Browse
Submit Data
Databases
API
Help

Dataset Information

22 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Sex-specific pubertal and metabolic regulation of Kiss1 neurons via Nhlh2.

ABSTRACT: Hypothalamic Kiss1 neurons control gonadotropin-releasing hormone release through the secretion of kisspeptin. Kiss1 neurons serve as a nodal center that conveys essential regulatory cues for the attainment and maintenance of reproductive function. Despite this critical role, the mechanisms that control kisspeptin synthesis and release remain largely unknown. Using Drop-Seq data from the arcuate nucleus of adult mice and in situ hybridization, we identified Nescient Helix-Loop-Helix 2 (Nhlh2), a transcription factor of the basic helix-loop-helix family, to be enriched in Kiss1 neurons. JASPAR analysis revealed several binding sites for NHLH2 in the Kiss1 and Tac2 (neurokinin B) 5' regulatory regions. In vitro luciferase assays evidenced a robust stimulatory action of NHLH2 on human KISS1 and TAC3 promoters. The recruitment of NHLH2 to the KISS1 and TAC3 promoters was further confirmed through chromatin immunoprecipitation. In vivo conditional ablation of Nhlh2 from Kiss1 neurons using Kiss1^Cre:Nhlh2^fl/fl mice induced a male-specific delay in puberty onset, in line with a decrease in arcuate Kiss1 expression. Females retained normal reproductive function albeit with irregular estrous cycles. Further analysis of male Kiss1^Cre:Nhlh2^fl/fl mice revealed higher susceptibility to metabolic challenges in the release of luteinizing hormone and impaired response to leptin. Overall, in Kiss1 neurons, Nhlh2 contributes to the metabolic regulation of kisspeptin and NKB synthesis and release, with implications for the timing of puberty onset and regulation of fertility in male mice.

SUBMITTER: Leon S

PROVIDER: S-EPMC8439651 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Sex-Specific Regulation of Inflammation and Metabolic Syndrome in Obesity.

Project description:OBJECTIVE:Metabolic dysregulation and inflammation are important consequences of obesity and impact susceptibility to cardiovascular disease. Anti-inflammatory therapy in cardiovascular disease is being developed under the assumption that inflammatory pathways are identical in women and men, but it is not known if this is indeed the case. In this study, we assessed the sex-specific relation between inflammation and metabolic dysregulation in obesity. Approach and Results: Three hundred two individuals were included, half with a BMI 27 to 30 kg/m2 and half with a BMI>30 kg/m2, 45% were women. The presence of metabolic syndrome was assessed according to the National Cholesterol Education Program-ATPIII criteria, and inflammation was studied using circulating markers of inflammation, cell counts, and ex vivo cytokine production capacity of isolated immune cells. Additionally, lipidomic and metabolomic data were gathered, and subcutaneous fat biopsies were histologically assessed. Metabolic syndrome is associated with an increased inflammatory profile that profoundly differs between women and men: women with metabolic syndrome show a lower concentration of the anti-inflammatory adiponectin, whereas men show increased levels of several pro-inflammatory markers such as IL (interleukin)-6 and leptin. Adipose tissue inflammation showed similar sex-specific associations with these markers. Peripheral blood mononuclear cells isolated from men, but not women, with metabolic syndrome display enhanced cytokine production capacity. CONCLUSIONS:We identified sex-specific pathways that influence inflammation in obesity. Excessive production of proinflammatory cytokines was observed in men with metabolic syndrome. In contrast, women typically showed reduced levels of the anti-inflammatory adipokine adiponectin. These different mechanisms of inflammatory dysregulation between women and men with obesity argue for sex-specific therapeutic strategies.

| S-EPMC7310302 | biostudies-literature

Estrogen signaling in arcuate Kiss1 neurons suppresses a sex-dependent female circuit promoting dense strong bones.

Project description:Central estrogen signaling coordinates energy expenditure, reproduction, and in concert with peripheral estrogen impacts skeletal homeostasis in females. Here, we ablate estrogen receptor alpha (ER?) in the medial basal hypothalamus and find a robust bone phenotype only in female mice that results in exceptionally strong trabecular and cortical bones, whose density surpasses other reported mouse models. Stereotaxic guided deletion of ER? in the arcuate nucleus increases bone mass in intact and ovariectomized females, confirming the central role of estrogen signaling in this sex-dependent bone phenotype. Loss of ER? in kisspeptin (Kiss1)-expressing cells is sufficient to recapitulate the bone phenotype, identifying Kiss1 neurons as a critical node in this powerful neuroskeletal circuit. We propose that this newly-identified female brain-to-bone pathway exists as a homeostatic regulator diverting calcium and energy stores from bone building when energetic demands are high. Our work reveals a previously unknown target for treatment of age-related bone disease.

| S-EPMC6329772 | biostudies-literature

Sex-specific expression of estrogen receptors ? and ? and Kiss1 in the postnatal rat amygdala.

Project description:The rodent amygdaloid complex is composed of numerous subnuclei important for the sex-specific regulation of sociosexual behavior. Although estrogen receptors (ERs) are critical for organizing functional and cytoarchitectural sex differences in these subnuclei, a detailed developmental profile of ER expression in the amygdaloid complex is not available. Moreover, the kisspeptin gene (Kiss1) was recently identified in the adult amygdala, but it remains unknown if it is expressed during development. To fill these data gaps, rat brains (5-7/group) were assessed on postnatal days (PNDs) 0, 2, 4, 7, and 19 for ER alpha (ER?; Esr1), beta (ER?; Esr2), and Kiss1 expression using in situ hybridization. Expression was quantified in the posterodorsal portion of the medial amygdala posterodorsal (MePD), lateral (PLCo), and medial (PMCo) components of the posterior cortical nucleus, and the amygdalohippocampal area (AHi). ER? expression was high throughout the amygdala at birth, but sexually dimorphic only in the AHi. ER? expression in the MePD and the PLCo showed a U-shaped expression pattern over time. In the PMCo, ER? expression decreased from PND 2 and remained low through PND 19. Sexually dimorphic expression of ER? in the MePD was observed on PND 0, with higher levels in females, but reversed by PND 4 due to declining levels in females. No Kiss1 signal was observed in the postnatal amygdala, suggesting that expression arises after puberty. These data reveal that ER expression is region-specific within the neonatal amygdala. These differences likely contribute to sex differences in sociosexual behavior across the lifespan.

| S-EPMC3492514 | biostudies-literature

Sex and Pubertal Status Influence Dendritic Spine Density on Frontal Corticostriatal Projection Neurons in Mice.

Project description:In humans, nonhuman primates, and rodents, the frontal cortices exhibit grey matter thinning and dendritic spine pruning that extends into adolescence. This maturation is believed to support higher cognition but may also confer psychiatric vulnerability during adolescence. Currently, little is known about how specific cell types in the frontal cortex mature or whether puberty plays a role in the maturation of some cell types but not others. Here, we used mice to characterize the spatial topography and adolescent development of cross-corticostriatal (cSTR) neurons that project through the corpus collosum to the dorsomedial striatum. We found that apical spine density on cSTR neurons in the medial prefrontal cortex decreased significantly between late juvenile (P29) and young adult time points (P60), with females exhibiting higher spine density than males at both ages. Adult males castrated prior to puberty onset had higher spine density compared to sham controls. Adult females ovariectomized before puberty onset showed greater variance in spine density measures on cSTR cells compared to controls, but their mean spine density did not significantly differ from sham controls. Our findings reveal that these cSTR neurons, a subtype of the broader class of intratelencephalic-type neurons, exhibit significant sex differences and suggest that spine pruning on cSTR neurons is regulated by puberty in male mice.

| S-EPMC7232997 | biostudies-literature

Metabolic trajectories across early adolescence: differences by sex, weight, pubertal status and race/ethnicity.

Project description:Background: Biomarkers of cardiovascular and metabolic risk track from adolescence into adulthood, therefore characterising the direction and magnitude of these changes is an important first step to identifying health trajectories that presage future disease risk.Aim: To characterise changes in metabolic biomarkers across early adolescence in a multi-ethnic cohort.Subjects and methods: Among 891 participants in Project Viva we estimated changes in insulin resistance (HOMA-IR), adipokines, lipids, and SBP between ages 6-10 years and 11-16 years. Next, we used multivariable linear regression to examine associations of sex, baseline overweight/obesity, baseline pubertal status and race/ethnicity with change in the biomarkers during follow-up.Results: Boys exhibited a larger decrement in adiponectin (-0.66 [95% CI = -1.14, -0.18)] ng/mL) and a greater increase in SBP (3.20 [2.10, 4.30] mmHg) than girls. Overweight/obese participants experienced larger increases in HOMA-IR, leptin, and triglycerides; and a steeper decrement in HDL. Pubertal youth showed larger decrements in total and LDL cholesterol than their pre-pubertal counterparts. In comparison to White participants, Black youth experienced a larger magnitude of increase in HOMA-IR, and Hispanic youth exhibited larger decrements in adiponectin and HDL.Conclusions: Change in metabolic biomarkers across early adolescence differed by sex, weight status, pubertal status and race/ethnicity. Some of the metabolic changes may reflect normal physiological changes of puberty, while others may presage future disease risk. Future studies are warranted to link metabolic changes during adolescence to long-term health.

| S-EPMC6960375 | biostudies-literature

SIRT1 mediates obesity- and nutrient-dependent perturbation of pubertal timing by epigenetically controlling Kiss1 expression.

Project description:Puberty is regulated by epigenetic mechanisms and is highly sensitive to metabolic and nutritional cues. However, the epigenetic pathways mediating the effects of nutrition and obesity on pubertal timing are unknown. Here, we identify Sirtuin 1 (SIRT1), a fuel-sensing deacetylase, as a molecule that restrains female puberty via epigenetic repression of the puberty-activating gene, Kiss1. SIRT1 is expressed in hypothalamic Kiss1 neurons and suppresses Kiss1 expression. SIRT1 interacts with the Polycomb silencing complex to decrease Kiss1 promoter activity. As puberty approaches, SIRT1 is evicted from the Kiss1 promoter facilitating a repressive-to-permissive switch in chromatin landscape. Early-onset overnutrition accelerates these changes, enhances Kiss1 expression and advances puberty. In contrast, undernutrition raises SIRT1 levels, protracts Kiss1 repression and delays puberty. This delay is mimicked by central pharmacological activation of SIRT1 or SIRT1 overexpression, achieved via transgenesis or virogenetic targeting to the ARC. Our results identify SIRT1-mediated inhibition of Kiss1 as key epigenetic mechanism by which nutritional cues and obesity influence mammalian puberty.

| S-EPMC6179991 | biostudies-literature

Conditional kisspeptin neuron-specific Kiss1 knockout with newly generated Kiss1-floxed and Kiss1-Cre mice replicates a hypogonadal phenotype of global Kiss1 knockout mice.

Project description:The present study aimed to evaluate whether novel conditional kisspeptin neuron-specific Kiss1 knockout (KO) mice utilizing the Cre-loxP system could recapitulate the infertility of global Kiss1 KO models, thereby providing further evidence for the fundamental role of hypothalamic kisspeptin neurons in regulating mammalian reproduction. We generated Kiss1-floxed mice and hypothalamic kisspeptin neuron-specific Cre-expressing transgenic mice and then crossed these two lines. The conditional Kiss1 KO mice showed pubertal failure along with a suppression of gonadotropin secretion and ovarian atrophy. These results indicate that newly-created hypothalamic Kiss1 KO mice obtained by the Cre-loxP system recapitulated the infertility of global Kiss1 KO models, suggesting that hypothalamic kisspeptin, but not peripheral kisspeptin, is critical for reproduction. Importantly, these Kiss1-floxed mice are now available and will be a valuable tool for detailed analyses of roles of each population of kisspeptin neurons in the brain and peripheral kisspeptin-producing cells by the spatiotemporal-specific manipulation of Cre expression.

| S-EPMC7470906 | biostudies-literature

The roles of leptin receptors on POMC neurons in the regulation of sex-specific energy homeostasis.

Project description:Leptin regulates energy homeostasis and reproduction. One key population of leptin receptors (Lepr) are found on proopiomelanocortin (POMC) neurons in the hypothalamic arcuate nucleus, and evidence links the action of gonadal estrogens to these same POMC neurons. To determine whether Lepr on POMC neurons are critical for reproductive capacity or for sex-specific energy and glucose homeostasis, we studied Cre/loxP mice lacking Lepr specifically on POMC neurons (Pomc-Cre, Lepr(flox/flox) mice) and their controls with normal Lepr (Lepr(flox/flox) mice). Pomc-Cre, Lepr(flox/flox) mice maintained normal reproductive capacity and accumulated more body fat than their same sex controls. Ovariectomy (OVX) was performed to investigate the effects of the estrogens and Lepr on POMC neurons on body fat accumulation and glucose tolerance. OVX Pomc-Cre, Lepr(flox/flox) females accumulated more fat than OVX Lepr(flox/flox) females did. Pomc-Cre, Lepr(flox/flox) males were glucose intolerant and insulin insensitive compared with control males. In contrast, control and Pomc-Cre, Lepr(flox/flox) females had similar glucose tolerance before and after OVX. Therefore leptin's action on POMC neurons reduces body fat accumulation, but is not critical for regulation of reproduction. The sex difference in leptin signaling on POMC neurons on glucose tolerance appears independent of ovarian hormones.

| S-EPMC3608195 | biostudies-literature

Transcriptional regulation of the human KiSS1 gene.

Project description:Kisspeptin, the product of the KiSS1 gene, has emerged as a key component of the mechanism by which the hypothalamus controls puberty and reproductive development. It does so by stimulating the secretion of gonadotropin releasing hormone (GnRH). Little is known about the transcriptional control of the KiSS1 gene. Here we show that a set of proteins postulated to be upstream components of a hypothalamic network involved in controlling female puberty regulates KiSS1 transcriptional activity. Using RACE-PCR we determined that transcription of KiSS1 mRNA is initiated at a single transcription start site (TSS) located 153-156bp upstream of the ATG translation initiation codon. Promoter assays performed using 293 MSR cells showed that the KiSS1 promoter is activated by TTF1 and CUX1-p200, and repressed by EAP1, YY1, and CUX1-p110. EAP1 and CUX-110 were also repressive in GT1-7 cells. All four TFs are recruited in vivo to the KiSS1 promoter and are expressed in kisspeptin neurons. These results suggest that expression of the KiSS1 gene is regulated by trans-activators and repressors involved in the system-wide control of mammalian puberty.

| S-EPMC3148268 | biostudies-literature

Increased neurokinin B (Tac2) expression in the mouse arcuate nucleus is an early marker of pubertal onset with differential sensitivity to sex steroid-negative feedback than Kiss1.

Project description:At puberty, neurokinin B (NKB) and kisspeptin (Kiss1) may help to amplify GnRH secretion, but their precise roles remain ambiguous. We tested the hypothesis that NKB and Kiss1 are induced as a function of pubertal development, independently of the prevailing sex steroid milieu. We found that levels of Kiss1 mRNA in the arcuate nucleus (ARC) are increased prior to the age of puberty in GnRH/sex steroid-deficient hpg mice, yet levels of Kiss1 mRNA in wild-type mice remained constant, suggesting that sex steroids exert a negative feedback effect on Kiss1 expression early in development and across puberty. In contrast, levels of Tac2 mRNA, encoding NKB, and its receptor (NK3R; encoded by Tacr3) increased as a function of puberty in both wild-type and hpg mice, suggesting that during development Tac2 is less sensitive to sex steroid-dependent negative feedback than Kiss1. To compare the relative responsiveness of Tac2 and Kiss1 to the negative feedback effects of gonadal steroids, we examined the effect of estradiol (E(2)) on Tac2 and Kiss1 mRNA and found that Kiss1 gene expression was more sensitive than Tac2 to E(2)-induced inhibition at both juvenile and adult ages. This differential estrogen sensitivity was tested in vivo by the administration of E(2). Low levels of E(2) significantly suppressed Kiss1 expression in the ARC, whereas Tac2 suppression required higher E(2) levels, supporting differential sensitivity to E(2). Finally, to determine whether inhibition of NKB/NK3R signaling would block the onset of puberty, we administered an NK3R antagonist to prepubertal (before postnatal d 30) females and found no effect on markers of pubertal onset in either WT or hpg mice. These results indicate that the expression of Tac2 and Tacr3 in the ARC are markers of pubertal activation but that increased NKB/NK3R signaling alone is insufficient to trigger the onset of puberty in the mouse.

| S-EPMC3512019 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data