Prokineticin 2 Is a Hypothalamic Neuropeptide That Potently Inhibits Food Intake

OBJECTIVE

Prokineticin 2 (PK2) is a hypothalamic neuropeptide expressed in central nervous system areas known to be involved in food intake. We therefore hypothesized that PK2 plays a role in energy homeostasis.

RESEARCH DESIGN AND METHODS

We investigated the effect of nutritional status on hypothalamic PK2 expression and effects of PK2 on the regulation of food intake by intracerebroventricular (ICV) injection of PK2 and anti-PK2 antibody. Subsequently, we investigated the potential mechanism of action by determining sites of neuronal activation after ICV injection of PK2, the hypothalamic site of action of PK2, and interaction between PK2 and other hypothalamic neuropeptides regulating energy homeostasis. To investigate PK2''s potential as a therapeutic target, we investigated the effect of chronic administration in lean and obese mice.

RESULTS

Hypothalamic PK2 expression was reduced by fasting. ICV administration of PK2 to rats potently inhibited food intake, whereas anti-PK2 antibody increased food intake, suggesting that PK2 is an anorectic neuropeptide. ICV administration of PK2 increased c-fos expression in proopiomelanocortin neurons of the arcuate nucleus (ARC) of the hypothalamus. In keeping with this, PK2 administration into the ARC reduced food intake and PK2 increased the release of α-melanocyte–stimulating hormone (α-MSH) from ex vivo hypothalamic explants. In addition, ICV coadministration of the α-MSH antagonist agouti-related peptide blocked the anorexigenic effects of PK2. Chronic peripheral administration of PK2 reduced food and body weight in lean and obese mice.

CONCLUSIONS

This is the first report showing that PK2 has a role in appetite regulation and its anorectic effect is mediated partly via the melanocortin system.Prokineticin 2 (PK2) is an 81–amino acid cysteine-rich protein structurally related to prokineticin 1 (PK1), with which it shares 44% sequence homology (1–3). Both bind to two related G-protein–coupled receptors, termed prokineticin receptor 1 (PKR1) and prokineticin receptor 2 (PKR2) (4–6). The prokineticins are so called because the first effect ascribed to them was the stimulation of guinea pig ileum smooth muscle contraction (2). Subsequently, PK2 has been shown to be involved in several developmental and physiological processes (7). It is thought to be critical for the development of the central nervous system (CNS) because mice lacking either PK2 or PKR2 have poorly developed olfactory bulbs (8–10). In addition, these mice have hypogonadotrophic hypogonadism due to abnormal gonadotrophin-releasing hormone neuronal migration (3,11). The same phenotype occurs in humans with mutations of PK2 or PKR2 (11–13).PK2 is expressed in several regions of the adult brain but is found in highest concentrations in the suprachiasmatic nucleus (SCN), the site of the master circadian oscillator. PK2 expression in the SCN varies with timing of the circadian cycle (14). These data suggest a role for PK2 in the regulation of the circadian clock (15). In accordance with this, mice with targeted deletion of either PK2 or PKR2 exhibit alterations in the circadian control of locomotor activity, thermoregulation, and sleep (16,17). Thus, PK2 may act as an output molecule for the SCN circadian clock (18).The hypothalamus is important in the regulation of energy homeostasis. Because PK2 receptors are expressed in hypothalamic nuclei known to regulate appetite (19,20), we hypothesized that PK2 may play a role in the control of appetite regulation. Indeed, intracerebroventricular (ICV) administration of an amphibian homologue of PK2 (Bv8) reduces food intake in rats (19). However, there are currently no reports of the effects of PK2 on appetite. We therefore investigated the role of PK2 in the control of energy homeostasis. Our data suggest that PK2 is a novel hypothalamic regulator of food intake.     

Longitudinal Changes in the B‐Type Natriuretic Peptide Levels in Normal Pregnancy and Postpartum

Normal levels of B‐type natriuretic peptide (BNP) are not well established in pregnancy. We obtained longitudinal BNP levels in 29 healthy pregnant women in each trimester and postpartum period, and compared these levels to the 25 nonpregnant controls. There were no significant differences among the cases and controls with respect to weight, diastolic blood pressure, and ethnicity. A total of 116 BNP values were obtained during pregnancy. The median (and range) BNP level during pregnancy was 19 (10–143) pg/ml versus 10 (10–37) pg/ml in the nonpregnant controls (p = 0.003). However, there were no statistically significant differences in the median BNP levels at various stages of pregnancy: first trimester 20 (10–115) pg/ml versus the second trimester 18 (10–112) pg/ml (p = 0.8), second trimester 18 pg/ml versus third trimester 26 (10–143) pg/ml (p = 0.06), and third trimester 26 pg/ml versus postpartum18 (10–62) pg/ml (p = 0.08). There were no significant differences between the BNP levels throughout the trimesters and postpartum period. Pregnant BNP levels were approximately twice as high as the nonpregnant BNP levels. Our study is unique in evaluating longitudinal changes in BNP levels in normal pregnancies and the postpartum period in comparison with healthy, nonpregnant controls. It demonstrates that pregnant BNP levels are approximately 2‐fold higher than their nonpregnant counterparts, and do not significantly fluctuate during pregnancy. In conclusion, pregnancy is associated with a significant, but small increase in the BNP levels compared with nonpregnant women. Copyright © 2009 Wiley Periodicals, Inc.     

Transcranial Magnetic and Direct Current Stimulation in Children

Promising results in adult neurologic and psychiatric disorders are driving active research into transcranial brain stimulation techniques, particularly transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS), in childhood and adolescent syndromes. TMS has realistic utility as an experimental tool tested in a range of pediatric neuropathologies such as perinatal stroke, depression, Tourette syndrome, and autism spectrum disorder (ASD). tDCS has also been tested as a treatment for a number of pediatric neurologic conditions, including ASD, attention-deficit/hyperactivity disorder, epilepsy, and cerebral palsy. Here, we complement recent reviews with an update of published TMS and tDCS results in children, and discuss developmental neuroscience considerations that should inform pediatric transcranial stimulation.     

Novel Nonsense Variants c.58C>T (p.Q20X) and c.256G>T (p.E85X) in the CHEK2 Gene Identified in Breast Cancer Patients from Balochistan

Breast cancer is very common and the leading cause of cancer deaths among women globally. Hereditary cases account for 510% of the total burden and CHEK2, which plays crucial role in response to DNA damage to promote cell cycle arrest and repair or induce apoptosis, is considered as a moderate penetrance breast cancer risk gene. Our objective in the current study was to analyze mutations in related to breast cancer. A total of 271 individuals including breast cancer patients and normal subjects were enrolled and all 14 exons of CHEK2 were amplified and sequenced. The majority of the patients (>95%) were affected with invasive ductal carcinoma (IDC), 52.1% were diagnosed with grade III tumors and 56.2% and 27.5% with advanced stages III and IV. Two novel nonsense variants i.e. c.58C>T (P.Q20X) and c.256G>T (p.E85X) at exon 1 and 2 in two breast cancer patients were identified, both novel and not reported elsewhere.     

Identification of critical regions for clinical features of distal 10q deletion syndrome

Array comparative genomic hybridization studies were performed to further characterize cytogenetic abnormalities found originally by karyotype and fluorescence in situ hybridization in five clinical cases of distal 10q deletions, including several with complex cytogenetic rearrangements and one with a partial male-to-female sex-reversal phenotype. These results have enabled us to narrow the previously proposed critical regions for the craniofacial, urogenital, and neuropsychiatric disease-related manifestations associated with distal 10q deletion syndrome. Furthermore, we propose that haploinsufficiency of the DOCK1 gene may play a crucial role in the pathogenesis of the 10q deletion syndrome. We hypothesize that alteration of DOCK1 and/or other genes involved in regulation and signaling of multiple pathways can explain the wide range of phenotypic variability between patients with similar or identical cytogenetic abnormalities.