kiss1-protein--human and Weight-Gain

Obesity is a global health problem even among pregnant women. Obesity alters quality of labor, such as preterm labor, prolonged labor, and higher oxytocin requirements in pregnant women. The most important factors to play a role in the altered gestational period and serve as drug targets to treat the consequences are female sexual hormones, calcium channels, adrenergic system, oxytocin, and prostaglandins. However, we have limited information about the impact of obesity on the pregnant uterine contractility and gestation time. Adipose tissue, which is the largest endocrine and paracrine organ, especially in obesity, is responsible for the production of adipokines and various cytokines and chemokines, and there are no reliable data available describing the relation between body mass index, glucose intolerance, and adipokines during pregnancy. Recent data suggest that the dysregulation of leptin, adiponectin, and kisspeptin during pregnancy contributes to gestational diabetes mellitus and pre-eclampsia. A preclinical method for obese pregnancy should be developed to clarify the action of adipokines and assess their impact in obesity. The deeper understanding of the adipokines-induced processes in obese pregnancy may be a step closer to the prevention and therapy of preterm delivery or prolonged pregnancy. Gestational weight gain is one of the factors that could influence the prenatal development, birth weight, and adiposity of newborn.

Topics: Adipokines; Adiponectin; Birth Weight; Body Mass Index; Female; Gestational Age; Humans; Infant, Newborn; Kisspeptins; Leptin; Obesity; Pregnancy; Uterus; Weight Gain

Kisspeptin is a critical regulator of normal reproductive function. A single injection of kisspeptin in healthy human volunteers potently stimulates gonadotropin release. However, the effects of kisspeptin on gonadotropin release in women with hypothalamic amenorrhea (HA) and the effects of repeated administration of kisspeptin to humans are unknown.. The aim of this study was to determine the effects of acute and chronic kisspeptin administration on gonadotropin release in women with HA.. We performed a prospective, randomized, double-blinded, parallel design study. Women with HA received twice-daily sc injections of kisspeptin (6.4 nmol/kg) or 0.9% saline (n = 5 per group) for 2 wk. Changes in serum gonadotropin and estradiol levels, LH pulsatility, and ultrasound measurements of reproductive activity were assessed.. On the first injection day, potent increases in serum LH and FSH were observed after sc kisspeptin injection in women with HA (mean maximal increment from baseline within 4 h after injection: LH, 24.0 +/- 3.5 IU/liter; FSH, 9.1 +/- 2.5 IU/liter). These responses were significantly reduced on the 14th injection day (mean maximal increment from baseline within 4 h postinjection: LH, 2.5 +/- 2.2 IU/liter, P < 0.05; FSH, 0.5 +/- 0.5 IU/liter, P < 0.05). Subjects remained responsive to GnRH after kisspeptin treatment. No significant changes in LH pulsatility or ultrasound measurements of reproductive activity were observed.. Acute administration of kisspeptin to women with infertility due to HA potently stimulates gonadotropin release, but chronic administration of kisspeptin results in desensitization to its effects on gonadotropin release. These data have important implications for the development of kisspeptin as a novel therapy for reproductive disorders in humans.

Topics: Adult; Amenorrhea; Body Mass Index; Body Weight; Female; Follicle Stimulating Hormone; Gonadotropins; Humans; Hypothalamus; Kisspeptins; Luteinizing Hormone; Spectrometry, Mass, Electrospray Ionization; Tachyphylaxis; Tumor Suppressor Proteins; Weight Gain; Young Adult

This work evaluated the effects of neonatal overfeeding, induced by litter size reduction, on fertility and the noradrenaline-kisspeptin-gonadotrophin releasing hormone (GnRH) pathway in adult female rats. The litter size was adjusted to 3 pups with each mother in the small litters (SL) and 10 pups with each mother in the normal litters (NL). SL females exhibited metabolic changes associated with reproductive dysfunctions, shown by earlier vaginal opening and first estrus, later regular cyclicity onset, and lower and higher occurrences of estrus and diestrus phases, respectively, as well as reduced fertility, estradiol plasma levels, and mRNA expressions of tyrosine hydroxylase in the locus coeruleus, kisspeptin, and GnRH in the preoptic area in adult females in the afternoon of proestrus. These results suggest that neonatal overfeeding in female rats promotes reproductive dysfunctions in adulthood, such as lower estradiol plasma levels associated with impairments in fertility and noradrenaline-kisspeptin-GnRH pathway during positive feedback.

Topics: Aging; Animals; Animals, Newborn; Blood Glucose; Brain Stem; Estradiol; Estrous Cycle; Female; Fertility; Gonadotropin-Releasing Hormone; Gonads; Hypothalamus; Kisspeptins; Lipids; Litter Size; Male; Norepinephrine; Overnutrition; Pituitary Gland; Rats, Wistar; RNA, Messenger; Sexual Maturation; Weight Gain

Kisspeptins, encoded by Kiss1, have emerged as essential regulators of puberty and reproduction by primarily acting on GnRH neurons, via their canonical receptor, Gpr54. Mounting, as yet fragmentary, evidence strongly suggests that kisspeptin signaling may also participate in the control of key aspects of body energy and metabolic homeostasis. However, characterization of such metabolic dimension of kisspeptins remains uncomplete, without an unambiguous discrimination between the primary metabolic actions of kisspeptins vs. those derived from their ability to stimulate the secretion of gonadal hormones, which have distinct metabolic actions on their own. In this work, we aimed to tease apart primary vs. secondary effects of kisspeptins in the control of key aspects of metabolic homeostasis using genetic models of impaired kisspeptin signaling and/or gonadal hormone status.. Body weight (BW) gain and composition, food intake and key metabolic parameters, including glucose tolerance, were comparatively analyzed, in lean and obesogenic conditions, in mice lacking kisspeptin signaling due to global inactivation of Gpr54 (displaying profound hypogonadism; Gpr54. In male mice, global elimination of kisspeptin signaling resulted in decreased BW, feeding suppression and increased adiposity, without overt changes in glucose tolerance, whereas Gpr54. Our data support a global role of kisspeptin signaling in the control of body weight and metabolic homeostasis, with a dominant contribution of gonadal hormone-dependent actions. However, our results document also discernible primary effects of kisspeptin signaling in the regulation of body weight gain, feeding and responses to obesogenic insults, which occur in a sexually-dimorphic manner.. Kisspeptins, master regulators of reproduction, may also participate in the control of key aspects of body energy and metabolic homeostasis; yet, the nature of such metabolic actions remains debatable, due in part to the fact that kisspeptins modulate gonadal hormones, which have metabolic actions on their own. By comparing the metabolic profiles of two mouse models with genetic inactivation of kisspeptin signaling but different gonadal status (hypogonadal vs. preserved gonadal function), we provide herein a systematic dissection of gonadal-dependent vs. -independent metabolic actions of kisspeptins. Our data support a global role of kisspeptin signaling in the control of body weight and metabolic homeostasis, with a dominant contribution of gonadal hormone-dependent actions. However, our results document also discernible primary effects of kisspeptin signaling in the regulation of body weight gain, feeding and responses to obesogenic insults, which occur in a sexually-dimorphic manner. These data pave the way for future analyses addressing the eventual contribution of altered kisspeptin signaling in the development of metabolic alterations, especially in conditions linked to reproductive dysfunction.

Topics: Animals; Body Weight; Diet; Eating; Female; Glucose Intolerance; Gonadal Hormones; Homeostasis; Kisspeptins; Male; Mice; Mice, Knockout; Obesity; Ovariectomy; Receptors, Kisspeptin-1; Signal Transduction; Weight Gain

Childhood obesity and obesity-related metabolic complications are induced by a high-fat postnatal diet. The lack of a suitable animal model, however, remains a considerable challenge in obesity studies. In the current study, we provided high-fat diet (HFD) to dams during lactation and to pups after weaning. We also developed a novel model of C57BL/6J mouse pups with HFD-induced postnatal obesity. Results showed that feeding with HFD induces fat deposition and obesity in pups. Furthermore, HFD more potently increased the body weight (BW) of male than female pups. HFD-fed female pups were obese, underwent precocious puberty, and showed increased kisspeptin expression in the hypothalamus. However, parental obesity and precocious puberty exerted no synergistic effects on the HFD-induced postnatal weight gain and puberty onset of the pups. Interestingly, some HFD-fed litters with normal BW also exhibited precocious puberty. This finding suggested that diet composition but not BW triggers puberty onset. Our model suggests good construction validity of obesity and precocious puberty. Furthermore, our model can also be used to explore the mutual interactions between diet-induced postnatal childhood obesity and puberty.

Topics: Animals; Animals, Newborn; Diet, High-Fat; Female; Kisspeptins; Lactation; Male; Mice; Mice, Inbred C57BL; Obesity; Puberty, Precocious; Sexual Maturation; Weaning; Weight Gain

We examined the development of the reproductive system in prepubertal Tibetan sheep ewes when fed only oat hay (CON) or supplemented with either lick blocks (BS) or concentrate feed (CS) during the cold season. The average daily gain of the CS ewes was greater than that of the BS ewes (P < 0.05), which was greater than that of the CON ewes. The same pattern was observed in the number of ovarian follicles (P < 0.001), that is, CS > BS > CON. Serum concentrations of gonadotropin-releasing hormone, follicle-stimulating hormone, luteotrophic hormone, estradiol and progesterone in the CS and BS groups were higher than in the CON group (P < 0.05). The messenger RNA (mRNA) expression of KiSS-1, GPR54 (G protein-coupled receptor 54), ERα (estradiol receptor α) in the hypothalamic anteroventral periventricular area of the CS group were higher than in both the BS and CON groups (P < 0.05), while the BS group was higher than in the CON group (P < 0.05). Similar differences among groups were observed for gonadotropin-releasing hormone receptor mRNA expression in the pituitary, follicle-stimulating hormone receptor and luteinizing hormone receptor mRNA expression in the ovary. These results indicated that the KiSS1/GPR54 system was more active with nutrition or trace mineral supplementation during the cold season. The system stimulated the hypothalamic-pituitary-gonadal axis and enhanced folliclar development in prepubertal Tibetan sheep ewes. We concluded that energy, protein and trace minerals supplements could improve the reproductive performance of Tibetan sheep on the Qinghai-Tibetan plateau.

Topics: Animal Feed; Animal Nutritional Physiological Phenomena; Animals; Cold Temperature; Diet; Dietary Supplements; Female; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Hypothalamus, Anterior; Kisspeptins; Ovarian Follicle; Ovary; Puberty; Receptors, G-Protein-Coupled; Receptors, Kisspeptin-1; Reproduction; RNA, Messenger; Seasons; Sheep; Trace Elements; Weight Gain

The neonatal leptin surge, occurring from postnatal day (PND) 5 to 13 and peaking at PND9 in rodents, is important for the development of neuroendocrine circuits involved in metabolic control and reproductive function. We previously demonstrated that treatment with a leptin antagonist from PND 5 to 9, coincident with peak leptin levels in the neonatal surge, modified trophic factors and markers of cell turnover and neuronal maturation in the hypothalamus of peri-pubertal rats. The kisspeptin system and metabolic neuropeptide and hormone levels were also modified. Here our aim was to investigate if the timing of pubertal onset is altered by neonatal leptin antagonism and if the previously observed peripubertal modifications in hormones and neuropeptides persist into adulthood and affect male sexual behavior. To this end, male Wistar rats were treated with a pegylated super leptin antagonist (5mg/kg, s.c.) from PND 5 to 9 and killed at PND102-103. The appearance of external signs of pubertal onset was delayed. Hypothalamic kiss1 mRNA levels were decreased in adult animals, but sexual behavior was not significantly modified. Although there was no effect on body weight or food intake, circulating leptin, insulin and triglyceride levels were increased, while hypothalamic leptin receptor, POMC and AgRP mRNA levels were decreased. In conclusion, alteration of the neonatal leptin surge can modify the timing of pubertal onset and have long-term effects on hypothalamic expression of reproductive and metabolic neuropeptides.

Topics: Animals; Animals, Newborn; Gene Expression; Hypothalamus; Kisspeptins; Leptin; Male; Nerve Tissue Proteins; Neuropeptide Y; Pro-Opiomelanocortin; Rats, Wistar; Receptors, Leptin; Sexual Behavior, Animal; Sexual Maturation; Signal Transduction; Weight Gain

Increased body weight (BW) gain during the juvenile period leads to early maturation of the reproductive neuroendocrine system. We investigated whether a nutritional regimen that advances the onset of puberty leads to alterations in the hypothalamic neuropeptide Y (NPY) circuitry that are permissive for enhanced gonadotropin-releasing hormone (GnRH) secretion. It was hypothesized that NPY mRNA and NPY projections to GnRH and kisspeptin neurons are reduced in heifers that gain BW at an accelerated rate, compared with a lower one, during the juvenile period. Heifers were weaned at approximately 4 mo of age and fed diets to promote relatively low (0.5 kg/day; low gain [LG]) or high (1.0 kg/day; high gain [HG]) rates of BW gain until 8.5 mo of age. Heifers that gained BW at a higher rate exhibited greater circulating concentrations of leptin and reduced overall NPY expression in the arcuate nucleus. The proportion of GnRH neurons in close apposition to NPY fibers and the magnitude of NPY projections to GnRH neurons located in the mediobasal hypothalamus were reduced in HG heifers. However, no differences in NPY projections to kisspeptin neurons in the arcuate nucleus were detected between HG and LG heifers. Results indicate that a reduction in NPY innervation of GnRH neurons, particularly at the level of the mediobasal hypothalamus, occurs in response to elevated BW gain during the juvenile period. This functional plasticity may facilitate early onset of puberty in heifers.

Topics: Animals; Arcuate Nucleus of Hypothalamus; Cattle; Female; Gonadotropin-Releasing Hormone; Kisspeptins; Leptin; Neurons; Neuropeptide Y; Sexual Maturation; Weight Gain

Nutrition during the juvenile period has a major impact on timing reproductive maturity in heifers. Restricted growth delays puberty, whereas elevated BW gain advances the onset of puberty. The initiation of high-frequency episodic release of GnRH and, consequently, LH during the peripubertal period is crucial for maturation of the reproductive axis and establishment of normal estrous cycles. Nutritional signals are perceived by metabolic-sensing cells in the hypothalamus, which interact with estradiol-receptive neurons to regulate the secretory activity of GnRH neurons. The orexigenic peptide, neuropeptide Y (NPY), and the anorexigenic peptide derived from the proopiomelanocortin (POMC) gene, melanocyte-stimulating hormone α (αMSH), are believed to be major afferent pathways that transmit inhibitory (NPY) and excitatory (αMSH) inputs to GnRH neurons. The neuropeptide kisspeptin is considered a major stimulator of GnRH secretion and has been shown to mediate estradiol's effect on GnRH neuronal activity. Kisspeptin may also integrate the neuronal pathways mediating the metabolic and gonadal steroid hormone control of gonadotropin secretion. Recent studies in our laboratories indicate that functional and structural changes in the pathways involving NPY, POMC, and kisspeptin neurons occur in response to high rates of BW gain during the juvenile period in heifers. Changes include regulation of expression in NPY, POMC, and KISS1 and plasticity in the neuronal projections to GnRH neurons and within the neuronal network comprising these cells. Moreover, an intricate pattern of differential gene expression in the arcuate nucleus of the hypothalamus occurs in response to feeding high concentrate diets that promote elevated BW gain. Genes involved include those controlling feeding intake and cell metabolism, neuronal growth and remodeling, and synaptic transmission. Characterizing the cellular pathways and molecular networks involved in the mechanisms that control the timing of pubertal onset will assist in improving existing strategies and facilitate the development of novel approaches to program puberty in heifers. These include the use of diets that elevate BW gain during strategic periods of prepubertal development.

Topics: Animal Nutritional Physiological Phenomena; Animals; Arcuate Nucleus of Hypothalamus; Cattle; Female; Gene Expression Regulation, Developmental; Gonadal Steroid Hormones; Hypothalamus; Kisspeptins; Luteinizing Hormone; Neuropeptide Y; Neuropeptides; Puberty; Sexual Maturation; Weight Gain

The present study assesses the effects of chronic administration of peptides to fish, termed kisspeptins, which are the products of the KISS1 and KISS2 genes, and have been shown to control the development of puberty in animals. Using ecologically and commercially important species (white bass, Morone chrysops, striped bass, Morone saxatilis, and their hybrid) as comparative models, we determined that repeated bi-weekly injections (over 7 weeks) differentially accelerate puberty, as evidenced by increases in the prevalence of spermatozoa in the testes of juvenile fish. Moreover, in sexually mature fish, kisspeptin treatment led to increased gonad weight, gonadosomatic index, and spermatocrit in some white and striped bass. Additionally, mature white bass treated with kisspeptins showed an advancement in oocyte development as determined by histological examination. These gonadal changes occurred in the absence of any photothermal manipulation or hormone injections. To date, this is the first description of kisspeptin-mediated pubertal initiation in fish, and the first evidence that kisspeptins could modulate gonad maturation. Although it remains to be determined how kisspeptins may best be utilized in practice, our findings are a basis for future studies to characterize the molecular underpinnings of the KISS system in various fish species.

Topics: Animals; Bass; Female; Gonads; Kisspeptins; Male; Oocytes; Puberty; Spermatozoa; Testis; Weight Gain