosterone levels and the number of Leydig cells in testicular tissue suggesting that apelin may play a role in the central regulation of testosterone release by suppressing LH secretion (cited by [START_REF] Kurowska | Apelin in Reproductive Physiology and Pathology of Different Species: A Critical Review[END_REF]). An increase of apelin expression in varicocele-induced testicular tissue suggests that apelin may have a role in the varicocele etiopathogenesis [START_REF] Akkan | The effect of experimental varicocele on the apelin and APJ expressions in rat testis tissue[END_REF]. Chemerin, CMKLR1 and GPR1 proteins are specifically localised in Leydig cells of the human and rat testis. In rat primary Leydig cell cultures, chemerin suppressed the testosterone production induced by human chorionic gonadotropin (hGC, Figure 3). CMKLR1 deficiency significantly reduced serum testosterone levels and the mRNA levels for some steroidogenic enzymes and transcriptional regulator genes in mouse Leydig cells and testis tissue in vivo [START_REF] Zhao | Chemokine-like receptor 1 deficiency leads to lower bone mass in male mice[END_REF].

Thus, apelin and chemerin systems are expressed in testis and may be target proteins that should be more investigated in male reproductive pathologies.

Pharmacological potential of APJ and chemerin receptors as novel therapeutic targets

Given their broad effects in metabolic and reproductive functions, apelin and chemerin, as well as their receptors, appear as promising candidates for the development of novel therapeutic strategies. At present, several agonists and antagonists of APJ and chemerin receptors have been discovered and synthesized and showed some effectiveness in both in vitro and in vivo animal and human studies [START_REF] Fischer | A patent review of apelin receptor (APJR) modulators (2014-2019)[END_REF][START_REF] Huang | Targeting drugs to APJ receptor: From signaling to pathophysiological effects[END_REF][START_REF] Read | International Union of Basic and Clinical Pharmacology. CVII. Structure and Pharmacology of the Apelin Receptor with a Recommendation that Elabela/Toddler Is a Second Endogenous Peptide Ligand[END_REF]. Concerning APJ, three recent reviews have already detailed its several modulators and their potential therapeutic implications [START_REF] Fischer | A patent review of apelin receptor (APJR) modulators (2014-2019)[END_REF][START_REF] Huang | Targeting drugs to APJ receptor: From signaling to pathophysiological effects[END_REF][START_REF] Read | International Union of Basic and Clinical Pharmacology. CVII. Structure and Pharmacology of the Apelin Receptor with a Recommendation that Elabela/Toddler Is a Second Endogenous Peptide Ligand[END_REF], reason why, here, we will present only agonists and antagonists of chemerin receptors (Table 1). To date, at least four antagonists have been reported for CMKLR1 [START_REF] Kennedy | International Union of Basic and Clinical Pharmacology CIII: Chemerin Receptors CMKLR1 (Chemerin(1)) and GPR1 (Chemerin(2)) Nomenclature, Pharmacology, and Function[END_REF], while no one has been still developed for GPR1. As shown in Table 1, several agonists for both CMKLR1 and GPR1 have been described. Most of these modulators have been tested in metabolic diseases, but only very few in reproductive disorders.

Conclusions

Apelin and chemerin receptors are GPCRs involved in both metabolic and reproductive functions in physiological and pathological conditions. The development of potent and selective drugs that target these signalling pathways remains a current need and an innovative perspective, not only as potential therapeutic agents, but also as pharmacological tools to better understand the role of chemerin and apelin systems. The canonical apelin signalling pathway involves the activation of inhibitory G proteins, Gi/o, leading to a dramatic decrease in intracytoplasmic cyclic adenosine monophosphate (cAMP) levels. However, in some cellular types, particularly in cardiomyocytes, APJ may also couple to Gq. Additionally, in Chinese hamster ovary cells stably expressing mouse APJ, apelin-13 and apelin-36 isoforms have been shown to activate the phosphorylation of ERK1/2 and in human umbilical vein endothelial cells (HUVECs), apelin seems to promote cell proliferation via ERK1/2-, mammalian target of rapamycin (mTOR)-, and Akt-dependent intracellular cascades, confirming that several downstream effectors can be triggered by APJ. Apelin binding to its receptor can also result in cytoplasmic β-arrestin recruitment, leading to its desensitization and internalization [START_REF] Luo | Apelin/APJ system: A critical regulator of vascular smooth muscle cell[END_REF][START_REF] Lv | Apelin/APJ system: A key therapeutic target for liver disease[END_REF]

Legends to figures

Table 1: List of some agonists and antagonist of CMKLR1 and GPR1 receptors

Most of the data are compiled from [START_REF] Kennedy | International Union of Basic and Clinical Pharmacology CIII: Chemerin Receptors CMKLR1 (Chemerin(1)) and GPR1 (Chemerin(2)) Nomenclature, Pharmacology, and Function[END_REF] Agonists Antagonists CMKLR1

Resolvin E1 through CMKLR1 mediates bone preservation [START_REF] Gao | Resolvin E1 and chemokine-like receptor 1 mediate bone preservation[END_REF], stimulates β arrestin recruitment and adenosine diphosphate activation of human platelets (reviewed in [START_REF] Kennedy | International Union of Basic and Clinical Pharmacology CIII: Chemerin Receptors CMKLR1 (Chemerin(1)) and GPR1 (Chemerin(2)) Nomenclature, Pharmacology, and Function[END_REF] ). C9 [chemerin(149-157)] prevents atherogenesis in vitro in human THP1 1 monocytes, HUVECs 2 , and HASMCs 3 and in vivo in aortic lesions in Apoe -/-mice [START_REF] Sato | Chemerin-9, a potent agonist of chemerin receptor (ChemR23), prevents atherogenesis[END_REF]. It causes concentration-dependent contraction in a rat conduit vessel (aorta) reviewed in [START_REF] Kennedy | International Union of Basic and Clinical Pharmacology CIII: Chemerin Receptors CMKLR1 (Chemerin(1)) and GPR1 (Chemerin(2)) Nomenclature, Pharmacology, and Function[END_REF].

CCX832 : it blocked C9-mediated β-arrestin recruitment at CMKLR1 in mesenchymal stromal cells , it also blocked chemerin induced cell. It blocks chemerin-induced vasoconstriction in rat aorta and human vessels in vitro (reviewed in [START_REF] Kennedy | International Union of Basic and Clinical Pharmacology CIII: Chemerin Receptors CMKLR1 (Chemerin(1)) and GPR1 (Chemerin(2)) Nomenclature, Pharmacology, and Function[END_REF]). α-NETA (2-(anaphthoyl) ethyltrimethylammonium iodide), it delays the onset of the autoimmune encephalomyelitis. Application in demyelinating disease [START_REF] Kumar | Novel CMKLR1 Inhibitors for Application in Demyelinating Disease[END_REF]. In reproduction, α-NETA intrauterinely injection into normal pregnant mice leads to the abortion of mouse embryos [START_REF] Yang | Role of chemerin/CMKLR1 in the maintenance of early pregnancy[END_REF]. C13 [chemerin(145-157)] reviewed in [START_REF] Kennedy | International Union of Basic and Clinical Pharmacology CIII: Chemerin Receptors CMKLR1 (Chemerin(1)) and GPR1 (Chemerin(2)) Nomenclature, Pharmacology, and Function[END_REF] CA4910 and CA5183 inhibit chemerin-induced intracellular Ca2+ release and antagonize chemotaxis of human monocute-derived dendritic cells. (reviewed in [START_REF] Kennedy | International Union of Basic and Clinical Pharmacology CIII: Chemerin Receptors CMKLR1 (Chemerin(1)) and GPR1 (Chemerin(2)) Nomenclature, Pharmacology, and Function[END_REF]). C15 [chemerin(141-155)] and C19 [chemerin(139-157)] terminal peptides stimulate glucose uptake in the presence of insulin by rat and mouse wild-type epididymal adipocytes [START_REF] Wargent | Evidence from studies in rodents and in isolated adipocytes that agonists of the chemerin receptor CMKLR1 may be beneficial in the treatment of type 2 diabetes[END_REF]. C20 [chemerin(138-157)] suppresses in vitro gonadal steroidogenesis in rat [START_REF] Li | Chemerin-Derived Peptide C-20 Suppressed Gonadal Steroidogenesis[END_REF] .

GPR1

C9 [chemerin(149-157)] through GPR1 is involved in β arrestin recruitment (reviewed in [START_REF] Kennedy | International Union of Basic and Clinical Pharmacology CIII: Chemerin Receptors CMKLR1 (Chemerin(1)) and GPR1 (Chemerin(2)) Nomenclature, Pharmacology, and Function[END_REF] ).

It doesn't yet exist antagonist for GPR1

C13 [chemerin(145-157)] through GPR1 is involved in β arrestin recruitment (reviewed in [START_REF] Kennedy | International Union of Basic and Clinical Pharmacology CIII: Chemerin Receptors CMKLR1 (Chemerin(1)) and GPR1 (Chemerin(2)) Nomenclature, Pharmacology, and Function[END_REF] ). C20 [chemerin(138-157)] suppresses in vitro gonadal steroidogenesis in rat [START_REF] Li | Chemerin-Derived Peptide C-20 Suppressed Gonadal Steroidogenesis[END_REF] .

Figure 1 :

 1 Figure 1 : Apelin and chemerin receptors signaling

Figure 2 :Figure 3 :

 23 Figure 2: Some examples of apelin and chemerin effects on metabolic tissues and role in

1

  Figure 1

Acknowledgements

The authors thank BIORENDER for the figures.

Abbreviations