**2.2. Prokineticin in the development of obesity**

have been studied as potential drugs in the treatment of obesity [3]. Recent evidence showed that some brain regions may not only be involved in food intake regulation but also play an important role in the regulation of cardiovascular blood homeostasis [4]. The rising prevalence of both obesity and heart failure make this association an important target for prevention. Therefore, it is important to determine the common mechanisms regulating both obesity and cardiovascular events. Identification of signaling pathways linking obesity and cardiovascular disease is importantforthedevelopmentofnoveltherapeutics.Here,we summarize the current informationonthe role of anorexigenicpeptideprokineticininobesityandcardiovascularrenal

Prokineticins are anorexigenic and angiogenic hormones. Because of the structural, signaling and functional similarities, prokineticins are considered as cytokines/chemokines [5]. They are released principally by macrophages and reproductive organs [6]. Recently, prokineticin is considered as an adipokine because a high level of prokineticins has been found in obese human WAT [7]. These small peptides (80–120 amino acids) are called prokineticins, because these molecules were first identified as potent contractile factors in the gastrointestinal tract [8]. Two isoforms of prokineticins have been identified: prokineticin‐1 and prokineticin‐2. Prokineticin‐1 has been originally called as endocrine gland‐derived vascular endothelial growth factor (EG‐VEGF), [9] because of its functional similarity to VEGF. Prokineticin‐2 is also called as Bv8. Both of these peptides are 45% identical with highly conserved N‐terminal AVITGA motif essential for their biological activity [6, 10]. Prokineticin activity is mediated

Circulating hormones and nutrients are integrated to mediate the regulation of short‐term and long‐term dietary intakes in the hypothalamus. A feeding and energy homeostasis control center in the hypothalamus is called as arcuate nucleus (ARC) [12, 13]. The ARC integrates most of the peripheral hormonal signals including leptin, insulin and ghrelin. The ARC has two major subpopulations of primary neurons that express neurohormones with opposing effects on food intake. ARC neurons that release the proopiomelanocortin (POMC)‐derived peptide alpha‐melanocyte‐stimulating hormone (α‐MSH) and cocaine‐ and amphetamine‐ regulated transcript (CART) peptide potently reduce food intake [13, 14]. However, neuro‐

Prokineticin‐2 is involved in the control of food intake and of fat mass through actions in the ARC in the hypothalamus [15]. PKR1 receptor is expressed on both NPY/AgRP and POMC/ CART neurons. Intracranial injection of prokineticin‐2 in rats strongly decreases food intake. Controversy, anti‐prokineticin‐2 antibody increases food intake. Anorexigenic effect of pro‐ kineticin‐2 is mediated at least partly via the hypothalamic ARC melanocortin system. Proki‐ neticin‐2 increases the release of alpha‐MSH from *ex vivo* hypothalamic explants. Recently,

diseases, emphasizing prokineticin receptor‐1 signaling in these events.

**2. Prokineticins and their receptors**

116 Adiposity - Omics and Molecular Understanding

by two G‐protein‐coupled receptors, PKR1 and PKR2 [11].

peptide Y (NPY)‐producing neurons in the ARC stimulate food intake.

**2.1. Prokineticin‐2 is an anorexigenic peptide**

The mechanisms underlying the development of obesity include the hypertrophy and/or hyperplasia of adipocytes, adipose tissue (AT) inflammation, impaired extracellular matrix remodeling and fibrosis together with an altered secretion of adipokines [20]. AT expansion involves two distinct mechanisms: an enlargement in adipose cells and an increase of adipo‐ cytes number [21]. Differentiated adipocytes are post‐mitotic and therefore hyperplasia is the result of increased *de novo* adipocyte formation (adipogenesis). Impaired adipogenesis is associated with insulin resistance [22]. The balance between proliferation and differentiation of preadipocytes and adipocyte apoptosis or necrosis determines adipocyte number.

Prokineticin‐2 levels were found to be high in obese human WAT [7]. Prokineticin‐2 suppresses AT expansion by two distinct mechanisms: the central regulation of food intake and limiting preadipocyte proliferation and differentiation. The central regulation of body weight is counteracted by loss of PKR1 in adipose tissue in mice. Indeed, an abnormally excessive abdominal fat mass accumulation was observed in these mice where the PKR1 specifically deleted in the adipocytes (PKR1*ad‐/‐*) [7]. The formation of new adipocytes in both PKR1 null and PKR1*ad‐/‐* mice was resulted from an acceleration of preadipocyte proliferation and differentiation. AT proliferative phenotype has switch to AT hypertrophic phenotype when these mice were treated with a high‐fat diet, implicating high calorie intake is involved in the conversion of hyperplasia to hypertrophy. In isolated preadipocytes, PKR1 activation sup‐ presses proliferation and adipogenic differentiation [38].

Both PKR1*null* and PKR1*ad‐/‐* mice display abdominal obesity [7] However, only PKR1*null* mice have peripheral obesity with a diabetes‐like syndrome. Thus, non‐adipocyte PKR1‐mediated events contribute to the development of a diabetes‐like syndrome. Indeed, endothelial‐specific PKR1‐knockout mice (PKR1*ec‐/‐*) [23] had insulin resistance in adipocytes. In PKR1*ec‐/‐* adipo‐ cytes, insulin cannot promote normal fat storage, resulting in excess circulating free fatty acids that, in turn, further contribute into insulin resistance in muscle, leading to diabetes‐like syndrome. However, it seems that PKR1 has no direct effect on fat deposition in adipocytes. PKR1ad‐/‐ mice did not have severe accumulation of fat tissue in their adipocytes. Since adipocytes are not created from other adipocytes, but they arise from precursor cells (preadi‐ pocytes), PKR1 suppress the ability of these precursor cells to become adipocytes (**Figure 1**) [7]. The expansion and metabolism of the adipose tissue are the major problem in obesity.

**Figure 1.** Prokineticin‐2/PKR1 signaling may act as a new connector between development of obesity, diabetes and car‐ diovascular diseases. Prokineticin‐2/PKR1 signaling in central nervous system (CNS) regulates food intake. Prokineti‐ cin‐2 released from adipocytes controls preadipocyte conversion to adipocyte via PKR1 signaling. Prokineticin‐2/PKR1 signaling promotes survival of cardiomyocytes and angiogenesis and involved in neovascularization by activating car‐ diac progenitor cells. Prokineticin‐2/PKR1 signaling contributes to heart and kidney development as well as kidney function. Whether this signaling involves heart and kidney regulation through CNS remains to be studied.
