Characterization of Kiss1 neurons using transgenic mouse models

Cravo, Roberta M.; Margatho, Lisandra Oliveira; Osborne-Lawrence, Sherri; Donato, José; Atkin, Stan; Bookout, Angie L.; Rovinsky, Sherry A.; Frazão, Renata; Lee, Charlotte E.; Gautron, Laurent; Zigman, Jeffrey M.; Elias, Carol F.

doi:10.1016/j.neuroscience.2010.11.022

Cited by 310 publications

(295 citation statements)

References 97 publications

(127 reference statements)

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“…Mice lacking LepR only in Kiss1 neurons were obtained by crossing Kiss1-Cre mice (line J2-4, pure C57BL/6 background) with mice homozygous for a loxP-modified Lepr allele (LepR lox/lox , mixed 129-C57BL/6 background). These mouse models have been previously verified and validated (31,35,36). Two cohorts of Kiss1-Cre LepR flox/flox mice (n = 13 males and n = 8 females) and LepR flox/flox littermates (n = 13 males and n = 11 females) were evaluated.…”

Section: Deletion Of Lepr Selectively From Kiss1 Neurons To Determinmentioning

confidence: 90%

Leptin’s effect on puberty in mice is relayed by the ventral premammillary nucleus and does not require signaling in Kiss1 neurons

Donato¹,

Cravo²,

Frazão³

et al. 2011

J. Clin. Invest.

304

292

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Studies in humans and rodents indicate that a minimum amount of stored energy is required for normal pubertal development. The adipocyte-derived hormone leptin is a key metabolic signal to the neuroendocrine reproductive axis. Humans and mice lacking leptin or the leptin receptor (LepR) (ob/ob and db/db mice, respectively) are infertile and fail to enter puberty. Leptin administration to leptin-deficient subjects and ob/ob mice induces puberty and restores fertility, but the exact site or sites of leptin action are unclear. Here, we found that genetic deletion of LepR selectively from hypothalamic Kiss1 neurons in mice had no effect on puberty or fertility, indicating that direct leptin signaling in Kiss1 neurons is not required for these processes. However, bilateral lesions of the ventral premammillary nucleus (PMV) of ob/ob mice blunted the ability of exogenous leptin to induce sexual maturation. Moreover, unilateral reexpression of endogenous LepR in PMV neurons was sufficient to induce puberty and improve fertility in female LepR-null mice. This LepR reexpression also normalized the increased hypothalamic GnRH content characteristic of leptin-signaling deficiency. These data suggest that the PMV is a key site for leptin's permissive action at the onset of puberty and support the hypothesis that the multiple actions of leptin to control metabolism and reproduction are anatomically dissociated. IntroductionThe existence of a fundamental link between nutrition and reproduction is well established. Early studies in humans and rodents suggested that a minimum amount of stored energy is required for normal pubertal development and to maintain the tone of the reproductive system (1, 2). This concept is based on the idea that when survival is threatened by scarcity of food or increased energy demands, males and females of most species divert energy away from reproduction. This includes sexual maturation, the production of reproductive hormones and gametes, and the maintenance of pregnancy and lactation. On the other hand, excess energy may have a negative impact on the reproductive physiology. For example, elevated adiposity in women aggravates polycystic ovarian syndrome and ovulatory dysfunctions and may induce hypothalamic hypogonadism (3, 4). Moreover, the increasing rates of childhood obesity have been associated with the advance in the timing of pubertal maturation and its deleterious consequences (5-8). Earlier menarche in girls is correlated with increased risk of adult obesity, type 2 diabetes, and breast cancer (9, 10). Thus, changing levels of key metabolic cues is an essential signal for the onset of puberty. But the assessment of the mechanisms underlying puberty initiation has been obstructed by the lack of information on the brain sites in which this event is integrated.

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Section: Deletion Of Lepr Selectively From Kiss1 Neurons To Determinmentioning

confidence: 90%

Leptin’s effect on puberty in mice is relayed by the ventral premammillary nucleus and does not require signaling in Kiss1 neurons

Donato¹,

Cravo²,

Frazão³

et al. 2011

J. Clin. Invest.

304

292

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“…(132) However, GnRH neurons lack leptin receptors, while kisspeptin neurons in the ARC express the leptin receptor gene. (47,133,134) Additionally, leptin-deficient rats have reduced Kiss1 mRNA in their ARC. (133,135) Leptin administration increased hypothalamic Kiss1 mRNA in fasted rats (125) and cell models.…”

Section: Kisspeptins and Energy Homeostasismentioning

confidence: 99%

Kisspeptin signalling and its roles in humans

Tng

2015

smedj

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Kisspeptins are a group of peptide fragments encoded by the KISS1 gene in humans. They bind to kisspeptin receptors with equal efficacy. Kisspeptins and their receptors are expressed by neurons in the arcuate and anteroventral periventricular nuclei of the hypothalamus. Oestrogen mediates negative feedback of gonadotrophin-releasing hormone secretion via the arcuate nucleus. Conversely, it exerts positive feedback via the anteroventral periventricular nucleus. The sexual dimorphism of these nuclei accounts for the differential behaviour of the hypothalamic-pituitary-gonadal axis between genders. Kisspeptins are essential for reproductive function. Puberty is regulated by the maturation of kisspeptin neurons and by interactions between kisspeptins and leptin. Hence, kisspeptins have potential diagnostic and therapeutic applications. Kisspeptin agonists may be used to localise lesions in cases of hypothalamic-pituitary-gonadal axis dysfunction and evaluate the gonadotrophic potential of subfertile individuals. Kisspeptin antagonists may be useful as contraceptives in women, through the prevention of premature luteinisation during in vitro fertilisation, and in the treatment of sex steroid-dependent diseases and metastatic cancers.

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“…Finally, slides were developed with D-19 developer (Kodak), counterstained with thionin, dehydrated in graded ethanol, cleared in xylenes, and coverslipped with Permaslip. Double-label ISH and IHC was performed as described previously (7,56). Briefly, free-floating sections from C57BL/6 OVX (n ϭ 4) and OVX ϩ E2 (n ϭ 4) females or Kiss1-Cre/GFP mice on diestrus (n ϭ 4), OVX (n ϭ 4), and OVX ϩ E 2 (n ϭ 4) were rinsed in DEPC-treated PBS and treated with 0.1% sodium borohydride for 15 min.…”

Section: ·Mlmentioning

confidence: 99%

Estradiol modulates Kiss1 neuronal response to ghrelin

Frazão

Lemko

Silva

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

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Ghrelin is a metabolic signal regulating energy homeostasis. Circulating ghrelin levels rise during starvation and fall after a meal, and therefore, ghrelin may function as a signal of negative energy balance. Ghrelin may also act as a modulator of reproductive physiology, as acute ghrelin administration suppresses gonadotropin secretion and inhibits the neuroendocrine reproductive axis. Interestingly, ghrelin's effect in female metabolism varies according to the estrogen milieu predicting an interaction between ghrelin and estrogens, likely at the hypothalamic level. Here, we show that ghrelin receptor (GHSR) and estrogen receptor-␣ (ER␣) are coexpressed in several hypothalamic sites. Higher levels of circulating estradiol increased the expression of GHSR mRNA and the co-xpression of GHSR mRNA and ER␣ selectively in the arcuate nucleus (ARC). Subsets of preoptic and ARC Kiss1 neurons coexpressed GHSR. Increased colocalization was observed in ARC Kiss1 neurons of ovariectomized estradiol-treated (OVX ϩ E2; 80%) compared with ovariectomized oil-treated (OVX; 25%) mice. Acute actions of ghrelin on ARC Kiss1 neurons were also modulated by estradiol; 75 and 22% of Kiss1 neurons of OVX ϩ E2 and OVX mice, respectively, depolarized in response to ghrelin. Our findings indicate that ghrelin and estradiol may interact in several hypothalamic sites. In the ARC, high levels of E2 increase GHSR mRNA expression, modifying the colocalization rate with ER␣ and Kiss1 and the proportion of Kiss1 neurons acutely responding to ghrelin. Our findings indicate that E2 alters the responsiveness of kisspeptin neurons to metabolic signals, potentially acting as a critical player in the metabolic control of the reproductive physiology. kisspeptin; hypothalamus; metabolism; growth hormone secretagogue receptor; reproduction IN MAMMALS, THE ABILITY TO REPRODUCE is gated by the availability of energy stores (25,49). Reproduction is metabolically expensive, and during starvation fertility is stopped to conserve energy for basic survival. Accumulating evidence has implicated circulating hormones as a means of transmitting information regarding peripheral energy availability to the central circuitry that controls the reproductive system. Among these metabolic signals is the stomach-derived hormone ghrelin (23,46). Ghrelin was recognized originally for its growth hormonestimulating action, but extensive research has since demonstrated that ghrelin is also a direct regulator of metabolism and energy balance (22,28,55). Ghrelin promotes the storage of lipids as fat, induces glucagon release, and suppresses insulin secretion and sensitivity (4, 5, 47). Interestingly, the effects of ghrelin to increase body weight vary according to the estrogen milieu, as a more pronounced orexigenic effect is observed in females upon ovariectomy (3, 6). In cycling rats, ghrelin stimulation of food intake is observed only in females in diestrus (when estrogen levels are low). Moreover, males treated with estradiol are resistant to the stimulatory effects of ghrelin...

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Characterization of Kiss1 neurons using transgenic mouse models

Cited by 310 publications

References 97 publications

Leptin’s effect on puberty in mice is relayed by the ventral premammillary nucleus and does not require signaling in Kiss1 neurons

Leptin’s effect on puberty in mice is relayed by the ventral premammillary nucleus and does not require signaling in Kiss1 neurons

Kisspeptin signalling and its roles in humans

Estradiol modulates Kiss1 neuronal response to ghrelin

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