Neuroanatomy of the Kisspeptin Signaling System in Mammals: Comparative and Developmental Aspects

Lehman, Michael N.; Hileman, Stanley M.; Goodman, Robert L.

doi:10.1007/978-1-4614-6199-9_3

Cited by 150 publications

(103 citation statements)

References 139 publications

(327 reference statements)

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“…Unilateral suppression of ARN KISS neuron activity was insufficient to alter LH pulsatility, whereas unilateral activation generated LH pulses. Contralateral projections between the bilateral ARN KISS neuron networks may maintain their synchronization (18,32), although activation of a unilateral population is sufficient to generate an LH pulse.…”

Section: Discussionmentioning

confidence: 99%

Definition of the hypothalamic GnRH pulse generator in mice

Clarkson

Han

Piet

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

315

287

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The pulsatile release of luteinizing hormone (LH) is critical for mammalian fertility. However, despite several decades of investigation, the identity of the neuronal network generating pulsatile reproductive hormone secretion remains unproven. We use here a variety of optogenetic approaches in freely behaving mice to evaluate the role of the arcuate nucleus kisspeptin (ARN KISS ) neurons in LH pulse generation. Using GCaMP6 fiber photometry, we find that the ARN KISS neuron population exhibits brief (∼1 min) synchronized episodes of calcium activity occurring as frequently as every 9 min in gonadectomized mice. These ARN KISS population events were found to be near-perfectly correlated with pulsatile LH secretion. The selective optogenetic activation of ARN KISS neurons for 1 min generated pulses of LH in freely behaving mice, whereas inhibition with archaerhodopsin for 30 min suppressed LH pulsatility. Experiments aimed at resetting the activity of the ARN KISS neuron population with halorhodopsin were found to reset ongoing LH pulsatility. These observations indicate the ARN KISS neurons as the long-elusive hypothalamic pulse generator driving fertility.fertility | GnRH | kisspeptin | pulse | arcuate nucleus

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Section: Discussionmentioning

confidence: 99%

Definition of the hypothalamic GnRH pulse generator in mice

Clarkson

Han

Piet

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

315

287

View full text Add to dashboard Cite

show abstract

“…Kisspeptin activates the reproductive axis by directly stimulating, via KISS1R, gonadotropin-releasing hormone (GnRH) neurons (4). Although kisspeptin is expressed in discrete brain regions (5), it is also present in some peripheral tissues (6)(7)(8). Likewise, Kiss1r is also expressed in multiple non-GnRH brain areas and in several peripheral tissues (8)(9)(10), including metabolic tissues like fat, liver, and pancreas.…”

Section: Introductionmentioning

confidence: 99%

Impaired kisspeptin signaling decreases metabolism and promotes glucose intolerance and obesity

Tolson¹,

Garcia²,

Yen³

et al. 2014

J. Clin. Invest.

176

226

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The neuropeptide kisspeptin regulates reproduction by stimulating gonadotropin-releasing hormone (GnRH) neurons via the kisspeptin receptor KISS1R. In addition to GnRH neurons, KISS1R is expressed in other brain areas and peripheral tissues, which suggests that kisspeptin has additional functions beyond reproduction. Here, we studied the energetic and metabolic phenotype in mice lacking kisspeptin signaling (Kiss1r KO mice). Compared with WT littermates, adult Kiss1r KO females displayed dramatically higher BW, leptin levels, and adiposity, along with strikingly impaired glucose tolerance. Conversely, male Kiss1r KO mice had normal BW and glucose regulation. Surprisingly, despite their obesity, Kiss1r KO females ate less than WT females; however, Kiss1r KO females displayed markedly reduced locomotor activity, respiratory rate, and energy expenditure, which were not due to impaired thyroid hormone secretion. The BW and metabolic phenotype in Kiss1r KO females was not solely reflective of absent gonadal estrogen, as chronically ovariectomized Kiss1r KO females developed obesity, hyperleptinemia, reduced metabolism, and glucose intolerance compared with ovariectomized WT females. Our findings demonstrate that in addition to reproduction, kisspeptin signaling influences BW, energy expenditure, and glucose homeostasis in a sexually dimorphic and partially sex steroid-independent manner; therefore, alterations in kisspeptin signaling might contribute, directly or indirectly, to some facets of human obesity, diabetes, or metabolic dysfunction. IntroductionThe neuropeptide kisspeptin (encoded by KISS1) and its receptor, KISS1R (formerly known as GPR54), are key regulators of reproduction. Humans and mice with mutations in these genes show impaired puberty, hypogonadism, and infertility (1-3). Kisspeptin activates the reproductive axis by directly stimulating, via KISS1R, gonadotropin-releasing hormone (GnRH) neurons (4). Although kisspeptin is expressed in discrete brain regions (5), it is also present in some peripheral tissues (6-8). Likewise, Kiss1r is also expressed in multiple non-GnRH brain areas and in several peripheral tissues (8-10), including metabolic tissues like fat, liver, and pancreas. This suggests that kisspeptin has additional uncharacterized roles outside of reproduction. Yet, thus far, virtually all research on kisspeptin signaling has focused on reproductive regulation. Changes in energy status or metabolic signals affect both reproduction and hypothalamic kisspeptin levels (11, 12), which suggests that kisspeptin neurons mediate metabolic effects on reproductive status. However, whether kisspeptin signaling also plays a reciprocal role in regulating energy and metabolic status is unclear. Young Kiss1 KO, Kiss1r KO, and WT mice display no genotype differences in BW (3); however, in that study, BW was only measured before full maturity, and other metabolic parameters were not assessed. Initial studies in male rats found no effects of central kisspeptin on

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“…This complex neuroendocrine network appears to be "supervised" by the kisspeptinneurokinin B-dynorphin neurons that reside in the arcuate nucleus and regulate GnRH neuronal function (111)(112)(113). Although the kisspeptin signaling system is highly sensitive to the feedback of sex steroid hormones and acts directly on a large proportion of the GnRH neurons (114)(115)(116)(117), there are findings suggesting a more modulatory role of the neurokin B/neurokinin B receptor 3 feedback (118-120). However, kisspeptin-neurokinin Bdynorphin neurons project their axons directly to GnRH neuron terminals that express the neurokinin B receptor 3 (TACR3) in the median eminence, suggesting a direct interaction of neurokin B with kisspeptin neurons (121,122).…”

Section: E the Complex Biology Of The Gnrh Genetic Networkmentioning

confidence: 99%

Discovering Genes Essential to the Hypothalamic Regulation of Human Reproduction Using a Human Disease Model: Adjusting to Life in the “-Omics” Era

2015

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The neuroendocrine regulation of reproduction is an intricate process requiring the exquisite coordination of an assortment of cellular networks, all converging on the GnRH neurons. These neurons have a complex life history, migrating mainly from the olfactory placode into the hypothalamus, where GnRH is secreted and acts as the master regulator of the hypothalamicpituitary-gonadal axis. Much of what we know about the biology of the GnRH neurons has been aided by discoveries made using the human disease model of isolated GnRH deficiency (IGD), a family of rare Mendelian disorders that share a common failure of secretion and/or action of GnRH causing hypogonadotropic hypogonadism. Over the last 30 years, research groups around the world have been investigating the genetic basis of IGD using different strategies based on complex cases that harbor structural abnormalities or single pleiotropic genes, endogamous pedigrees, candidate gene approaches as well as pathway gene analyses. Although such traditional approaches, based on well-validated tools, have been critical to establish the field, new strategies, such as next-generation sequencing, are now providing speed and robustness, but also revealing a surprising number of variants in known IGD genes in both patients and healthy controls. Thus, before the field moves forward with new genetic tools and continues discovery efforts, we must reassess what we know about IGD genetics and prepare to hold our work to a different standard. The purpose of this review is to: 1) look back at the strategies used to discover the "known" genes implicated in the rare forms of IGD; 2) examine the strengths and weaknesses of the methodologies used to validate genetic variation; 3)substantiate the role of known genes in the pathophysiology of the disease; and 4) project forward as we embark upon a widening use of these new and powerful technologies for gene discovery.

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Neuroanatomy of the Kisspeptin Signaling System in Mammals: Comparative and Developmental Aspects

Cited by 150 publications

References 139 publications

Definition of the hypothalamic GnRH pulse generator in mice

Definition of the hypothalamic GnRH pulse generator in mice

Impaired kisspeptin signaling decreases metabolism and promotes glucose intolerance and obesity

Discovering Genes Essential to the Hypothalamic Regulation of Human Reproduction Using a Human Disease Model: Adjusting to Life in the “-Omics” Era

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