A role for kisspeptin in islet function

Aims/hypothesis We investigated the production of kisspeptin (KISS1) and the KISS1 receptor, GPR54, in pancreatic islets and determined the effects of exogenous kisspeptin on insulin secretion.Methods RT-PCR and immunohistochemistry were used to detect expression of KISS1 and GPR54 mRNAs and the production of KISS1 and GPR54 in human and mouse islets and in beta (MIN6) and alpha- (alphaTC1) cell lines. The effects of KISS1 on basal and glucose-induced insulin secretion from mouse and human islets were measured in a perifusion system.Results KISS1 and GPR54 mRNAs were both detected in human and mouse islets, and GPR54 mRNA expression was also found in the MIN6 and alphaTC1 endocrine cell lines. In sections of mouse pancreas, KISS1 and GPR54 immunoreactivities were co-localised in both beta and alpha cells within islets, but were not detected in the exocrine pancreas. Exposure of mouse and human islets to KISS1 caused a stimulation of glucose-induced (20 mmol/l) insulin secretion, but had no effect on the basal rate of secretion at a sub-stimulatory concentration of glucose (2 mmol/l). In contrast, KISS1 inhibited insulin secretion from MIN6 cells at both 2 and 20 mmol/l glucose. KISS1 had no significant effect on glucagon secretion from mouse islets.Conclusions/interpretation This is the first report to show that the GPR54/KISS1 system is expressed in the endocrine pancreas, where it influences beta cell secretory function. These observations suggest an important role for this system in the normal regulation of islet function.     

Expression of kisspeptin/GPR54 and PIBF/PR in the first trimester trophoblast and decidua of women with recurrent spontaneous abortion

Kisspeptin and its receptor GPR54 play a major role in trophoblast invasion, and progesterone-induced blocking factor (PIBF) is needed for maintaining pregnancy. The expression of kisspeptin/GPR54 and PIBF/progesterone receptor (PR) in trophoblasts and deciduas and the relationship between kisspeptin and PIBF were investigated in the same women with recurrent spontaneous abortion (RSA). Trophoblastic and decidual tissues were collected from 32 RSA women who miscarried a genetically normal fetus, and 35 women who had voluntary abortion. Kisspeptin, GPR54, PIBF and PR were investigated using immunohistochemistry. Kisspeptin, GPR54 and PIBF expressions in syncytiotrophoblasts and cytotrophoblasts were decreased in RSA women as compared to controls (P < 0.05). Kisspeptin, PIBF and PR expressions in deciduas were significantly decreased in RSA women as compared to controls (P < 0.01). GPR54 expression in deciduas nearly showed no difference between the RSA group and the control group (P = 0.958). Kisspeptin and PIBF expressions in syncytiotrophoblasts, cytotrophoblasts and deciduas were correlated with each other in the RSA group (Kappa = 0.602, P = 0.001; Kappa = 0.590, P = 0.001; Kappa = 0.392, P = 0.011). These data support the hypothesis that decreased kisspeptin and PIBF expressions in trophoblasts and deciduas are associated with RSA.     

Potent effect of KISS1-54 DNA vaccine compared with KISS1-10 DNA vaccine in inhibiting the fertility of female rats

BackgroundMost studies on immunocastration currently focused on male animals. However, immunization of male animals does not completely inhibit sexual behavior and fertility. This study aimed to compare the immunocastration effect of KISS1 DNA vaccines encoding different lengths of kisspeptins in female rats for effective castration effects on both male and female rats.MethodsFifteen female rats were randomly divided into three groups. The rats in T1 group or T2 group was orally given respectively KISS1-54 or KISS1-10 DNA vaccines with fused tPA signal peptide, and the control group (Group C) was orally administered with empty vector vaccine, at a dose of 5 × 10⁹ CFU/rat at weeks 0, 3 and 6 of the study. Blood samples were collected by retroorbital bleeding before primary immunization and at weeks 3 and 9 after primary immunization.ResultsBoth KISS1-54 and KISS1-10 DNA vaccines induced the body’s humoral immune response, and the anti-kisspeptin antibody titres in the T1 group were significantly higher than that in T2 and C groups (p < 0.05). The rats in T1 group has lower serum kisspeptin and estradiol levels than those in T2 and C groups and smaller litter size of rats than those in the control group after mating (p < 0.05). No significant difference was observed between T2 and C groups. The levels of KISS1 and GPR54 mRNA in the hypothalamus and ovaries of the T1 group were significantly lower than that in control group. However, the levels of KISS1 mRNA in the T2 group were significantly lower than that in the control group only in ovaries (p < 0.05).ConclusionThe oral KISS1-54 DNA vaccine with fused tPA signal peptide was more effective than that KISS1-10 DNA vaccine in suppressing fertility of female rats.     

Cellular mechanisms and integrative timing of neuroendocrine control of GnRH secretion by kisspeptin

The hypothalamus integrates endogenous and exogenous inputs to control the pituitary–gonadal axis. The ultimate hypothalamic influence on reproductive activity is mediated through timely secretion of GnRH in the portal blood, which modulates the release of gonadotropins from the pituitary. In this context neurons expressing the RF-amide neuropeptide kisspeptin present required features to fulfill the role of the long sought-after hypothalamic integrative centre governing the stimulation of GnRH neurons. Here we focus on the intracellular signaling pathways triggered by kisspeptin through its cognate receptor KISS1R and on the potential role of proteins interacting with this receptor. We then review evidence implicating both kisspeptin and RFRP3 – another RF-amide neuropeptide – in the temporal orchestration of both the pre-ovulatory LH surge in female rodents and the organization of seasonal breeding in photoperiodic species.     

Aging-related changes in RP3V kisspeptin neurons predate the reduced activation of GnRH neurons during the early reproductive decline in female mice

Kisspeptin neurons in the rostral periventricular area of the third ventricle (RP3V) play a key role in relaying the positive feedback effects of estradiol that activate gonadotropin-releasing hormone (GnRH) neurons and drive a surge in the GnRH/luteinizing hormone (LH) level. However, the precise role of kisspeptin neurons during female reproductive senescence remains unclear. Focusing on middle-aged intact female mice with irregular estrous cycles, we found a parallel decline in c-Fos–positive kisspeptin neurons and c-Fos–positive GnRH neurons at the time of the GnRH/LH surge. Furthermore, in kisspeptin neurons, the expression of estrogen receptor α (ERα), but not progesterone receptor (PR), decreased with age. Interestingly, some kisspeptin neurons in the RP3V, but none of the GnRH neurons in the rostral preoptic area (rPOA), had a characteristic cellular senescence in middle-aged mice and old mice. These data suggest that, among the groups of neurons involved in reproductive control, the kisspeptin neurons in the RP3V are likely among the earliest to undergo aging processes and thus participate in initiating the early reproductive decline.     

Prognostic value of repeated serum kisspeptin measurements in early first trimester pregnancy: a preliminary study

Research question

What is the diagnostic value of maternal kisspeptin in patients with asymptomatic first-trimester pregnancies, and what is the prognostic significance of kisspeptin versus beta-HCG in early pregnancies.

Delayed puberty in prenatally glucocorticoid administered female rats occurs independently of the hypothalamic Kiss1-Kiss1r-GnRH system

Intrauterine growth retardation (IUGR) is an important risk factor for the pathogenesis of diseases after birth. Long-lasting alterations in the structure and function of tissues and the neuroendocrine system, which are known as ‘programming effects’, increase the risks of these diseases. To investigate the pathophysiology of programming effects, several kinds of IUGR rodent models have been used in experiments. Sexual maturation and the onset of puberty are delayed in these models. We have previously reported that decreased action of hypothalamic kisspeptin, which is a positive regulator of GnRH, contributes to the delayed onset of puberty in undernutrition-induced IUGR rats. The aim of this study was to evaluate whether the hypothalamic Kiss1-Kiss1r-GnRH system is also altered in dexamethasone-induced IUGR rats. Compared with offspring from an untreated mother (control), offspring from a dexamethasone administered mother (DEX) showed a significant reduction in body weight throughout the experimental period (from birth to the prepubertal period) and the delayed onset of puberty. There were no significant differences between the control and DEX groups with regard to their hypothalamic Kiss1, Kiss1r, GnRH, CRH, NPY and POMC mRNA levels during the experimental period or their serum LH, FSH, or leptin concentrations at postnatal day 28 or vaginal opening (VO). Compared with the control, DEX showed significantly lower ovarian weight at postnatal day 28, but not at VO. These results suggested that the delayed onset of puberty induced by maternal dexamethasone administration would occur independently of hypothalamic Kiss1-Kiss1r-GnRH system.