Kisspeptin (a product of the Kiss1 gene) and its receptor (GPR54 or Kiss1r) have emerged as key players in the regulation of reproduction. Mutations in humans or genetically targeted deletions in mice of either Kiss1 or Kiss1r cause profound hypogonadotropic hypogonadism. Neurons that express Kiss1/kisspeptin are found in discrete nuclei in the hypothalamus, as well as other brain regions in many vertebrates, and their distribution, regulation, and function varies widely across species. Kisspeptin neurons directly innervate and stimulate GnRH neurons, which are the final common pathway through which the brain regulates reproduction. Kisspeptin neurons are sexually differentiated with respect to cell number and transcriptional activity in certain brain nuclei, and some kisspeptin neurons express other cotransmitters, including dynorphin and neurokinin B (whose physiological significance is unknown). Kisspeptin neurons express the estrogen receptor and the androgen receptor, and these cells are direct targets for the action of gonadal steroids in both male and female animals. Kisspeptin signaling in the brain has been implicated in mediating the negative feedback action of sex steroids on gonadotropin secretion, generating the preovulatory GnRH/LH surge, triggering and guiding the tempo of sexual maturation at puberty, controlling seasonal reproduction, and restraining reproductive activity during lactation. Kisspeptin signaling may also serve diverse functions outside of the classical realm of reproductive neuroendocrinology, including the regulation of metastasis in certain cancers, vascular dynamics, placental physiology, and perhaps even higher-order brain function.

Kisspeptin Signaling in the Brain

Procreation is essential for survival of species. Not surprisingly, complex neuronal networks have evolved to mediate the diverse internal and external environmental inputs that regulate reproduction in vertebrates. Ultimately, these regulatory factors impinge, directly or indirectly, on a final common pathway, the neurons producing the gonadotropin-releasing hormone (GnRH), which stimulates pituitary gonadotropin secretion and thereby gonadal function. Compelling evidence, accumulated in the last few years, has revealed that kisspeptins, a family of neuropeptides encoded by the Kiss1 gene and produced mainly by neuronal clusters at discrete hypothalamic nuclei, are pivotal upstream regulators of GnRH neurons. As such, kisspeptins have emerged as important gatekeepers of key aspects of reproductive maturation and function, from sexual differentiation of the brain and puberty onset to adult regulation of gonadotropin secretion and the metabolic control of fertility. This review aims to provide a comprehensive account of the state-of-the-art in the field of kisspeptin physiology by covering in-depth the consensus knowledge on the major molecular features, biological effects, and mechanisms of action of kisspeptins in mammals and, to a lesser extent, in nonmammalian vertebrates. This review will also address unsolved and contentious issues to set the scene for future research challenges in the area. By doing so, we aim to endow the reader with a critical and updated view of the physiological roles and potential translational relevance of kisspeptins in the integral control of reproductive function.

Kisspeptins and Reproduction: Physiological Roles and Regulatory Mechanisms

Sustainability in livestock production system is largely affected by climate change. An imbalance between metabolic heat production inside the animal body and its dissipation to the surroundings results to heat stress (HS) under high air temperature and humid climates. The foremost reaction of animals under thermal weather is increases in respiration rate, rectal temperature and heart rate. It directly affect feed intake thereby, reduces growth rate, milk yield, reproductive performance, and even death in extreme cases. Dairy breeds are typically more sensitive to HS than meat breeds, and higher producing animals are, furthermore, susceptible since they generates more metabolic heat. HS suppresses the immune and endocrine system thereby enhances susceptibility of an animal to various diseases. Hence, sustainable dairy farming remains a vast challenge in these changing climatic conditions globally.

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Impact of heat stress on health and performance of dairy animals: A review

Invited review : New Perspectives on the Roles of Nutrition and Metabolic Priorities in the Subfertility of High-Producing Dairy Cows

Risk factors for resumption of postpartum estrous cycles and embryonic survival in lactating dairy cows.

Bovine C-terminal octapeptide of RFamide-related peptide-3 suppresses luteinizing hormone (LH) secretion from the pituitary as well as pulsatile LH secretion in bovines.

Direct kisspeptin-10 stimulation on luteinizing hormone secretion from bovine and porcine anterior pituitary cells.

This study was conducted to estimate the effects of kisspeptin-10 on blood concentrations of LH and GH in prepubertal dairy heifers. Heifers received a single injection of 1 mg kisspeptin-10 (n=5) or saline (n=5) intravenously, and serial blood samples were collected at 15-min intervals to analyze the response curves of both LH and GH after injection. Peak-shaped responses were observed for concentrations of LH and GH, and the peaks were observed at 27+/-3 and 75+/-9 min, respectively, after injection, only in heifers injected with kisspeptin-10. These data suggest various possible important links among kisspeptin, the reproductive axis, and also the somatotropic axis in prepubertal Holstein heifers.

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Peripheral administration of kisspeptin-10 increases plasma concentrations of GH as well as LH in prepubertal Holstein heifers.

During early lactation, dairy cattle are in negative energy balance and the delay to first post-partum ovulation depends on the time taken to recover from this situation. Lactating cows rely heavily on body fat to meet their requirements, leading to the suggestion that leptin, a hormone secreted mainly by adipocytes, is acting as a metabolic signal to sites that control the reproductive axis. The relationship between plasma leptin concentrations and the timing of the first ovulation post partum in 20 high-producing Holstein dairy cows, using a radioimmunoassay based on recombinant bovine leptin was studied. Plasma leptin concentrations declined after parturition, reached a nadir of 0.74 +/- 0.17 ng mL(-1) on 10.1 +/- 2.2 days after parturition (all values are mean +/- SEM). They then increased and became stable near the time of ovulation. Leptin concentrations averaged 1.81 +/- 0.31 ng mL(-1) in the 14 days prepartum, 1.32 +/- 0.21 ng mL(-1) in the post-partum preovulatory period and 1.61 +/- 0.24 ng mL(-1) in the post-ovulatory period. The differences between periods were significant (P<0.01). The interval from parturition to first ovulation averaged 25.9 +/- 2.0 days and was not correlated with the prepartum, preovulatory or post-ovulatory leptin values. However, the interval to first ovulation correlated significantly (r = 0.83 P < 0.0001) with the interval from parturition to the leptin nadir. These results show that plasma concentrations of leptin decrease in dairy cows in the early post-partum period and suggest that a delay in the recovery of leptin secretion increases the delay to the first ovulation.

Relationships between changes in plasma concentrations of leptin before and after parturition and the timing of first post-partum ovulation in high-producing Holstein dairy cows

In response to changes in society and thus the marketplace, we need a vision for the future of our animal industries, including both on-farm and off-farm activities, that is "clean, green and ethical". Using small ruminants as a case study, we describe three "clean, green and ethical" strategies that farmers could use to improve reproductive performance. The first allows control of the timing of reproductive events by using socio-sexual signals (the "male effect") to induce synchronised ovulation in females. The second strategy, "focus feeding", is based on using short periods of nutritional supplements that are precisely timed and specifically designed for each event in the reproductive process (eg, gamete production, embryo survival, fetal programming, colostrum production). The third strategy aims to maximize offspring survival by a combination of management, nutrition and genetic selection for behaviour (temperament). All of these approaches involve non-pharmacological manipulation of the endogenous control systems of the animals and complement the detailed information from ultrasound that is now becoming available. Importantly, these approaches all have a solid foundation in reproductive biology. In several cases, they are currently used in commercial practice, but there is still room for improvement through both basic and applied research. Ultimately, these "clean, green and ethical" tools can be cost-effective, increase productivity and, at the same time, greatly improve the image of meat and milk industries in society and the marketplace.

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Hiroya Kadokawa

Papers

Bovine C-terminal octapeptide of RFamide-related peptide-3 suppresses luteinizing hormone (LH) secretion from the pituitary as well as pulsatile LH secretion in bovines.

Direct kisspeptin-10 stimulation on luteinizing hormone secretion from bovine and porcine anterior pituitary cells.

Peripheral administration of kisspeptin-10 increases plasma concentrations of GH as well as LH in prepubertal Holstein heifers.

Relationships between changes in plasma concentrations of leptin before and after parturition and the timing of first post-partum ovulation in high-producing Holstein dairy cows

"Clean, green and ethical" animal production. Case study: reproductive efficiency in small ruminants.