Cocaine- and Amphetamine-Regulated Transcript Is a Potent Stimulator of GnRH and Kisspeptin Cells and May Contribute to Negative Energy Balance-induced Reproductive Inhibition in Females

True, Cadence; Verma, Saurabh; Grove, Kevin L.; Smith, M. Susan

doi:10.1210/en.2013-1156

Cited by 81 publications

(94 citation statements)

References 55 publications

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“…3). Importantly, the authors here noted that CART could also directly activate GNRH neurons, using GNRH-GFP rats (True et al 2013). This relationship was previously noted in mice for both products of POMC/CART neurons but also with NPY, showing Y1 receptor-mediated suppression of GNRH neuron activity (Roa & Herbison 2012).…”

Section: Pomc/cart Neuronssupporting

confidence: 77%

“…Using electrophysiological recordings from Kiss1-GFP mice, CART has been shown to postsynaptically depolarize kisspeptin neurons in the ARC (True et al 2013). Thus, the stimulatory role of positive energy balance mediators on kisspeptin and fertility may also involve this neuropeptide (Fig.…”

Section: Pomc/cart Neuronsmentioning

confidence: 99%

“…These represent the major anorexigenic pathway in the control of food intake and energy expenditure (Barsh & Schwartz 2002). Like their counterparts, POMC/CART neurons also send projections to kisspeptin neurons in sheep (Backholer et al 2010) and mice , True et al 2013. In mice, subsets of kisspeptin neurons also express melanocortin receptor type 4 and melanocortin (one of the neuropeptides produced from these neurons) agonist (MTII) stimulates LH release in luteal phase ewes and increases Kiss1 mRNA expression in the POA (Backholer et al 2009).…”

Section: Pomc/cart Neuronsmentioning

confidence: 99%

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Kisspeptin and energy balance in reproduction

Bond¹,

Smith²

2014

Reproduction

100

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Kisspeptin is vital for the neuroendocrine regulation of GNRH secretion. Kisspeptin neurons are now recognized as a central pathway responsible for conveying key homeostatic information to GNRH neurons. This pathway is likely to mediate the well-established link between energy balance and reproductive function. Thus, in states of severely altered energy balance (either negative or positive), fertility is compromised, as is Kiss1 expression in the arcuate nucleus. A number of metabolic modulators have been proposed as regulators of kisspeptin neurons including leptin, ghrelin, pro-opiomelanocortin (POMC), and neuropeptide Y (NPY). Whether these regulate kisspeptin neurons directly or indirectly will be discussed. Moreover, whether the stimulatory role of leptin on reproduction is mediated by kisspeptin directly will be questioned. Furthermore, in addition to being expressed in GNRH neurons, the kisspeptin receptor (Kiss1r) is also expressed in other areas of the brain, as well as in the periphery, suggesting alternative roles for kisspeptin signaling outside of reproduction. Interestingly, kisspeptin neurons are anatomically linked to, and can directly excite, anorexigenic POMC neurons and indirectly inhibit orexigenic NPY neurons. Thus, kisspeptin may have a direct role in regulating energy balance. Although data from Kiss1r knockout and WT mice found no differences in body weight, recent data indicate that kisspeptin may still play a role in food intake and glucose homeostasis. Thus, in addition to regulating reproduction, and mediating the effect of energy balance on reproductive function, kisspeptin signaling may also be a direct regulator of metabolism.

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Section: Pomc/cart Neuronssupporting

confidence: 77%

Section: Pomc/cart Neuronsmentioning

confidence: 99%

Section: Pomc/cart Neuronsmentioning

confidence: 99%

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Kisspeptin and energy balance in reproduction

Bond¹,

Smith²

2014

Reproduction

100

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“…Several studies have identified various hormones that modulate the activity of kisspeptin neurons including estradiol, leptin, glucocorticoids and PRL (Smith et al 2006b, Herbison 2008, Araujo-Lopes et al 2014. Electrophysiological studies also have identified several afferent neurotransmitters on kisspeptin, including glutamate, gamma aminobutyric acid (GABA), cocaine-and amphetamine-regulated transcript (CART), and neurokinin B (de Croft et al 2013, True et al 2013, Zhang et al 2013. However, identification of the origin of the afferent projections on kisspeptin neurons are insufficient except for a study by Williams et al (2011) reporting afferent input on AVPV kisspeptin neurons of vasopressin fibers from the suprachiasmatic nucleus.…”

Section: Discussionmentioning

confidence: 99%

Rapid modulation of hypothalamic Kiss1 levels by the suckling stimulus in the lactating rat

Higo¹,

Aikawa²,

Iijima³

et al. 2015

Journal of Endocrinology

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In mammals, lactation suppresses GnRH/LH secretion resulting in transient infertility. In rats, GnRH/LH secretion is rescued within 18-48 h after pup separation (PS) and rapidly re-suppressed by subsequent re-exposure of pups. To elucidate the mechanisms underlying these rapid modulations, changes in the expression of kisspeptin, a stimulator of GnRH secretion, in several lactating conditions (normal-lactating; 4-h PS; 18-h PS; 4-h PS C1-h re-exposure of pups; non-lactating) were examined using in situ hybridization. PS for 4 h or 18 h increased Kiss1 expressing neurons in both the anteroventral periventricular nucleus (AVPV) and the arcuate nucleus (ARC), and subsequent exposure of pups re-suppressed Kiss1 in the AVPV. A change in Kiss1 expression was observed prior to the reported time of the change in GnRH/LH, indicating that the change in GnRH/LH results from changes in kisspeptin. We further examined the mechanisms underlying the rapid modulation of Kiss1. We first investigated the possible involvement of ascending sensory input during the suckling stimulus. Injection of the anterograde tracer to the subparafascicular parvocellular nucleus (SPFpc) in the midbrain, which relays the suckling stimulus, revealed direct neuronal connections between the SPFpc and kisspeptin neurons in both the AVPV and ARC. We also examined the possible involvement of prolactin (PRL). Administration of PRL for 1 h suppressed Kiss1 expression in the AVPV but not in the ARC. These results indicate that suckling stimulus rapidly modulates Kiss1 expression directly via neuronal connections and indirectly through serum PRL, resulting in modulation in GnRH/LH secretion.

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“…These neurons play a key role in energy homeostasis by promoting satiety and suppressing feeding (Baskin et al 1999, Meister 2007); yet, they have also been shown to promote GNRH neuron activity, presumably via direct actions (Leranth et al 1988, Roa & Herbison 2012, True et al 2013. Sub-populations of POMC neurons have been shown to co-express GABA and glutamate (Table 2).…”

Section: Pomc/cart-expressing Neuronsmentioning

confidence: 99%

Neuroendocrine integration of nutritional signals on reproduction

Evans

Anderson

2017

Journal of Molecular Endocrinology

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Reproductive function in mammals is energetically costly and therefore tightly regulated by nutritional status. To enable this integration of metabolic and reproductive function, information regarding peripheral nutritional status must be relayed centrally to the gonadotropin-releasing hormone (GNRH) neurons that drive reproductive function. The metabolically relevant hormones leptin, insulin and ghrelin have been identified as key mediators of this 'metabolic control of fertility'. However, the neural circuitry through which they act to exert their control over GNRH drive remains incompletely understood. With the advent of Cre-LoxP technology, it has become possible to perform targeted gene-deletion and gene-rescue experiments and thus test the functional requirement and sufficiency, respectively, of discrete hormone-neuron signaling pathways in the metabolic control of reproductive function. This review discusses the findings from these investigations, and attempts to put them in context with what is known from clinical situations and wild-type animal models. What emerges from this discussion is clear evidence that the integration of nutritional signals on reproduction is complex and highly redundant, and therefore, surprisingly difficult to perturb. Consequently, the deletion of individual hormone-neuron signaling pathways often fails to cause reproductive phenotypes, despite strong evidence that the targeted pathway plays a role under normal physiological conditions. Although transgenic studies rarely reveal a critical role for discrete signaling pathways, they nevertheless prove to be a good strategy for identifying whether a targeted pathway is absolutely required, critically involved, sufficient or dispensable in the metabolic control of fertility.

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Cocaine- and Amphetamine-Regulated Transcript Is a Potent Stimulator of GnRH and Kisspeptin Cells and May Contribute to Negative Energy Balance-induced Reproductive Inhibition in Females

Cited by 81 publications

References 55 publications

Kisspeptin and energy balance in reproduction

Kisspeptin and energy balance in reproduction

Rapid modulation of hypothalamic Kiss1 levels by the suckling stimulus in the lactating rat

Neuroendocrine integration of nutritional signals on reproduction

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