Disrupted Kisspeptin Signaling in GnRH Neurons Leads to Hypogonadotrophic Hypogonadism

Novaira, Horacio J.; Sonko, Momodou L.; Hoffman, Gloria E.; Koo, Yongbum; Ko, Chemyong; Wolfe, Andrew; Radovick, Sally

doi:10.1210/me.2013-1319

Cited by 98 publications

(88 citation statements)

References 68 publications

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“…In human females, however, there is evidence that the same neurons in the infundibular nucleus express KISS1 [11], DYN [12], and NKB [13]. Thus, while there appear to be species and gender differences in the presence and roles of these peptides, there is a consensus that KP, signaling through its receptor (KISS1R) located on the surface of GnRH neurons, is a direct trigger of GnRH secretion in mammals [14,15,16,17,18,19,20,21,22]. GnRH then regulates the synthesis and secretion patterns of gonadotropins from pituitary gonadotropes through changes in pulse frequency and amplitude [23,24,25,26].…”

Section: Introductionmentioning

confidence: 99%

KISS1R: Hallmarks of an Effective Regulator of the Neuroendocrine Axis

Millar

Babwah

2015

Neuroendocrinology

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Kisspeptin (KP) is now well recognized as a potent stimulator of gonadotropin-releasing hormone (GnRH) secretion and thereby a major regulator of the neuroendocrine-reproductive axis. KP signals via KISS1R, a G protein-coupled receptor (GPCR) that activates the G proteins Gα_q/11. Modulation of the interaction of KP with KISS1R is therefore a potential new therapeutic target for stimulating (in infertility) or inhibiting (in hormone-dependent diseases) the reproductive hormone cascade. Major efforts are underway to target KISS1R in the treatment of sex steroid hormone-dependent disorders and to stimulate endogenous hormonal responses along the neuroendocrine axis as part of in vitro fertilization protocols. The development of analogs modulating KISS1R signaling will be aided by an understanding of the intracellular pathways and dynamics of KISS1R signaling under normal and pathological conditions. This review focuses on KISS1R recruitment of intracellular signaling (Gα_q/11- and β-arrestin-dependent) pathways that mediate GnRH secretion and the respective roles of rapid desensitization, internalization, and recycling of resensitized receptors in maintaining an active population of KISS1R at the cell surface to facilitate prolonged KP signaling. Additionally, this review summarizes and discusses the major findings of an array of studies examining the desensitization of KP signaling in man, domestic and laboratory animals. This discussion highlights the major effects of ligand efficacy and concentration and the physiological, developmental, and metabolic status of the organism on KP signaling. Finally, the potential for the utilization of KP and analogs in stimulating and inhibiting the reproductive hormone cascade as an alternative to targeting the downstream GnRH receptor is discussed.

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Section: Introductionmentioning

confidence: 99%

KISS1R: Hallmarks of an Effective Regulator of the Neuroendocrine Axis

Millar

Babwah

2015

Neuroendocrinology

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“…Humans, mice, and rats with mutations in these genes show impaired puberty, hypogonadism, and infertility (1)(2)(3)(4)(5)(6). In addition to being expressed in reproductive areas of the brain, kisspeptin is also expressed in multiple peripheral tissues (7)(8)(9)(10).…”

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confidence: 99%

Metabolism and Energy Expenditure, But Not Feeding or Glucose Tolerance, Are Impaired in Young Kiss1r KO Female Mice

et al. 2016

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Kisspeptin regulates reproduction via signaling through the receptor, Kiss1r, in GnRH neurons. However, both kisspeptin and Kiss1r are produced in several peripheral tissues, and recent studies have highlighted a role for kisspeptin signaling in metabolism and glucose homeostasis. We recently reported that Kiss1r KO mice display a sexually-dimorphic metabolic phenotype, with KO females displaying obesity, impaired metabolism, and glucose intolerance at 4 -5 months of age. However, it remains unclear when this metabolic phenotype first emerges in development, or which aspects of the pleiotropic phenotype underlie the metabolic defects and which are secondary to the obesity. Here, we studied Kiss1r KO females at different ages, including several weeks before the emergence of body weight differences and later when obesity is present. We determined that at young adult ages (6 weeks old), KO females already exhibit altered adiposity, leptin levels, metabolism, and energy expenditure, despite having normal body weights at this time. In contrast, food intake, water intake, and glucose tolerance are normal at young ages, and only show impairments at older adult ages, suggesting that these impairments may be secondary to earlier alterations in metabolism and adiposity. We also demonstrate that, in addition to body weight, all other facets of the adult metabolic phenotype persist even when gonadal sex steroids are similar between genotypes. Collectively, these data highlight the developmental emergence of a metabolic phenotype induced by disrupted kisspeptin signaling, and reveal that multiple-but not all-aspects of this phenotype are already disrupted prior to detectable changes in body weight.

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“…The selective targeting of Gpr54 deletion to GnRH neurons in this mouse line is further defined here by showing that pituitary gonadotroph responses to GnRH are intact in GnRH-Cre +/- /Gpr54 flox/flox mice. A recently published study by Novaira et al [38] using a different GnRH neuron-targeted Gpr54 -null mouse line has also shown such mice to exhibit an absence of the post-OVX increment in LH secretion. Together, these studies indicate that it is a failure of kisspeptin signaling at the GnRH neuron itself, rather than other neurons [39] or reproductive tissues [30], which is responsible for the defective negative feedback mechanism.…”

Section: Discussionmentioning

confidence: 99%

Kisspeptin-Gpr54 Signaling at the GnRH Neuron Is Necessary for Negative Feedback Regulation of Luteinizing Hormone Secretion in Female Mice

Yeo¹,

Clarkson²,

Herbison³

2014

Neuroendocrinology

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Kisspeptin-Gpr54 signaling is critical for regulating the activity of gonadotropin-releasing hormone (GnRH) neurons in mammals. Previous studies have shown that the negative feedback mechanism is disrupted in global Gpr54-null mutants. The present investigation aimed to determine (1) if a lack of cyclical estrogen exposure of the GnRH neuronal network in the life-long hypogonadotropic Gpr54-null mice contributed to their failed negative feedback mechanism and (2) the cellular location of disrupted kisspeptin-Gpr54 signaling. Plasma luteinizing hormone (LH) concentrations were determined in individual adult female mice when intact, following ovariectomy (OVX) and in response to an acute injection of 17β-estradiol (E2). Control mice exhibited a characteristic rise in LH after OVX that was suppressed by acute E2. Global Gpr54-null mice failed to exhibit any post-OVX increase in LH or response to E2. Adult female global Gpr54-null mice given a cyclical regimen of estradiol for three cycles prior to OVX also failed to exhibit any post-OVX increase in LH or response to E2. To address whether Gpr54 signaling at the GnRH neuron itself was necessary for the failed response to OVX in global Gpr54-null animals, adult female mice with a GnRH neuron-selective deletion of Gpr54 were examined. These mice also failed to exhibit any post-OVX increase in LH or response to E2. These experiments demonstrate defective negative feedback in global Gpr54-null mice that cannot be attributed to a lack of prior exposure of the GnRH neuronal network to cyclical estradiol. The absence of negative feedback in GnRH neuron-selective Gpr54-null mice demonstrates the necessity of direct kisspeptin signaling at the GnRH neuron for this mechanism to occur.

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Disrupted Kisspeptin Signaling in GnRH Neurons Leads to Hypogonadotrophic Hypogonadism

Cited by 98 publications

References 68 publications

KISS1R: Hallmarks of an Effective Regulator of the Neuroendocrine Axis

KISS1R: Hallmarks of an Effective Regulator of the Neuroendocrine Axis

Metabolism and Energy Expenditure, But Not Feeding or Glucose Tolerance, Are Impaired in Young Kiss1r KO Female Mice

Kisspeptin-Gpr54 Signaling at the GnRH Neuron Is Necessary for Negative Feedback Regulation of Luteinizing Hormone Secretion in Female Mice

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