Leptin receptor null mice with reexpression of LepR in GnRHR expressing cells display elevated FSH levels but remain in a prepubertal state

Allen, Susan J.; García-Galiano, David; Borges, Beatriz de Carvalho; Burger, Laura L.; Boehm, Ulrich; Elias, Carol F.

doi:10.1152/ajpregu.00529.2015

Cited by 17 publications

(17 citation statements)

References 57 publications

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“…The Prokr2-Cre mice express iCre recombinase driven by Prokr2 promoter, visualized using two distinct R26 reporter mice (Allen et al 2016; Cravo et al 2011, 2013). The expression pattern of Cre-induced reporter gene (GFP and tdTom) was compared with previous published data (Cheng et al 2006) and our own analysis of Prokr2 mRNA distribution.…”

Section: Discussionmentioning

confidence: 99%

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Sexually dimorphic distribution of Prokr2 neurons revealed by the Prokr2-Cre mouse model

et al. 2017

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Prokineticin receptor 2 (PROKR2) is predominantly expressed in the mammalian central nervous system. Loss-of-function mutations of PROKR2 in humans are associated with Kallmann syndrome due to the disruption of gonadotropin releasing hormone neuronal migration and deficient olfactory bulb morphogenesis. PROKR2 has been also implicated in the neuroendocrine control of GnRH neurons post-migration and other physiological systems. However, the brain circuitry and mechanisms associated with these actions have been difficult to investigate mainly due to the widespread distribution of Prokr2-expressing cells, and the lack of animal models and molecular tools. Here, we describe the generation, validation and characterization of a new mouse model that expresses Cre recombinase driven by the Prokr2 promoter, using CRISPR-Cas9 technology. Cre expression was visualized using reporter genes, tdTomato and GFP, in males and females. Expression of Cre-induced reporter genes was found in brain sites previously described to express Prokr2, e.g., the paraventricular and the suprachiasmatic nuclei, and the area postrema. The Prokr2-Cre mouse model was further validated by colocalization of Cre-induced GFP and Prokr2 mRNA. No disruption of Prokr2 expression, GnRH neuronal migration or fertility was observed. Comparative analysis of Prokr2-Cre expression in male and female brains revealed a sexually dimorphic distribution confirmed by in situ hybridization. In females, higher Cre activity was found in the medial preoptic area, ventromedial nucleus of the hypothalamus, arcuate nucleus, medial amygdala and lateral parabrachial nucleus. In males, Cre was higher in the amygdalo-hippocampal area. The sexually dimorphic pattern of Prokr2 expression indicates differential roles in reproductive function and, potentially, in other physiological systems.

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Section: Discussionmentioning

confidence: 99%

“…Following the identification of a Prokr2-Cre founder, the mouse was bred with two distinct lines of Cre-induced reporter genes (GFP and tdTom) to evaluate the efficiency of loxP recombination (Allen et al 2016; Borges et al 2016; Cravo et al 2011, 2013). In both cases, we found a similar distribution of labeled cells throughout the brain.…”

Section: Discussionmentioning

confidence: 99%

Sexually dimorphic distribution of Prokr2 neurons revealed by the Prokr2-Cre mouse model

et al. 2017

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“…We could hypothesise that the lack of PI3K downstream of other hormones and/or growth factors in ovaries, for example, has contributed to the LR Δα mouse phenotype. LR‐Cre reporter gene is expressed in theca cells and studies have suggested that insulin signalling in theca cells is associated with an obesity‐induced increase in oestrous cycle length . Deletion of insulin receptor in theca cells or gonadotrophs blocked this response, allowing females to maintain normal oestrous cycles under obese conditions .…”

Section: Pros and Cons Of Using The Lr‐cre Line As A Metabolically Rementioning

confidence: 99%

“…97 We have also shown that LR expression only in gonadotrophs is not sufficient to improve the metabolic or reproductive phenotypes of the LR null mice. 98 Similarly, initial studies have suggested that the reproductive deficits caused by a lack of leptin signalling are not mediated by the gonads, 99 indicating that the brain is the main target of leptin in neuroendocrine regulation.…”

Section: Pros and Con S Of Us Ing The Lr-cre Line A S A Me Taboli Cmentioning

confidence: 99%

PI3K signalling in leptin receptor cells: Role in growth and reproduction

García-Galiano

Borges

Allen

et al. 2019

J Neuroendocrinology

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Nutrition and growth are important signals for pubertal development, although how they are perceived and integrated in brain circuits has not been well defined. Growth hormones and metabolic cues both recruit phosphatidylinositol 3‐kinase (PI3K) signalling in hypothalamic sites, although whether they converge into the same neuronal population(s) is also not known. In this review, we discuss recent findings from our laboratory showing the role of PI3K subunits in cells directly responsive to the adipocyte‐derived hormone leptin in the coordination of growth, pubertal development and fertility. Mice with deletion of PI3K p110α and p110β catalytic subunits in leptin receptor cells (LRΔα+β) have a lean phenotype associated with increased energy expenditure, locomotor activity and thermogenesis. The LRΔα+β mice also show deficient growth and delayed puberty. Deletion of a single subunit (ie, p110α) in LR cells (LRΔα) causes a similar phenotype of increased energy expenditure, deficient growth and delayed pubertal development, indicating that these functions are preferably controlled by p110α. The LRΔα mice show enhanced leptin sensitivity in metabolic regulation but, remarkably, these mice are unresponsive to the effects of leptin on growth and puberty. PI3K is also recruited by insulin and a subpopulation of LR neurones is responsive to i.c.v. insulin administration. Deletion of insulin receptor in LR cells causes no changes in body weight or linear growth and induces only a mild delay in pubertal completion. Our findings demonstrate that PI3K in LR cells plays an essential role in growth and reproduction. We will also discuss the potential neural pathways underlying these effects.

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“…More probable is the influence of body fat on ovaries before their isolation, either via a non-specific effect on metabolism and resistance of cells to environmental toxins, or through the action of fat-derived adipokines whose influence on ovarian functions in mammals including mice is well documented (Kubandová et al 2014a;Kubandová et al 2014b;Janštová et al 2017, Sirotkin. 2011Allen et al 2016;Cheng et al 2016). From a practical viewpoint, the variability in metabolic status/fat content can explain the individual variability of human and animals in their resistance to environmental contaminants.…”

Section: Does Metabolic State Affect the Response Of Ovarian Hormonesmentioning

confidence: 99%

Metabolic state can define the ovarian response to environmental contaminants and medicinal plants

Sirotkin

Fabian

Babeľová

et al. 2017

Appl. Physiol. Nutr. Metab.

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Environmental contaminants and medicinal plants can affect reproductive processes. The aim of this study was to investigate the effect of maternal metabolic status on the response of mouse ovaries to the environmental contaminants benzene and xylene, as well as to extracts of the medicinal plant yucca. Ovaries isolated from normal-lean and slightly obese mice were cultured with or without 0.1% benzene or xylene for 24 h. Similarly, ovaries isolated from normal-lean, slightly obese, and significantly obese mice were cultured for 24 h with or without an extract of Yucca shidigera (YS, 10 μ g/mL). We found that the metabolic status did not influence the release of basal progesterone (P4), testosterone (T), or insulin-like growth factor I (IGF-I), but obesity influenced the effects of the environmental contaminants and YS. Benzene reduced P4 output in ovaries from obese but not normal-lean mice; it also reduced IGF-I (but not T) release from ovaries irrespective of the metabolic status. Xylene dramatically increased P4 and T (but not IGF-I) release by ovaries from normal-lean mice, but there were no changes in P4 and only small increases in T output in obese mice. YS increased P4 (but not T or IGF-I) release in normal-lean and slightly obese animal ovaries, whilst significant obesity was associated with a lack of P4 response to YS. Obesity might affect the basal ovarian release of T or IGF-I and increases the sensitivity of ovaries to the action of benzene but decreases their responsiveness to xylene and YS.

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Leptin receptor null mice with reexpression of LepR in GnRHR expressing cells display elevated FSH levels but remain in a prepubertal state

Abstract: CF. Leptin receptor null mice with reexpression of LepR in GnRHR expressing cells display elevated FSH levels but remain in a prepubertal state.

Cited by 17 publications

References 57 publications

Sexually dimorphic distribution of Prokr2 neurons revealed by the Prokr2-Cre mouse model

Sexually dimorphic distribution of Prokr2 neurons revealed by the Prokr2-Cre mouse model

PI3K signalling in leptin receptor cells: Role in growth and reproduction

Metabolic state can define the ovarian response to environmental contaminants and medicinal plants

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