Christophe Magnan

Stéphanie Migrenne-Li
email: stephanie.migrenne@u-paris.fr

Pleiotropic effects of prokineticin 2 in the control of energy metabolism 1

Prokineticins are family of small proteins involved in many important biological processes including food intake and control of energy balance. The prokineticin 2 (PROK2) is expressed in several peripheral tissues and areas in the central nervous system. PROK2 activates G protein-coupled receptors, namely, prokineticin receptor 1 (PROKR1) and prokineticin receptor 2 (PROKR2). Preclinical models exhibiting disturbances of the PROK2 pathway (at the level of PROK2 or its receptors) are characterized by changes in food intake, feeding behavior and insulin sensitivity related to a dysfunction of the energy balance control. In Humans, mutations of PROK2 and PROKR2 genes are associated to the Kallmann syndrome (KS) that affects both the hormonal reproductive axis and the sense of smell and may also lead to obesity. Moreover, plasma PROK2 concentration has been correlated with various cardiometabolic risk factors and type 2 diabetes (T2D). The present review summarizes knowledge on PROK2 structure, signaling and function focusing on its role in control of food intake and energy homeostasis.

Introduction

The first members of the prokineticin family were described in the 1980s in reptiles, then amphibians and finally mammals and humans. The role of prokineticins including prokineticin 2 (PROK2, the subject of this review) has been increasingly studied since the beginning of the 2000s. Physiological or pharmacological effects of PROK2 and its function in mechanisms as diverse as nociception, circadian rhythms, angiogenesis, neurogenesis, reproduction, etc. have begun to be well characterized as well as its role in energy metabolism including food intake, dietary behavior and insulin action. In the human species, a disturbance of the PROK2 signaling pathway has been identified as responsible for Kallmann syndrome disorder, whose affected patients present a hypogonadism and anosmia that is sometimes accompanied by a deregulation of the energy balance. With these pleiotropic effects, PROK2 and more broadly the prokineticin family provides a relevant endocrine study model of interorgan dialogue that takes place in a multicellular organism throughout its development and life. Finally, from a pharmacological point of view, the prokineticin system could also be of therapeutic interest in the context of metabolic diseases, such as obesity and type 2 diabetes (T2D). This review is an update on the scientific knowledge on PROK2, focusing on its structure, signaling and function in energy balance, glucose homeostasis and feeding behavior.

PROK2 and PROK2 receptors

PROK2

The prokineticin family

The first member of the prokineticin family to be identified was Mamba Intestinal Toxin 1 (MIT1) isolated from the venom of the black mamba snake [START_REF] Joubert | Snake venom. The amino acid sequence of protein A from Dendroaspis polylepis polylepis (black mamba) venom, Hoppe-Seyler's[END_REF] that showed the ability to stimulate contraction of the guinea pig ileum [START_REF] Schweitz | Purification and pharmacological characterization of peptide toxins from the black mamba (Dendroaspis polylepis) venom[END_REF][START_REF] Schweitz | MIT(1), a black mamba toxin with a new and highly potent activity on intestinal contraction[END_REF]. The Bombina variegata (Bv8) was then isolated from the skin secretion of a frog and was found to stimulate the contraction of gastrointestinal (GI) smooth muscle with high potency.

Bv8 has 58% identity with MIT1 and was reported to induce hyperalgesia and colon relaxation in rats in addition to its contracting effects on guinea pig, rat, and mouse ileum. Homologus of Bv8 were identified in other amphibians, lizards, fishes, and ortologues were described in mammals : they were named prokineticin because of their ability to contract GI smooth muscle, with no effect on vascular or respiratory smooth muscle.

The prokineticin family comprises prokineticin 1 (PROK1 also called EGVEGF for endocrine gland vascular endothelial growth factor [START_REF] Lecouter | Bv8 and endocrine glandderived vascular endothelial growth factor stimulate hematopoiesis and hematopoietic cell mobilization[END_REF]) and PROK2, that are codified by two different genes, Prok1 (mouse chromosome 3 synthenic with human chromosome 1p13.1) and Prok2 (mouse chromosome 6 and human 3p21). These small protein contain 10 conserved cysteines residues with identical spacing forming five disulfide bonds in the carboxy-terminal region. Their mature forms consist of 86 and 81 amino acids, respectively for PROK1 and PROK2, and show a highly conserved N-terminal AVITGA sequence essential for their biological activity [START_REF] Li | Identification of two prokineticin cDNAs: recombinant proteins potently contract gastrointestinal smooth muscle[END_REF].

Substitutions, deletions, or insertions to this hexapeptide result in the loss of agonist activity on prokineticin receptors [START_REF] Bullock | Structural determinants required for the bioactivities of prokineticins and identification of prokineticin receptor antagonists[END_REF][START_REF] Kaser | The AVIT protein family. Secreted cysteine-rich vertebrate proteins with diverse functions[END_REF]. PROK1 will not be discussed in the present review.

Tissue expression (Table 1)

Prok2 primary transcript has two alternative splice variants : Prok2 mRNA, that encodes the 81 AA protein PROK2 and Prok2 long form (Prok2L) mRNA, that encodes a protein of 102 amino acids, PROK2L, consisting of an insert of 21 basic amino acids (encoded by an exon) in PROK2 sequence. In mammalian cells, secreted PROK2L is processed by proteolytic cleavage into a smaller peptide, called PROK2beta, that retains the receptor binding and activation domain [START_REF] Chen | Identification and pharmacological characterization of prokineticin 2 beta as a selective ligand for prokineticin receptor 1[END_REF][START_REF] Lattanzi | PK2β ligand, a splice variant of prokineticin 2, is able to modulate and drive signaling through PKR1 receptor[END_REF].

Prok2 mRNA is present in GI tract, enteric plexus, myocardial tissue [START_REF] Li | Identification of two prokineticin cDNAs: recombinant proteins potently contract gastrointestinal smooth muscle[END_REF][START_REF] Chen | Identification and pharmacological characterization of prokineticin 2 beta as a selective ligand for prokineticin receptor 1[END_REF][START_REF] Negri | The Prokineticins: Neuromodulators and Mediators of Inflammation and Myeloid Cell-Dependent Angiogenesis[END_REF][START_REF] Urayama | The prokineticin receptor-1 (GPR73) promotes cardiomyocyte survival and angiogenesis[END_REF], uterus, testis [START_REF] Negri | The Prokineticins: Neuromodulators and Mediators of Inflammation and Myeloid Cell-Dependent Angiogenesis[END_REF][START_REF] Lecouter | The endocrine-gland-derived VEGF homologue Bv8 promotes angiogenesis in the testis: Localization of Bv8 receptors to endothelial cells[END_REF], adrenal glands [START_REF] Chen | Identification and pharmacological characterization of prokineticin 2 beta as a selective ligand for prokineticin receptor 1[END_REF], Kuppfer cells in the liver [START_REF] Chen | Identification and pharmacological characterization of prokineticin 2 beta as a selective ligand for prokineticin receptor 1[END_REF][START_REF] Negri | The Prokineticins: Neuromodulators and Mediators of Inflammation and Myeloid Cell-Dependent Angiogenesis[END_REF] as well as in progenitors and mature blood cells in peripheral blood and bone marrow [START_REF] Lecouter | Bv8 and endocrine glandderived vascular endothelial growth factor stimulate hematopoiesis and hematopoietic cell mobilization[END_REF][START_REF] Giannini | The chemokine Bv8/prokineticin 2 is up-regulated in inflammatory granulocytes and modulates inflammatory pain[END_REF]. Its expression is associated with the infiltrating cells, predominantly neutrophiles, at sites of inflammation.

In the brain, Prok2 mRNA is expressed in the hypothalamus, mainly in the suprachiasmatic nucleus (SCN) [START_REF] Cheng | Regulation of prokineticin 2 expression by light and the circadian clock[END_REF][START_REF] Cheng | Prokineticin 2 transmits the behavioural circadian rhythm of the suprachiasmatic nucleus[END_REF][START_REF] Zhang | Efferent projections of prokineticin 2 expressing neurons in the mouse suprachiasmatic nucleus[END_REF][START_REF] Cheng | Expression of prokineticins and their receptors in the adult mouse brain[END_REF] and dense clusters are also found in medial preoptic area (MPA) and in the hippocampus [START_REF] Negri | The Prokineticins: Neuromodulators and Mediators of Inflammation and Myeloid Cell-Dependent Angiogenesis[END_REF][START_REF] Cheng | Expression of prokineticins and their receptors in the adult mouse brain[END_REF][START_REF] Melchiorri | The mammalian homologue of the novel peptide Bv8 is expressed in the central nervous system and supports neuronal survival by activating the MAP kinase/PI-3-kinase pathways[END_REF][START_REF] Gardiner | Prokineticin 2 is a hypothalamic neuropeptide that potently inhibits food intake[END_REF]. Moderate expression of Prok2 mRNA was evidenced in nucleus accumbens shell and hypothalamic arcuate nucleus (ARC) [START_REF] Cheng | Expression of prokineticins and their receptors in the adult mouse brain[END_REF]. Prok2 mRNA was also detected in amygdala, cerebral cortex (high levels being detected in layer II) and cerebellum, in mice dorsal and ventral horns of the spinal cord (mainly in astrocytes), in nucleus of solitary tract (NTS) [START_REF] Negri | The Prokineticins: Neuromodulators and Mediators of Inflammation and Myeloid Cell-Dependent Angiogenesis[END_REF][START_REF] Cheng | Expression of prokineticins and their receptors in the adult mouse brain[END_REF][START_REF] Melchiorri | The mammalian homologue of the novel peptide Bv8 is expressed in the central nervous system and supports neuronal survival by activating the MAP kinase/PI-3-kinase pathways[END_REF] and in some dorsal root ganglion (DRG) neurons coexpressing the vanilloid receptors TRPV1 (transient receptor potential cation channel subfamily V member 1) [START_REF] Negri | The Prokineticins: Neuromodulators and Mediators of Inflammation and Myeloid Cell-Dependent Angiogenesis[END_REF][START_REF] Maftei | Abnormal Pain Sensation in Mice Lacking the Prokineticin Receptor PKR2: Interaction of PKR2 with Transient Receptor Potential TRPV1 and TRPA1[END_REF][START_REF] Negri | Impaired nociception and inflammatory pain sensation in mice lacking the prokineticin receptor PKR1: focus on interaction between PKR1 and the capsaicin receptor TRPV1 in pain behavior[END_REF].

Immunofluorescence studies from cortical and hippocampal cultures of embryonic day 17-18 brain rats embryos localized PROK2 in body neurons (NeuN + cells) and in astrocytes processes (GFAP+ cells) [START_REF] Severini | Bv8/prokineticin 2 is involved in Aβ-induced neurotoxicity[END_REF]. Prok2 mRNA shows also an intense expression in the olfactory bulb (OB), mainly in in the glomerular, granular and mitral cell layers, in a subset of granule cells and tufted cells [START_REF] Negri | The Prokineticins: Neuromodulators and Mediators of Inflammation and Myeloid Cell-Dependent Angiogenesis[END_REF][START_REF] Cheng | Expression of prokineticins and their receptors in the adult mouse brain[END_REF][START_REF] Mortreux | New roles for prokineticin 2 in feeding behavior, insulin resistance and type 2 diabetes: Studies in mice and humans[END_REF][START_REF] Ng | Dependence of olfactory bulb neurogenesis on prokineticin 2 signaling[END_REF]. A few PROK2positive cells that are not neural progenitors or migrating neuroblasts were found in the medial part of the rostral migratory stream (RMS). No staining was detected in the subventricular zone (SVZ) of the lateral ventricle [START_REF] Wen | The PROK2/PROKR2 signaling pathway is required for the migration of most olfactory bulb interneurons[END_REF].

Prok2L mRNA was detected in murine and human testis, in macrophages [START_REF] Negri | The Prokineticins: Neuromodulators and Mediators of Inflammation and Myeloid Cell-Dependent Angiogenesis[END_REF][START_REF] Giannini | The chemokine Bv8/prokineticin 2 is up-regulated in inflammatory granulocytes and modulates inflammatory pain[END_REF],

OB and hypothalamus of rodents [START_REF] Mortreux | New roles for prokineticin 2 in feeding behavior, insulin resistance and type 2 diabetes: Studies in mice and humans[END_REF] as well as in lung and spleen where its expression was higher than that of Prok2 mRNA [START_REF] Chen | Identification and pharmacological characterization of prokineticin 2 beta as a selective ligand for prokineticin receptor 1[END_REF].

Gene regulation

The Bv8/Prok2 human and mouse promoter sequences are highly conserved, indicating a related transcriptional regulation in these species. The Prok2 promoter is replete with multiple E-box sequences (CACGTG) that bind basic helix-loop-helix (bHLH) transcription factors such as Hypoxia-inducible factor 1-alpha (HIF1α), which regulates Prok2 expression during angiogenesis [START_REF] Lecouter | EG-VEGF and Bv8. a novel family of tissue-selective mediators of angiogenesis, endothelial phenotype, and function[END_REF]. In the OB, two proneural basic helix-loop-helix (bHLH) factors, Neurogenin1 (NGN1) and mammalian achaete scute homolog-1 (MASH1), were found to upregulate Prok2 transcription by binding to Ebox motifs. On the contrary, Distal-Less Homeobox 1 and 2 (DLX 1 and 2) was identified as a repressor [START_REF] Zhang | Prokineticin 2 is a target gene of proneural basic helix-loop-helix factors for olfactory bulb neurogenesis[END_REF]. In the SCN, Prok2 gene expression is controled by clock genes Circadian Locomotor Output Cycles Kaput (Clock) and Brain and Muscle ARNT-Like 1 (Bmal1) acting on E-box enhancers in the gene's promoter. In the immune system cells, as well as in sensitive neurons and in central nervous system (CNS) after nerve damage or neuroinflammation [START_REF] Maftei | The prokineticin receptor antagonist PC1 rescues memory impairment induced by β amyloid administration through the modulation of prokineticin system[END_REF], Prok2 is positively regulated by granulocyte colony stimulating factor (GCSF) (see review in [START_REF] Negri | The Prokineticins: Neuromodulators and Mediators of Inflammation and Myeloid Cell-Dependent Angiogenesis[END_REF]).

Prokineticin receptors

PROK2 acts on the two plasma membrane G protein-coupled receptors (GPCR), namely, prokineticin receptor 1 (PROKR1, ProkR1 gene : 2p13.3 in humans and chromosome 6 in mouse) and prokineticin receptor 2 (PROKR2 ; ProkR2 gene : 20p13 in humans and chromosome 2 in mouse). They have about 85% sequence identity [START_REF] -H. Lin | Identification and molecular characterization of two closely related G proteincoupled receptors activated by prokineticins/endocrine gland vascular endothelial growth factor[END_REF] and show ~80% identity to the previously described mouse orphan receptor GPR73 [START_REF] Parker | Y-receptor-like genes GPR72 and GPR73: molecular cloning, genomic organisation and assignment to human chromosome 11q21.1 and 2p14 and mouse chromosome 9 and 6[END_REF].

Tissue expression

In the periphery, both PROKR are detected in immune and endothelial cells and have a tissue-specific expression pattern. For example PROKR1 is the only isoform detected in adipose tissue [START_REF] Szatkowski | Prokineticin receptor 1 as a novel suppressor of preadipocyte proliferation and differentiation to control obesity[END_REF] and it is more abundantly expressed than PROKR2 in the gut, with its expression varing all along the lenght of the intestine. PROKR1 is also detected in endocrine glands and organs of the reproductive system, the gastrointestinal tract, lungs, and the circulatory system [START_REF] Battersby | Expression and regulation of the prokineticins (endocrine gland-derived vascular endothelial growth factor and Bv8) and their receptors in the human endometrium across the menstrual cycle[END_REF][START_REF] Soga | Molecular cloning and characterization of prokineticin receptors[END_REF].

Both PROKR are also expressed in the CNS. In adult rodents, ProkR2 mRNA was evidenced in several brain areas including the SCN, the cortex, the paraventricular hypothalamic nucleus (PVN), the dorso-median nucleus (DMN), the paraventricular (PVT) and paratenial thalamic nuclei, the paracentral thalamic nucleus, the lateral habenular nucleus, the lateral septal nucleus, the lateral globus pallidus and the amygdala [START_REF] Cheng | Prokineticin 2 transmits the behavioural circadian rhythm of the suprachiasmatic nucleus[END_REF]. ProkR2 mRNA also showed prominent expression in hippocampus, NTS, DRG neurons and circumventricular organs [START_REF] Cheng | Expression of prokineticins and their receptors in the adult mouse brain[END_REF][START_REF] -H. Lin | Identification and molecular characterization of two closely related G proteincoupled receptors activated by prokineticins/endocrine gland vascular endothelial growth factor[END_REF][START_REF] Negri | Nociceptive sensitization by the secretory protein Bv8[END_REF]. Interestingly, studies of ProkR2-Cre mouse evidenced a sexually dimorphic pattern of ProkR2 expression in brain [START_REF] Mohsen | Sexually dimorphic distribution of Prokr2 neurons revealed by the Prokr2-Cre mouse model[END_REF]. Indeed, in females, higher Cre activity was found in the MPA, ventromedial nucleus of the hypothalamus (VMN), ARC, medial amygdala and lateral parabrachial nucleus, whereas in males, Cre was higher in the amygdalo-hippocampal area. This suggests differential roles of PROKR2 signaling in reproductive function and, potentially, in other physiological systems. In the OB of rodents, intense expression of both transcripts was observed, in the granular and subependymal cell layers as well as in the ependyma and olfactory ventricle, an embryologic cavity inside the OB that persists in some species [START_REF] Burmeister | Olfactory bulb ventricles as a frequent finding--a myth or reality? Evaluation using high resolution 3 Tesla magnetic resonance imaging[END_REF][START_REF] Puverel | Prokineticin receptor 2 expression identifies migrating neuroblasts and their subventricular zone transient-amplifying progenitors in adult mice[END_REF]. ProkR2 transcript and protein were also evidenced in the SVZ -where Prok2 is not expressed-, in almost all migrating neuroblasts as well as in a large population of their precursors. Along the RMS and in the OB, ProkR2 expression was absent in astrocytes. ProkR1 mRNA was found in fewer brain regions including SVZ, RMS, olfactory ventricle in the OB, hippocampus and dorsal motor nucleus of the vagus (DMV) [START_REF] Cheng | Expression of prokineticins and their receptors in the adult mouse brain[END_REF][START_REF] Ng | Dependence of olfactory bulb neurogenesis on prokineticin 2 signaling[END_REF].

Signaling pathways

PROKRs have been reported to couple to i) Gq proteins [START_REF] Urayama | The prokineticin receptor-1 (GPR73) promotes cardiomyocyte survival and angiogenesis[END_REF][START_REF] -H. Lin | Identification and molecular characterization of two closely related G proteincoupled receptors activated by prokineticins/endocrine gland vascular endothelial growth factor[END_REF][START_REF] Soga | Molecular cloning and characterization of prokineticin receptors[END_REF][START_REF] Negri | Nociceptive sensitization by the secretory protein Bv8[END_REF][START_REF] Koyama | Expression of prokineticin receptors in mouse cultured astrocytes and involvement in cell proliferation[END_REF][START_REF] Mok | Prokineticin receptor 1 ameliorates insulin resistance in skeletal muscle[END_REF][START_REF] Chaly | The Melanocortin Receptor Accessory Protein 2 promotes food intake through inhibition of the Prokineticin Receptor-1[END_REF][START_REF] Vellani | Sensitization of transient receptor potential vanilloid 1 by the prokineticin receptor agonist Bv8[END_REF][START_REF] Nguyen | Role of Prokineticin Receptor-1 in Epicardial Progenitor Cells[END_REF][START_REF] Guilini | Divergent roles of prokineticin receptors in the endothelial cells: angiogenesis and fenestration[END_REF] to mediate the intracellular calcium mobilization or mitogen-activated protein kinase (MAPK)/Akt pathways activation, ii) Gi proteins [START_REF] Lecouter | Bv8 and endocrine glandderived vascular endothelial growth factor stimulate hematopoiesis and hematopoietic cell mobilization[END_REF][START_REF] -H. Lin | Identification and molecular characterization of two closely related G proteincoupled receptors activated by prokineticins/endocrine gland vascular endothelial growth factor[END_REF][START_REF] Monnier | Prokineticin 1 induces CCL4, CXCL1 and CXCL8 in human monocytes but not in macrophages and dendritic cells[END_REF], leading to phosphorylation of p44/p42 MAPK, or iii) Gs proteins [START_REF] Chen | Identification and pharmacological characterization of prokineticin 2 beta as a selective ligand for prokineticin receptor 1[END_REF][START_REF] Chaly | The Melanocortin Receptor Accessory Protein 2 promotes food intake through inhibition of the Prokineticin Receptor-1[END_REF], leading to adenylate cyclase activation and cAMP accumulation (Table 2). However it seems that Gq-signaling pathways are the most common ones associated with PROKRs stimulation. For instance, addition of PROK2 to mouse cultured astrocytes causes increases in astrocytic cytosolic Ca 2+ levels through PROKR1 activation and astrocytic proliferation [START_REF] Koyama | Expression of prokineticin receptors in mouse cultured astrocytes and involvement in cell proliferation[END_REF].

PROK2 also induced calcium mobilization in a dose-dependent manner in PROKR1overexpressed HEK293T cells. In skeletal muscle cells, PROKR1 signaling activated Gq-mediated PI3K/AKT and MAPK/ERK signaling pathways and also promoted the translocation of glucose transporter 4 (GLUT4) into the plasma membrane that influences insulin sensitivity [START_REF] Mok | Prokineticin receptor 1 ameliorates insulin resistance in skeletal muscle[END_REF]. Interestingly, PROKR1 signaling is significantly and specifically inhibited by the Melanocortin Receptor Accessory Protein 2 (MRAP2) an important regulator of energy homeostasis [START_REF] Chaly | The Melanocortin Receptor Accessory Protein 2 promotes food intake through inhibition of the Prokineticin Receptor-1[END_REF].

As Prok2, ProkR2 expression may be directly or indirectly regulated by MASH1 since Mash1 -/-mutant mice show a highly marked decrease of ProkR2 expression [START_REF] Puverel | Prokineticin receptor 2 expression identifies migrating neuroblasts and their subventricular zone transient-amplifying progenitors in adult mice[END_REF].

Prokineticins exhibit different affinities for their receptors : PROK2 binds PROKRs with higher affinity than does PROK1 [START_REF] Chen | Identification and pharmacological characterization of prokineticin 2 beta as a selective ligand for prokineticin receptor 1[END_REF] and PROK2beta displays clear selectivity for PROKR1 [START_REF] Lattanzi | PK2β ligand, a splice variant of prokineticin 2, is able to modulate and drive signaling through PKR1 receptor[END_REF]. However, all the natural prokineticins bind and activate both receptors in nanomolar range. Functional studies showed that PROK2 and PROK2beta stimulate intracellular Ca2+ responses in PROKR1-expressing cells with similar potencies. However, the PROK2beta stimulus of Ca2+ responses in PROKR2expressing cells is at least 10-fold less potent than that of PROK2. PROK2 has been shown to modulate the electrical activity of neurons in the area postrema (AP), subfornical organ (SFO), PVN and SCN [START_REF] Cottrell | Prokineticin 2 modulates the excitability of subfornical organ neurons[END_REF][START_REF] Ingves | Prokineticin 2 modulates the excitability of area postrema neurons in vitro in the rat[END_REF][START_REF] Ren | Prokineticin 2 regulates the electrical activity of rat suprachiasmatic nuclei neurons[END_REF][START_REF] Yuill | Prokineticin 2 depolarizes paraventricular nucleus magnocellular and parvocellular neurons[END_REF]. Current-clamp recordings, slow voltage ramps and ion-substitution experiments evidenced that focal application of PROK2 produced depolarizations (38%) and hyperpolarizations (28%) of dissociated AP cells, i) in a concentration-dependent manner and ii) that were the result of PROK2-induced Cl -current and inhibition of a nonselective cation current respectively [START_REF] Ingves | Prokineticin 2 modulates the excitability of area postrema neurons in vitro in the rat[END_REF]. Similarly, PROK2 induced depolarizations in 40% of dissociated SFO neurons, that were accompanied by an increase in action potential frequency in responding cells. This excitatory effect appeared to be, in part, attributable to a PROK2-induced decrease in the delayed rectifier potassium current (I(K)) [START_REF] Cottrell | Prokineticin 2 modulates the excitability of subfornical organ neurons[END_REF].

PROK2 was also evidenced to depolarize the majority (76%) of magnocellular (MNC) neurons of the PVN through the activation of glutamate interneurons within the hypothalamic slice. Although parvocellular preautonomic (PA), and parvocellular neuroendocrine (NE) of the PVN also depolarized in response to PROK2 (respectively 68 % and 67%), this effect was directly induced by activation of PROK2R and a MAPK signalling mechanism [START_REF] Yuill | Prokineticin 2 depolarizes paraventricular nucleus magnocellular and parvocellular neurons[END_REF]. Finally, whole cell patch-clamp recording in SCN slices evidenced that PROK2 dose-dependently increased spontaneous firing rates in most neurons from the dorsal SCN. Moreover, PROK2 acted postsynaptically to reduce γ-aminobutyric acid (GABA)-ergic function within the SCN and reduced the amplitude but not frequency of miniature inhibitory postsynaptic currents (mIPSCs). PROK2 also suppressed exogenous GABA-induced currents. The inhibitory effect of PROK2 required PKC activation in the postsynaptic cells [START_REF] Ren | Prokineticin 2 regulates the electrical activity of rat suprachiasmatic nuclei neurons[END_REF].

In vitro studies indicated that both PROKRs undergo rapidly (in 1 min) agonistinduced endocytosis. For the PROK2-PROKR2 couple, this process is G-proteincoupled receptor kinase 2 (GRK2) -and clathrin-dependent, but beta-arrestinindependent. Internalization is maximal at 30-60 min and the receptor recycles back to the plasma membrane after the removal of ligand. Protein kinase C activation also induced PROKR2 endocytosis, however, it was not necessary for the PROK2induced PROKR2 endocytosis [START_REF] Yin | Mechanisms that underlie the internalization and extracellular signal regulated kinase 1/2 activation by PKR2 receptor[END_REF]. Receptors desensitization was also evidenced in vivo after persistent intracerebroventricular (ICV) infusion of Bv8/PROK2 [START_REF] Cheng | Prokineticin 2 transmits the behavioural circadian rhythm of the suprachiasmatic nucleus[END_REF].

Physiological role of PROK2 in control of energy balanceThere is now growing

amount of evidences that PROK2 is involved in regulation of energy metabolism through pleiotropic effects as depicted in Figure 1. PROK2 has a major role in regulation of circadian cycles that rhythm the day/night metabolic and biological behaviors. It is also involved in the regulation of energy balance and eating pattern, acting in the CNS and/or in peripheral organs. It may participate to the regulation of cell growth and differentiation of metabolic tissues such as the adipose tissue.

Role in the circadian clock of physiologic functions

In mammals, the pacemaker that drives circadian rhythms of physiology and behavior such as body temperature, sleep, locomotor activity, energy metabolism resides in the SCN of the anterior hypothalamus [START_REF] Moore | Circadian rhythms: basic neurobiology and clinical applications[END_REF]. Light exposure is the main input for entraining and resetting of the SCN clock. Prok2 mRNA is expressed in the SCN with a circadian profile, with high levels during the day and low or undetectable levels at night [START_REF] Cheng | Regulation of prokineticin 2 expression by light and the circadian clock[END_REF]. PROK2 has been suggested as a candidate that would link SCN and its efferent targets since projections of neurons expressing Prok2 were evidenced in brain area including the ventral lateral septum, medial preoptic area, subparaventricular zone, PVN, DMH, lateral hypothalamic area and PVT [START_REF] Zhang | Efferent projections of prokineticin 2 expressing neurons in the mouse suprachiasmatic nucleus[END_REF].

Prok2 oscillation in the SCN is abolished in mutant mice lacking the functional clockwork, meaning that Prok2 is predominantly controlled by the endogenous circadian clock. This suggests that light plays a modulatory role, but light can also induce Prok2 expression independently of the circadian oscillator [START_REF] Cheng | Regulation of prokineticin 2 expression by light and the circadian clock[END_REF].

ProkR2 is also expressed in the SCN -with an non-oscillating pathway-as well as in virtually all known primary SCN targets [START_REF] Cheng | Prokineticin 2 transmits the behavioural circadian rhythm of the suprachiasmatic nucleus[END_REF] leading to the idea that the PROK2/PROKR2 system may have a function in synchronizing SCN output.

ICV injection of PROK2 suppressed the high level of wheel running behaviour associated with dark phase in rats, suggesting that PROK2, which is normally at high levels during subjective day, inhibits wheel-running activity. During subjective night, when endogenous Prok2 mRNA levels are low, the wheel running activity is disinhibited [START_REF] Cheng | Prokineticin 2 transmits the behavioural circadian rhythm of the suprachiasmatic nucleus[END_REF]. Prok2 null mice evidenced reduction of locomotor rhythms and displayed significantly reduced rhythmicity for a variety of other physiological and behavioral parameters, including sleep-wake cycle, body temperature, circulating glucocorticoid and glucose levels, as well as the expression of peripheral clock genes. In addition, Prok2-null mice showed accelerated acquisition of food anticipatory activity during a daytime food restriction which suggests a weaker SCN control in Prok2 null mice for the locomotor activity and a higher control of food entrained oscillators [START_REF] Li | Attenuated circadian rhythms in mice lacking the prokineticin 2 gene[END_REF].

The PVN is a primary SCN efferent nucleus involved in the direct regulation of endocrine rhythms. Because ProkR2 is expressed in the PVN, SCN-derived PROK2 may regulate physiological parameters through this pathway, exciting or inhibiting PVN neurons (as magnocellular, parvocellular preautonomic, and parvocellular neuroendocrine neurons). Prok2 is also detected in the PVN and its expression is increased by fasting while it fells to the basal undetectable level after refeeding. Administration of 2-deoxy-D-glucose (2-DG), an inhibitor of glucose utilization, also rapidly induced Prok2 expression in the PVN implying that the induction was a response to the dwindling energy reserves. Thermosensitive neurons in the PVN can detect variations of body temperature and activate the sympathetic nervous system which regulates the heat production through general activity, shivering, and brown fat thermogenesis. Interestingly, ProkR2 null mice showed sporadic bouts of torpor with decreased locomotor activities, oxygen consumption and respiratory quotient, under ad libitum feeding and constant temperature. The remove of food for a period induced a deeper and longer hypothermia in ProkR2 null mice compared to their wild type littermates, suggesting that PROKR2 pathway is involved in energy balance and thermoregulation [START_REF] Jethwa | Loss of prokineticin receptor 2 signaling predisposes mice to torpor[END_REF]. In the same way, Prok2 null mice entered torpor after fasting with no difference in activity compared to wild type mice, but with lower energy expenditure and lower body weight loss. Wild type animals responded to reduced food availability by becoming more wakeful and active -a phenomenon called fastinginduced arousal (FIA) -so as to maintain body temperature in a normal range and be ready for food supply. Once food was applied, they ingested the food and utilized it to compensate the body weight loss. Contrary to wild type mice, Prok2 null mice exhibited no appreciable increase in arousal during the entire fasting period. Supply of limited food daily during fasting rescued the body weight loss and hypothermal phenotype in wild type mice, but not in Prok2 null mice, suggesting a deficit of food utilization in transgenic mice during refeeding period. The assumption is that fasting increases Prok2 level in the PVN to facilitate the sensing of hypothermia and activation of the sympathetic nerve system which in turn leads to increasing activity, expanding the wake periods, and using body energy storage [START_REF] Zhou | Prokineticin 2 is involved in the thermoregulation and energy expenditure[END_REF].

Recently, the role of PROK2 as a SCN input signal was also investigated. Mice with Prok2 overexpression displayed reduced oscillation of Prok2 expression in the SCN because of increased Prok2 expression during the dark phase. They also had decreased amplitude of circadian locomotor rhythms and altered molecular rhythms of core clockwork, particularly the amplitude of Bmal1. It is likely that PROK2 could exert a signalling role from the intrinsically photosensitive retinal ganglion cells that project to SCN neurons [START_REF] Li | Overexpression of Prokineticin 2 in Transgenic Mice Leads to Reduced Circadian Behavioral Rhythmicity and Altered Molecular Rhythms in the Suprachiasmatic Clock[END_REF].

Interestingly, in zebrafish, a diurnal vertebrate, both overexpression and mutation of the Prok2 affect sleep/wake behaviors in a light-dependent but circadian-independent manner. Indeed, in light, Prok2 overexpression increases sleep and induces expression of galanin (galn), a hypothalamic sleep-inducing peptide [START_REF] Chen | Light-Dependent Regulation of Sleep and Wake States by Prokineticin 2 in Zebrafish[END_REF].

Role in feeding behavior and glucose homeostasis

In rats and mice, acute peripheral administration of PROK2 decreases food intake while it reduces both food intake and body weight when administered chronically, in lean and diet-induced obese (DIO) mice [START_REF] Gardiner | Prokineticin 2 is a hypothalamic neuropeptide that potently inhibits food intake[END_REF]. Interestingly, DIO mice pair fed to the PROK2-treated group lost a similar amount of weight as the mice given PROK2, suggesting that the effect of PROK2 on body weight was mediated predominantly via a reduction in food intake. Mice models lacking Prok2 have not been reported to show an increased body weight compared with their wild-type littermates, that could be explained by a compensation in embryonic knockout models [START_REF] Gardiner | Prokineticin 2 is a hypothalamic neuropeptide that potently inhibits food intake[END_REF]. Peripheral injection of PROK2 does not alter food intake in ProkR1 deficient mice or in wild type mice with co-administration of a PROKR1 antagonist, suggesting that the anorectic effect induced by peripheral PROK2 is PROKR1-dependent. It also increases cfoslike immunoreactivity in the DMV of the brainstem, suggesting that peripherally administered PROK2 may directly act through the DMV to inhibit food intake. Acute or chronic PROK2 administration did not have any adverse effect on glucose tolerance or insulin sensitivity in wild type mice [START_REF] Beale | Peripheral administration of prokineticin 2 potently reduces food intake and body weight in mice via the brainstem[END_REF]. However, we may assume that ProkR1 deficiency would alter glucose homeostasis since endothelial PROKR1 has been characterized as a positive regulator of insulin sensitivity [START_REF] Dormishian | Prokineticin receptor-1 is a new regulator of endothelial insulin uptake and capillary formation to control insulin sensitivity and cardiovascular and kidney functions[END_REF]. Moreover, in palmitate-induced insulin-resistant myotubes, PROKR1 enhanced insulin-stimulated AKT phosphorylation, GLUT4 translocation, and glucose uptake. mRNA and protein levels of PROKR1 were significantly decreased in skeletal muscle and white adipose tissue of DIO mice, and the amount of PROKR1 was significantly decreased in human skeletal muscle cell-derived myotubes under insulin resistance conditions [START_REF] Mok | Prokineticin receptor 1 ameliorates insulin resistance in skeletal muscle[END_REF].

In the hypothalamus which plays a key role in the regulation of food intake both in humans and rodents, Prok2 expression is reduced by fasting [START_REF] Gardiner | Prokineticin 2 is a hypothalamic neuropeptide that potently inhibits food intake[END_REF], as soon as the early neonatal period [START_REF] Iwasa | Changes in the responsiveness of hypothalamic prokineticin 2 mRNA expression to food deprivation in developing female rats[END_REF]. This is in contrast to what was evidenced in the PVN and may be linked to the study of the entire hypothalamus compared to a single nucleus.

ICV administration of Bv8/PROK2 reduces food intake in rodents and significantly decreases the number of feeding episodes without impacting energy expenditure or locomotor activity [START_REF] Gardiner | Prokineticin 2 is a hypothalamic neuropeptide that potently inhibits food intake[END_REF][START_REF] Negri | Bv8, the amphibian homologue of the mammalian prokineticins, modulates ingestive behaviour in rats[END_REF]. It also significantly increases the number of arcuate proopiomelanocortin (POMC)-expressing neurons exhibiting c-fos immunoreactivity, while peripheral administration of PROK2 does not [START_REF] Gardiner | Prokineticin 2 is a hypothalamic neuropeptide that potently inhibits food intake[END_REF][START_REF] Beale | Peripheral administration of prokineticin 2 potently reduces food intake and body weight in mice via the brainstem[END_REF]. This suggests that the anorectic effect of central PROK2 is dependent on hypothalamic activation. In the same way, PROK2 significantly stimulates the release by hypothalamic explants of anorexigenic POMC-derived peptide alpha-melanocyte-stimulating hormone (α-MSH), while coadministration of the orexigenic neuropeptide Agouti-related protein (AgRP) attenuated the PROK2 effect. However ICV injection of PROK2 significantly decreases food intake both in wild type and Mc4r (melanocortin-4 receptor) -deficient fasted mice [START_REF] Chaly | The Melanocortin Receptor Accessory Protein 2 promotes food intake through inhibition of the Prokineticin Receptor-1[END_REF]. This implies that PROK2 can promote an anorectic effect through a mechanism that is distinct and independent from the activation of MC4R. MRAP2 is a potentiator of MC4R signaling and loss of function mutations in Mrap2 have been recently associated to hyperphagic obesity complicated with hyperglycemia and hypertension [START_REF] Baron | Loss-offunction mutations in MRAP2 are pathogenic in hyperphagic obesity with hyperglycemia and hypertension[END_REF]. MRAP2 likely regulates energy homeostasis through both MC4Rmediated and MC4R-independent pathways [START_REF] Asai | Loss of function of the melanocortin 2 receptor accessory protein 2 is associated with mammalian obesity[END_REF]. Interestingly, in contrast to its activity on MC4R, MRAP2 inhibits PROKR1 signaling both in vitro and in vivo.

Indeed, the anorexigenic effect induced by ICV injection of PROK2 was more pronounced in Mrap2-deficient mice than in wild type mice. This suggests that MRAP2-mediated inhibition of PROKR1 promotes hunger and that PROK2dependent activation of PROKR1 may counteract this effect [START_REF] Chaly | The Melanocortin Receptor Accessory Protein 2 promotes food intake through inhibition of the Prokineticin Receptor-1[END_REF][START_REF] Asai | Loss of function of the melanocortin 2 receptor accessory protein 2 is associated with mammalian obesity[END_REF].

Prok2 expression and function have been also studied in the OB which is another main CNS structure involved in the regulation of food intake and energy balance [START_REF] Palouzier-Paulignan | Olfaction under metabolic influences[END_REF] and whose neuro-and morphogenesis are dependent on PROK2 signaling pathway [START_REF] Ng | Dependence of olfactory bulb neurogenesis on prokineticin 2 signaling[END_REF][START_REF] Wen | The PROK2/PROKR2 signaling pathway is required for the migration of most olfactory bulb interneurons[END_REF][START_REF] Zhang | Prokineticin 2 is a target gene of proneural basic helix-loop-helix factors for olfactory bulb neurogenesis[END_REF]. Our group showed that 24 h fasting had no effect on Prok2 mRNA expression in the OB compared to the fed state, whereas it decreased that of Prok2L [START_REF] Mortreux | New roles for prokineticin 2 in feeding behavior, insulin resistance and type 2 diabetes: Studies in mice and humans[END_REF]. This was concomitant with a lower ProkR1 and a higher ProkR2 mRNAs expression. Because Prok2L encodes the PROK2beta isoform that was shown to preferentially bind PROKR1, these results suggest that, in the OB, the PROK2beta/PROKR1 could be the main couple regulator of feeding behavior.

Interestingly, we observed that PROK2 injection in the OB strongly decreased food intake and induced an increase in the buried food discovery time of fasted mice [START_REF] Mortreux | New roles for prokineticin 2 in feeding behavior, insulin resistance and type 2 diabetes: Studies in mice and humans[END_REF].

Moreover mice injected with Prok2 shRNA in the OB showed altered pattern of feeding behavior, as increased feeding frequency and meal duration associated with decreased meal size. Concerning glucose homeostasis, Prok2 shRNA-injected mice developed insulin resistance and showed decreased glucose uptake in the subcutaneous adipose tissue. These data highlight PROK2 as a new target in the OB that links olfaction with eating behavior and energy balance [START_REF] Mortreux | New roles for prokineticin 2 in feeding behavior, insulin resistance and type 2 diabetes: Studies in mice and humans[END_REF].

Role in adipose tissue expansion

In addition to its anorectic role, PROK2 also influences body weight homeostasis through a suppressive effect of adipose tissue expansion mediated by PROKR1. Indeed, ProkR1-null mice (ProkR1 -/-) have excessive abdominal adipose tissue and develop severe obesity and impaired adipocyte insulin signaling, that are exacerbated by a high fat diet. The loss of PROKR1 in endothelial cells also led to obstruction of new capillaries development, what created a hypoxic environment.

Interestingly, adipocyte-specific mutant mice (ProkR1 ad-/-) do not show such a severe phenotype, despite increased proliferating preadipocytes and newly formed adipocyte levels, leading to expansion of adipose tissue. They also display substantial infiltration of macrophages in the adipose tissue, which is one other component of obesity. How does PROKR1 do to preserve adequate adipocyte function in obesity is unknown but it strongly suggests that PROKR1 agonists are potent therapeutic targets against obesity [START_REF] Szatkowski | Prokineticin receptor 1 as a novel suppressor of preadipocyte proliferation and differentiation to control obesity[END_REF][START_REF] Nebigil | Prokineticin Is a New Linker between Obesity and Cardiovascular Diseases[END_REF].

The origin of PROK2 acting in the adipose tissue is not clear but it is suggested that PROK2 is an adipokine which exhibits an angiogenic activity [START_REF] Szatkowski | Prokineticin receptor 1 as a novel suppressor of preadipocyte proliferation and differentiation to control obesity[END_REF]. As PROK2 is released by inflammatory cells [START_REF] Giannini | The chemokine Bv8/prokineticin 2 is up-regulated in inflammatory granulocytes and modulates inflammatory pain[END_REF] and expressed in lymphocytic tissues, cells, and cell lines [START_REF] Lecouter | Bv8 and endocrine glandderived vascular endothelial growth factor stimulate hematopoiesis and hematopoietic cell mobilization[END_REF], we can not exclude that endothelial cells, pericytes, T cells, and M2 macrophages contained in the stroma vascular fraction could secrete PROK2.

Role in angiogenesis and heart protection

In mouse and human myocardial tissue, PROK2 promotes cardiomyocyte survival and angiogenesis, mainly through PROKR1 signaling. PROK2 or PROKR1 overexpression induce vessel-like formation in cultured cardiac endothelial cells and activate Akt in cardiomyocytes to protect cardiomyocytes against oxidative stress [START_REF] Urayama | The prokineticin receptor-1 (GPR73) promotes cardiomyocyte survival and angiogenesis[END_REF]. Exposure of cardiomyocytes to high glucose/high palmitic acid induces oxydative stress that is accompagnied by suppression of PROK2, PROKR1, and PROKR2 expression. These effects are robustly prevented by PROK2, through an Akt-related signalling pathway [START_REF] Yang | Prokineticin 2 (PK2) Rescues Cardiomyocytes from High Glucose/High Palmitic Acid-Induced Damage by Regulating the AKT/GSK3β Pathway In Vitro[END_REF]. Interestingly, the antidiabetic metformin (Met) that exerts cardioprotective effects, attenuated the decreases of PROK2, PROKR1, and PROKR2 expression observed in cardiomyocytes of streptozotocin-treated mice [START_REF] Yang | Metformin Ameliorates Diabetic Cardiomyopathy by Activating the PK2/PKR Pathway[END_REF].

In mouse heart, as well as in kidney, PROKR1 up regulates PROK2 to promote progenitor cells differentiation into a vasculogenic cell type or into endothelial and smooth muscle cells respectively [START_REF] Boulberdaa | Prokineticin receptor 1 (PKR1) signalling in cardiovascular and kidney functions[END_REF]. The crucial transcription factor for embryonic development, T-Box Transcription Factor 20 (TBX20), regulates angiogenesis through the PROK2-PROKR1 pathway in both development and disease [START_REF] Meng | TBX20 Regulates Angiogenesis Through the Prokineticin 2-Prokineticin Receptor 1 Pathway[END_REF].

PROKR1 signaling is also involved in regulation of cardiac, renal, and metabolic functions by regulating transendothelial insulin uptake and endothelial cell proliferation. Indeed, a genetically -induced PROKR1 loss in the endothelial cells (ec-PROKR1 -/-) causes the impaired capillary formation and transendothelial insulin delivery, leading to insulin resistance and cardiovascular and renal disorders. Despite having a lean body phenotype, ec-PROKR1 -/-mice exhibited polyphagia, polydipsia, polyurinemia, and hyperinsulinemia, which are reminiscent of human lipodystrophy [START_REF] Dormishian | Prokineticin receptor-1 is a new regulator of endothelial insulin uptake and capillary formation to control insulin sensitivity and cardiovascular and kidney functions[END_REF].

Humans data

In Humans, PROK2 or PROKR2 gene deficiency cause the development of the Kallmann syndrome (KS) [START_REF] Hardelin | Kallmann syndrome: towards molecular pathogenesis[END_REF][START_REF] Sarfati | A comparative phenotypic study of kallmann syndrome patients carrying monoallelic and biallelic mutations in the prokineticin 2 or prokineticin receptor 2 genes[END_REF][START_REF] Abreu | Loss-of-function mutations in the genes encoding prokineticin-2 or prokineticin receptor-2 cause autosomal recessive Kallmann syndrome[END_REF][START_REF] Dodé | Kallmann syndrome: mutations in the genes encoding prokineticin-2 and prokineticin receptor-2[END_REF]. KS is genetically heterogeneous and its clinical features are congenital hypogonadotropic hypogonadism (HH) with anosmia or hyposmia that is sometimes accompanied by a deregulation of the energy balance.

Patients carrying biallelic mutations in PROK2 or PROKR2 have consistently a severe, complete KS phenotype. Such mutations in homozygous state were found in a few patients, the main part of the KS patients carrying only heterozygous mutations. In that case of monoallelic mutations, the phenotype of patients is more variable and likely depends on the additional genetic hits [START_REF] Dodé | PROK2/PROKR2 Signaling and Kallmann Syndrome[END_REF]. Dodé et al. studied a cohort of 192 KS patients using a candidate gene strategy and identified ten and four different point mutations in the genes encoding PROKR2 and PROK2 respectively. Interestingly, one patient carrying the mutation p.R73C in PROK2 gene suffered from a severe sleep disorder and marked obesity, which might be related to the known circadian function of PROK2 and its potential roles in sleepwake regulation and ingestive behavior [START_REF] Dodé | Kallmann syndrome: mutations in the genes encoding prokineticin-2 and prokineticin receptor-2[END_REF]. Abreu et al. reported the case of three KS patients who presented mutations in the PROKR2 gene (p.L173R or p.R268C mutations in the heterozygous state), all were obese and one developed metabolic syndrome [START_REF] Abreu | Loss-of-function mutations in the genes encoding prokineticin-2 or prokineticin receptor-2 cause autosomal recessive Kallmann syndrome[END_REF].

Two other human studies addressed the relationship between PROK2 and metabolic syndrom (MetS), since PROK2 is involved in inflammation which plays an important role in the pathogenesis of MetS. Although its origin has not been clearly demonstrated, it is thus likely that the main source of plasma PROK2 are lymphoid organs, circulating leukocytes and hematopoietic cells in humans, as it is the case in mice. In the first study, serum PROK2 levels were measured in 162 middle-aged and elderly Chinese patients with cardiovascular risk factors [START_REF] Wang | Prokineticin-2 is associated with metabolic syndrome in a middle-aged and elderly Chinese population[END_REF]. They were found to be positively correlated with various cardiometabolic risk factors including blood lipid, fasting plasma glucose, HbA1c, blood pressure, body mass index (BMI), and uric acid. One limitation of this study was the lack of healthy control group [START_REF] Wang | Prokineticin-2 is associated with metabolic syndrome in a middle-aged and elderly Chinese population[END_REF]. In the second study, our group assumed that circulating PROK2 could be used as a biomarker of MetS or T2D in subjects from the DESIR cohort (Data from an Epidemiological Study on the Insulin-Resistance syndrome) [START_REF] Balkau | Predicting diabetes: clinical, biological, and genetic approaches: data from the Epidemiological Study on the Insulin Resistance Syndrome (DESIR)[END_REF]. We found that plasma PROK2 was lower in T2D patients compared to the nondiabetic ones, but this association between plasma PROK2 and T2D disappeared after adjustment for BMI and/or caloric intake [START_REF] Mortreux | New roles for prokineticin 2 in feeding behavior, insulin resistance and type 2 diabetes: Studies in mice and humans[END_REF]. In univariate regression studies, PROK2 was significantly inversely associated with BMI, waist girth, fasting glycemia, HbA1c, total cholesterol, and LDL cholesterol [START_REF] Mortreux | New roles for prokineticin 2 in feeding behavior, insulin resistance and type 2 diabetes: Studies in mice and humans[END_REF]. Associations with incident hyperglycemia and incident MetS were observed even after adjustment for BMI and with obesity incidence. They were compatible with the additive model, showing an allele dose effect, but also most of the times with the dominant model meaning that carrying one or two alleles makes no difference. Actually, these results indicate associations between phenotypes and genetic variation but cannot allow to conclude firmly on the genetic model.

Conclusion

PROK2 is involved in many physiological processes both in rodents and mammals including Humans. In the metabolic field, it is invovled in the regulation of physiological circadian rhythms as body temperature, sleep behavior and glucose homeostasis, bearing in mind that the extrapolation from rodents data to humans can not be automatic. PROK2 reduces food intake when administered in an acute peripheral or central way to mice [START_REF] Gardiner | Prokineticin 2 is a hypothalamic neuropeptide that potently inhibits food intake[END_REF][START_REF] Mortreux | New roles for prokineticin 2 in feeding behavior, insulin resistance and type 2 diabetes: Studies in mice and humans[END_REF][START_REF] Beale | Peripheral administration of prokineticin 2 potently reduces food intake and body weight in mice via the brainstem[END_REF]. Activation of the PROKR1 pathway restrains adipose tissue expansion and positively regulates insulin sensitivity in adipocytes, skeletal muscle and endothelial cells [START_REF] Szatkowski | Prokineticin receptor 1 as a novel suppressor of preadipocyte proliferation and differentiation to control obesity[END_REF][START_REF] Mok | Prokineticin receptor 1 ameliorates insulin resistance in skeletal muscle[END_REF][START_REF] Dormishian | Prokineticin receptor-1 is a new regulator of endothelial insulin uptake and capillary formation to control insulin sensitivity and cardiovascular and kidney functions[END_REF]. Finally, PROK2 attenuates high glucose/high palmitic acid-induced cardiomyocyte apoptosis [START_REF] Yang | Prokineticin 2 (PK2) Rescues Cardiomyocytes from High Glucose/High Palmitic Acid-Induced Damage by Regulating the AKT/GSK3β Pathway In Vitro[END_REF] and it has been suggested that the known cardioprotective effects of metformin could be mediated, at least in part, through an increase in PROK2 signalling [START_REF] Yang | Metformin Ameliorates Diabetic Cardiomyopathy by Activating the PK2/PKR Pathway[END_REF]. All of these studies suggest that PROKR agonists could be used as potent therapeutic targets for the treatment of obesity and associated disorders, such as cardiovascular diseases [START_REF] Désaubry | Prokineticin signaling in heartbrain developmental axis: Therapeutic options for heart and brain injuries[END_REF]. A PROKR1 non-peptide agonist has already been evidenced to contribute to myocardial repair and collateral vessel growth. However, it should not be forgotten that activation of PROKR signalling pathway may also have adverse effects, as exacerbation of pain, inflammation or CNS neurotoxicity. Thus, much work is still needed to precisely characterize the multiple physiological effects of this promising family of proteins in the hope of developing new therapeutic molecules targeting this signalling pathway.

Declarations of interest

None.

Ethical approval

This is a review article that cites the peer reviewed papers from PubMed. The study designs and ethical statements are detailed in the primary papers, and therefore this review article does not include a study design with direct ethical statements.

Statement of original publication

Tables Table 1. Expression pattern of prokineticin 2 in adult mouse peripheral tissues and brain regions.

Table 2 .

 2 G protein-dependent signaling pathways induced by activation of prokineticin receptors.

Figure legend Figure 1 .

 legend1 Figure legend

Acknowledgements

The authors receive recurrent funding from the University of Paris and the CNRS as well as grants from the French National Research Agency (ANR-16-CE14-0026).

Tissue

Expression level References

Peripheral tissues

Blood cells and bone marrow /inflammatory blood cells ++/+++ [START_REF] Lecouter | Bv8 and endocrine glandderived vascular endothelial growth factor stimulate hematopoiesis and hematopoietic cell mobilization[END_REF][START_REF] Negri | The Prokineticins: Neuromodulators and Mediators of Inflammation and Myeloid Cell-Dependent Angiogenesis[END_REF][START_REF] Giannini | The chemokine Bv8/prokineticin 2 is up-regulated in inflammatory granulocytes and modulates inflammatory pain[END_REF] Urogenital tract (Testis, Uterus) ++ [START_REF] Negri | The Prokineticins: Neuromodulators and Mediators of Inflammation and Myeloid Cell-Dependent Angiogenesis[END_REF][START_REF] Lecouter | The endocrine-gland-derived VEGF homologue Bv8 promotes angiogenesis in the testis: Localization of Bv8 receptors to endothelial cells[END_REF] Myocardial tissue ++ [START_REF] Chen | Identification and pharmacological characterization of prokineticin 2 beta as a selective ligand for prokineticin receptor 1[END_REF][START_REF] Negri | The Prokineticins: Neuromodulators and Mediators of Inflammation and Myeloid Cell-Dependent Angiogenesis[END_REF][START_REF] Urayama | The prokineticin receptor-1 (GPR73) promotes cardiomyocyte survival and angiogenesis[END_REF] GI tract, Enteric plexus ++ [START_REF] Li | Identification of two prokineticin cDNAs: recombinant proteins potently contract gastrointestinal smooth muscle[END_REF][START_REF] Chen | Identification and pharmacological characterization of prokineticin 2 beta as a selective ligand for prokineticin receptor 1[END_REF][START_REF] Negri | The Prokineticins: Neuromodulators and Mediators of Inflammation and Myeloid Cell-Dependent Angiogenesis[END_REF] Kupfer cells in the liver ++ [START_REF] Chen | Identification and pharmacological characterization of prokineticin 2 beta as a selective ligand for prokineticin receptor 1[END_REF][START_REF] Negri | The Prokineticins: Neuromodulators and Mediators of Inflammation and Myeloid Cell-Dependent Angiogenesis[END_REF] Some dorsal root ganglion (DRG) neurons ++ [START_REF] Negri | The Prokineticins: Neuromodulators and Mediators of Inflammation and Myeloid Cell-Dependent Angiogenesis[END_REF][START_REF] Maftei | Abnormal Pain Sensation in Mice Lacking the Prokineticin Receptor PKR2: Interaction of PKR2 with Transient Receptor Potential TRPV1 and TRPA1[END_REF][START_REF] Negri | Impaired nociception and inflammatory pain sensation in mice lacking the prokineticin receptor PKR1: focus on interaction between PKR1 and the capsaicin receptor TRPV1 in pain behavior[END_REF] Adrenal glands, Spleen ++ [START_REF] Chen | Identification and pharmacological characterization of prokineticin 2 beta as a selective ligand for prokineticin receptor 1[END_REF] Brain regions Suprachiasmatic nucleus of the hypothalamus ++++ [START_REF] Cheng | Regulation of prokineticin 2 expression by light and the circadian clock[END_REF][START_REF] Cheng | Prokineticin 2 transmits the behavioural circadian rhythm of the suprachiasmatic nucleus[END_REF][START_REF] Zhang | Efferent projections of prokineticin 2 expressing neurons in the mouse suprachiasmatic nucleus[END_REF][START_REF] Cheng | Expression of prokineticins and their receptors in the adult mouse brain[END_REF] Olfactory bulb ++++ [START_REF] Negri | The Prokineticins: Neuromodulators and Mediators of Inflammation and Myeloid Cell-Dependent Angiogenesis[END_REF][START_REF] Cheng | Expression of prokineticins and their receptors in the adult mouse brain[END_REF][START_REF] Melchiorri | The mammalian homologue of the novel peptide Bv8 is expressed in the central nervous system and supports neuronal survival by activating the MAP kinase/PI-3-kinase pathways[END_REF][START_REF] Mortreux | New roles for prokineticin 2 in feeding behavior, insulin resistance and type 2 diabetes: Studies in mice and humans[END_REF][START_REF] Ng | Dependence of olfactory bulb neurogenesis on prokineticin 2 signaling[END_REF] Medial preoptic area of the hypothalamus +++ [START_REF] Negri | The Prokineticins: Neuromodulators and Mediators of Inflammation and Myeloid Cell-Dependent Angiogenesis[END_REF][START_REF] Cheng | Expression of prokineticins and their receptors in the adult mouse brain[END_REF] Hippocampus +++ [START_REF] Negri | The Prokineticins: Neuromodulators and Mediators of Inflammation and Myeloid Cell-Dependent Angiogenesis[END_REF][START_REF] Cheng | Expression of prokineticins and their receptors in the adult mouse brain[END_REF][START_REF] Melchiorri | The mammalian homologue of the novel peptide Bv8 is expressed in the central nervous system and supports neuronal survival by activating the MAP kinase/PI-3-kinase pathways[END_REF] Islands of Callejia ++ [START_REF] Cheng | Expression of prokineticins and their receptors in the adult mouse brain[END_REF] Cerebral cortex (high levels in layer II) ++ [START_REF] Negri | The Prokineticins: Neuromodulators and Mediators of Inflammation and Myeloid Cell-Dependent Angiogenesis[END_REF][START_REF] Melchiorri | The mammalian homologue of the novel peptide Bv8 is expressed in the central nervous system and supports neuronal survival by activating the MAP kinase/PI-3-kinase pathways[END_REF] Medial amygdala ++ [START_REF] Negri | The Prokineticins: Neuromodulators and Mediators of Inflammation and Myeloid Cell-Dependent Angiogenesis[END_REF][START_REF] Cheng | Expression of prokineticins and their receptors in the adult mouse brain[END_REF][START_REF] Melchiorri | The mammalian homologue of the novel peptide Bv8 is expressed in the central nervous system and supports neuronal survival by activating the MAP kinase/PI-3-kinase pathways[END_REF] Cerebellar cortex ++ [START_REF] Negri | The Prokineticins: Neuromodulators and Mediators of Inflammation and Myeloid Cell-Dependent Angiogenesis[END_REF][START_REF] Melchiorri | The mammalian homologue of the novel peptide Bv8 is expressed in the central nervous system and supports neuronal survival by activating the MAP kinase/PI-3-kinase pathways[END_REF] Spinal Cord (dorsal and ventral horns) ++ [START_REF] Negri | The Prokineticins: Neuromodulators and Mediators of Inflammation and Myeloid Cell-Dependent Angiogenesis[END_REF][START_REF] Melchiorri | The mammalian homologue of the novel peptide Bv8 is expressed in the central nervous system and supports neuronal survival by activating the MAP kinase/PI-3-kinase pathways[END_REF] Nucleus of solitary tract ++ [START_REF] Melchiorri | The mammalian homologue of the novel peptide Bv8 is expressed in the central nervous system and supports neuronal survival by activating the MAP kinase/PI-3-kinase pathways[END_REF] Arcuate nucleus of the hypothalamus ++/+ [START_REF] Negri | The Prokineticins: Neuromodulators and Mediators of Inflammation and Myeloid Cell-Dependent Angiogenesis[END_REF][START_REF] Cheng | Expression of prokineticins and their receptors in the adult mouse brain[END_REF] Nucleus