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

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

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, PKR1 has been shown as the first non‐melanocortin GPCR to be regulated by the melanocor‐ tin receptor accessory protein 2 (MRAP2). Indeed, MRAP2 significantly and specifically in‐ hibits PKR1 signaling [16].

Peripheral administration of prokineticin‐2 reduces food intake and body weight in both lean mice and diet‐induced obesity models [17]. This effect of prokineticin‐2 is not evident when appetite is increased or feeding behavior is promoted. Hypothalamic prokineticin‐2 levels were found extremely high in the early neonatal period. However, a decreased level of prokineticin‐2 was evident under fasting conditions [18]. Prokineticin‐2‐knockout mice be‐ came obese at the late age. Humans with the inactivating mutations of prokineticin‐2 gene are also obese [17, 19]. The anorectic effects of prokineticin‐2 are abolished by PKR1 antago‐ nists and not observed in mice lacking PKR1 [17]. Thus, the anorectic effects of prokineticin‐ 2 in the hypothalamus are mediated by PKR1.
