ERα Signaling in GHRH/Kiss1 Dual-Phenotype Neurons Plays Sex-Specific Roles in Growth and Puberty

García-Galiano, David; Cara, Alexandra L.; Tata, Zachary; Allen, Susan J.; Myers, Martin G.; Schipani, Ernestina; Elias, Carol F.

doi:10.1523/jneurosci.2069-20.2020

Cited by 14 publications

(4 citation statements)

References 74 publications

(97 reference statements)

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“…Specifically, all of them were predicted to interact with estrogen receptor 1 (ESR1), whereas the sole apigenin displayed putative interactions with tyrosine-protein kinase HCK (HCK), playing a key role in regulating the innate immune response and with the apoptosis marker myeloid cell leukemia 1 (MCL1). Both ESR1 and MCL1 are expressed in the hypothalamus [ 52 , 53 ], whereas the bioinformatics platform STRINGH highlighted putative interactions with BDNF and TNFα ( Figure 6 ). Therefore, the present bioinformatics analysis suggests that ESR1 and MCL1 could be targets of the selected phenolic compounds for mediating, at least in part, the inhibition of the gene expression of both BDNF and TNFα in the hypothalamus.…”

Section: Resultsmentioning

confidence: 99%

Chemical Composition and Biological Properties of Two Jatropha Species: Different Parts and Different Extraction Methods

et al. 2021

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Jatropha L. species, in particular, J. curcas and J. gossypiifolia, are well known medicinal plants used for treating various diseases. In the present study, leaf and stem bark extracts of J. curcas and J. gossypiifolia obtained by maceration or homogenizer assisted extraction, were investigated for their phytochemical contents and biological potential as antioxidants, enzyme inhibitors and neuromodulators. In this regard, the gene expression of tumor necrosis factor α (TNFα) and brain-derived neurotrophic factor (BDNF) was investigated in hypothalamic HypoE22 cells. Finally, a bioinformatics analysis was carried out with the aim to unravel the putative mechanisms consistent with both metabolomic fingerprints and pharmacological effects. The leaf extracts of J. curcas showed higher total phenolic content (TPC) and total flavonoid content (TFC) than the stem bark extracts (range: 5.79–48.95 mg GAE/g and 1.64–13.99 mg RE/g, respectively), while J. gossypiifolia possessed TPC and TFC in the range of 42.62–62.83 mg GAE/g and 6.97–17.63 mg RE/g, respectively. HPLC-MS/MS analysis revealed that the leaf extracts of both species obtained by homogenizer assisted extraction are richer in phytochemical compounds compared to the stem bark extracts obtained by the same extraction method. In vitro antioxidant potentials were also demonstrated in different assays (DPPH: 6.89–193.93 mg TE/g, ABTS: 20.20–255.39 mg TE/g, CUPRAC: 21.07–333.30 mg TE/g, FRAP: 14.02–168.93 mg TE/g, metal chelating activity: 3.21–17.51 mg EDTAE/g and phosphomolybdenum assay: 1.76–3.55 mmol TE/g). In particular, the leaf extract of J. curcas and the stem bark extract of J. gossypiifolia, both obtained by homogenizer assisted extraction, showed the most potent antioxidant capacity in terms of free radical scavenging and reducing activity, which could be related to their higher TPC and TFC. Furthermore, anti-neurodegenerative (acetylcholinesterase inhibition:1.12–2.36 mg GALAE/g; butyrylcholinetserase inhibition: 0.50–3.68 mg GALAE/g), anti-hyperpigmentation (tyrosinase inhibition: 38.14–57.59 mg KAE/g) and antidiabetic (amylase inhibition: 0.28–0.62 mmol ACAE/g; glucosidase inhibition: 0.65–0.81 mmol ACAE/g) properties were displayed differentially by the different extracts. Additionally, the extracts were effective in reducing the gene expression of both TNFα and BDNF, which could be partially mediated by phenolic compounds such as naringenin, apigenin and quercetin. Indeed, the scientific data obtained from the present study complement the several other reports highlighting the pharmacological potentials of these two species, thus supporting their uses as therapeutically active plants.

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Section: Resultsmentioning

confidence: 99%

Chemical Composition and Biological Properties of Two Jatropha Species: Different Parts and Different Extraction Methods

et al. 2021

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“…It should be noted that GH receptor ablation in kisspeptin neurons did not affect pubertal timing, estrous cycle length, body weight, or body length [69]. Interestingly, during puberty in female mice a subpopulation of ERα positive GHRH neurons become Kiss1-positive neurons, potentially permitting crosstalk between the growth and reproductive axes [70].…”

Section: Discussionmentioning

confidence: 99%

IGF-1 Acts through Kiss1-expressing Cells to Influence Metabolism and Reproduction

Wang,

Pugh,

Daboul

et al. 2024

Preprint

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ObjectiveKisspeptin, encoded by theKiss1gene, ties puberty and fertility to energy status; however, the metabolic factors that controlKiss1-expressing cells need to be clarified.MethodsTo evaluate the impact of IGF-1 on the metabolic and reproductive functions of kisspeptin producing cells, we created mice with IGF-1 receptor deletion driven by theKiss1promoter (IGF1RKiss1mice). Previous studies have shown IGF-1 and insulin can bind to each other’s receptor, permitting IGF-1 signaling in the absence of IGF1R. Therefore, we also generated mice with simultaneous deletion of the IGF1R and insulin receptor (IR) inKiss1-expressing cells (IGF1R/IRKiss1mice).ResultsLoss of IGF1R inKiss1cells caused stunted body length. In addition, female IGF1RKiss1mice displayed lower body weight and food intake plus higher energy expenditure and physical activity. This phenotype was linked to higher proopiomelanocortin (POMC) expression and heightened brown adipose tissue (BAT) thermogenesis. Male IGF1RKiss1mice had mild changes in metabolic functions. Moreover, IGF1RKiss1mice of both sexes experienced delayed puberty. Notably, male IGF1RKiss1mice had impaired adulthood fertility accompanied by lower gonadotropin and testosterone levels. Thus, IGF1R inKiss1-expressing cells impacts metabolism and reproduction in a sex-specific manner. IGF1R/IRKiss1mice had higher fat mass and glucose intolerance, suggesting IGF1R and IR inKiss1-expressing cells together regulate body composition and glucose homeostasis.ConclusionsOverall, our study shows that IGF1R and IR inKiss1have cooperative roles in body length, metabolism, and reproduction.

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“…Second, GH regulates the sex bias of static male-biased DHS as well, as evidenced by their widespread closure in male liver following continuous GH infusion (Table S2E). It is important to note, however, that hepatocyte-specific knockout of androgen receptor (AR) does, in fact, dysregulate ∼15% of sex-biased genes, albeit with a much lower effect size than global AR knockout [52] due to the systemic disruption of the somatotropic axis and circulating GH secretory profiles [53, 54]. Conceivably, AR could regulate these genes by a direct binding mechanism, acting either alone or in concert with GH-activated STAT5 to keep chromatin open constitutively at a subset of static male-biased DHS, of which 32% undergo at least partial closure in male liver following hypophysectomy (Fig.…”

Section: Discussionmentioning

confidence: 99%

Plasma Growth Hormone Pulses Induce Male-biased Pulsatile Chromatin Opening and Epigenetic Regulation in Adult Mouse Liver

Rampersaud,

Connerney,

Waxman

2023

Preprint

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Summary- Sex-differences in plasma growth hormone (GH) profiles, pulsatile in males and persistent in females, regulate sex differences in hepatic STAT5 activation linked to sex differences in gene expression and liver disease susceptibility, but little is understood about the fundamental underlying, GH pattern-dependent regulatory mechanisms. Here, DNase hypersensitivity site (DHS) analysis of liver chromatin accessibility in a cohort of 21 individual male mice established that the endogenous male rhythm of plasma GH pulse-stimulated liver STAT5 activation induces repeated cycles of chromatin opening and closing at several thousand liver DHS and comprises one of two distinct mechanisms conferring male bias to liver chromatin accessibility. Sex-dependent transcription factor binding patterns and chromatin state analysis identified key factors and epigenetic features distinguishing this dynamic, STAT5-driven mechanism of male-biased chromatin opening from that operative at static male-biased DHS, which are constitutively open in male but not female liver. Notably, dynamic but not static male-biased DHS adopt a bivalent epigenetic state in female liver, as do female-biased DHS in male liver, albeit using distinct repressive histone marks in each sex (H3K27me3 at female-biased DHS in male liver, H3K9me3 at male-biased DHS in female liver). Strikingly, a single physiological replacement dose of GH given to hypophysectomized male mice restored, within 30 min, liver STAT5 activity and chromatin accessibility at 83% of the dynamic male-biased DHS that closed following pituitary hormone ablation. Pulsatile chromatin opening stimulated by endogenous, physiological hormone pulses is thus a novel mechanism for establishing widespread sex differences in chromatin accessibility and transcription factor binding, which are closely linked to sex-biased gene expression and the sexual dimorphism of liver function.

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ERα Signaling in GHRH/Kiss1 Dual-Phenotype Neurons Plays Sex-Specific Roles in Growth and Puberty

Cited by 14 publications

References 74 publications

Chemical Composition and Biological Properties of Two Jatropha Species: Different Parts and Different Extraction Methods

Chemical Composition and Biological Properties of Two Jatropha Species: Different Parts and Different Extraction Methods

IGF-1 Acts through Kiss1-expressing Cells to Influence Metabolism and Reproduction

Plasma Growth Hormone Pulses Induce Male-biased Pulsatile Chromatin Opening and Epigenetic Regulation in Adult Mouse Liver

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