Distinct effects of growth hormone deficiency and disruption of hypothalamic kisspeptin system on reproduction of male mice

Paula, Daniella G. de; Bohlen, Tabata Mariz; Zampieri, Thais T.; Mansano, Naira S.; Vieira, Henrique Rodrigues; Gusmao, Daniela O.; Wasinski, Frederick; Donato, José; Frazão, Renata

doi:10.1016/j.lfs.2021.119970

Cited by 11 publications

(5 citation statements)

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“…Common upregulated genes encode three hormone receptors (Ghsr, Pgr, Npr2) indicating that ghrelin (and growth hormone), progesterone and natriuretic peptide may exert regulatory effects on estrogen feedback via acting on both kisspeptin cell populations. This notion is in accord with previously published data about the regulatory role of these hormones on kisspeptin neurons (36)(37)(38). Other common E2-dependent genes include Gad2, transcriptional activation of which may results in increased GABA synthesis in kisspeptin neurons.…”

Section: E2 Evokes Different Transcriptional Responses In Preoptic An...supporting

confidence: 93%

Estrogen differentially regulates transcriptional landscapes of preoptic and arcuate kisspeptin neuron populations

et al. 2022

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Kisspeptin neurons residing in the rostral periventricular area of the third ventricle (KPRP3V) and the arcuate nucleus (KPARC) mediate positive and negative estrogen feedback, respectively. Here, we aim to compare transcriptional responses of KPRP3V and KPARC neurons to estrogen. Transgenic mice were ovariectomized and supplemented with either 17β-estradiol (E2) or vehicle. Fluorescently tagged KPRP3V neurons collected by laser-capture microdissection were subjected to RNA-seq. Bioinformatics identified 222 E2-dependent genes. Four genes encoding neuropeptide precursors (Nmb, Kiss1, Nts, Penk) were robustly, and Cartpt was subsignificantly upregulated, suggesting putative contribution of multiple neuropeptides to estrogen feedback mechanisms. Using overrepresentation analysis, the most affected KEGG pathways were neuroactive ligand-receptor interaction and dopaminergic synapse. Next, we re-analyzed our previously obtained KPARC neuron RNA-seq data from the same animals using identical bioinformatic criteria. The identified 1583 E2-induced changes included suppression of many neuropeptide precursors, granins, protein processing enzymes, and other genes related to the secretory pathway. In addition to distinct regulatory responses, KPRP3V and KPARC neurons exhibited sixty-two common changes in genes encoding three hormone receptors (Ghsr, Pgr, Npr2), GAD-65 (Gad2), calmodulin and its regulator (Calm1, Pcp4), among others. Thirty-four oppositely regulated genes (Kiss1, Vgf, Chrna7, Tmem35a) were also identified. The strikingly different transcriptional responses in the two neuron populations prompted us to explore the transcriptional mechanism further. We identified ten E2-dependent transcription factors in KPRP3V and seventy in KPARC neurons. While none of the ten transcription factors interacted with estrogen receptor-α, eight of the seventy did. We propose that an intricate, multi-layered transcriptional mechanism exists in KPARC neurons and a less complex one in KPRP3V neurons. These results shed new light on the complexity of estrogen-dependent regulatory mechanisms acting in the two functionally distinct kisspeptin neuron populations and implicate additional neuropeptides and mechanisms in estrogen feedback.

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Section: E2 Evokes Different Transcriptional Responses In Preoptic An...supporting

confidence: 93%

Estrogen differentially regulates transcriptional landscapes of preoptic and arcuate kisspeptin neuron populations

et al. 2022

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“…The MSG-obesity induction causes cytotoxic injury in hypothalamic nuclei that induces significant changes in the development of animals, mainly due to cell loss in the GH-secreting hypothalamic nuclei [28], as well described in the literature [7] and previously identified in works by our research group [9,21,29,30]. The relationship between reduced body growth and reduced muscle growth has also been extensively explored [1,22,28], with a consensus in the literature that MSG cytotoxicity still results in a model of short stature due to hormonal insufficiency that leads to low growth [22,31]. In this sense, the reduction in body weight gain accompanied by a shorter nasoanal length of MSG animals, suggests that from the second day after the end of injections (PND07) such changes are being established, corroborating that the effects of MSG reach different tissues, since the beginning of the exhibition.…”

Section: Discussionmentioning

confidence: 99%

“…The reduction in body growth of animals exposed to the MSG model has been evidenced by several authors [1,9,[21][22][23]. Depending on the concentration and frequency of injections, the condition can be identified immediately after the induction period and is also confirmed in adulthood [22,24]. Also, in addition to changes in growth, it has been identified that the changes caused by this model are not reversible when considering muscle tissue, which suggests that metabolic impairment may be established early to has been described in the literature, and may resemble models of metabolic programming that affect muscle development and maturation [25][26][27].…”

Section: Introductionmentioning

confidence: 92%

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Early and Sustained Inflammatory State Induces Muscle Changes and Establishes Obesogenic Characteristics in Wistar Rats Exposed to MSG-Induced Obesity Model

Zazula¹,

Saraiva²,

Theodoro³

et al. 2022

Preprint

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The model of obesity induced by monosodium glutamate cytotoxicity on the hypothalamic nuclei is widely used in the literature. However, MSG promotes persistent muscle changes and there is a significant lack of studies that seek to elucidate the mechanisms by which damage refractory to reversal is established. This study aimed to investigate the early and chronic effects of MSG in-duction of obesity upon systemic and muscular parameters of Wistar rats. Animals were exposed to MSG subcutaneously (4 mg.g-1 b.w.) or saline (1.25 mg.g-1 b.w.) daily from PND01 to PND05 (n = 24). After, in PND15, 12 animals were euthanized to determine the plasma and inflammatory profile and to assess muscle damage. In PND142, the remaining animals were euthanized, and samples for histological and biochemical analyses were obtained. Our results suggest that early exposure to MSG reduced growth, and increased adiposity, induction hyperinsulinemia, and a pro-inflammatory scenario. In adulthood were found, peripheral insulin resistance, reduced muscle mass, oxidative capacity, neuromuscular junctions, increased fibrosis, and oxidative distress. Thus, we can conclude that the condition found in adult life and the difficulty in restoring the muscle profile are related to the metabolic damages established early.

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“…In‐house sensitive sandwich enzyme‐linked immunosorbent assays (ELISA) were adapted from published protocols to determine plasma LH (Brown et al, 2019; Quaresma et al, 2021) and FSH (De Paula et al, 2021; Ongaro et al, 2021) levels. A 96‐well high‐binding plate (9018, Corning) was coated with 50 μl of monoclonal mouse anti‐bovine LH beta subunit antibody (1:2500; Pablo Ross, UC Davis, 518B7; RRID: AB_2756886) or polyclonal guinea pig anti‐mouse FSH antibody (1:20,000; AFP1760191, NIDDK‐NHPP; RRID: AB_2665512) overnight at 4°C.…”

Section: Methodsmentioning

confidence: 99%

Pattern of gonadotropin secretion along the estrous cycle of C57BL/6 female mice

Gusmao

Vieira

Mansano

et al. 2022

Physiological Reports

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The pattern of gonadotropin secretion along the estrous cycle was elegantly described in rats. Less information exists about the pattern of gonadotropin secretion in gonad‐intact mice, particularly regarding the follicle‐stimulating hormone (FSH). Using serial blood collections from the tail‐tip of gonad‐intact C57BL/6 mice on the first day of cornification (transition from diestrus to estrus; hereafter called proestrus), we observed that the luteinizing hormone (LH) and FSH surge cannot be consistently detected since only one out of eight females (12%) showed increased LH levels. In contrast, a high percentage of mice (15 out of 21 animals; 71%) exhibited LH and FSH surges on the proestrus when a single serum sample was collected. Mice that exhibited LH and FSH surges on the proestrus showed c‐Fos expression in gonadotropin‐releasing hormone‐ (GnRH; 83.4% of co‐localization) and kisspeptin‐expressing neurons (42.3% of co‐localization) of the anteroventral periventricular nucleus (AVPV). Noteworthy, mice perfused on proestrus, but that failed to exhibit LH surge, showed a smaller, but significant expression of c‐Fos in GnRH (32.7%) and AVPVKisspeptin (14.0%) neurons. Finally, 96 serial blood samples were collected hourly in eight regular cycling C57BL/6 females to describe the pattern of LH and FSH secretion along the estrous cycle. Small elevations in LH and FSH levels were detected at the time expected for the LH surge. In summary, the present study improves our understanding of the pattern of gonadotropin secretion and the activation of central components of the hypothalamic–pituitary‐gonadal axis along the estrous cycle of C57BL/6 female mice.

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Distinct effects of growth hormone deficiency and disruption of hypothalamic kisspeptin system on reproduction of male mice

Cited by 11 publications

References 89 publications

Estrogen differentially regulates transcriptional landscapes of preoptic and arcuate kisspeptin neuron populations

Estrogen differentially regulates transcriptional landscapes of preoptic and arcuate kisspeptin neuron populations

Early and Sustained Inflammatory State Induces Muscle Changes and Establishes Obesogenic Characteristics in Wistar Rats Exposed to MSG-Induced Obesity Model

Pattern of gonadotropin secretion along the estrous cycle of C57BL/6 female mice

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