Insulin augments GnRH-stimulated LHβ gene expression by Egr-1

Buggs, Colleen; Weinberg, Frank; Kim, Ellen; Wolfe, Andrew; Radovick, Sally; Wondisford, Fredric E.

doi:10.1016/j.mce.2006.02.001

Cited by 40 publications

(35 citation statements)

References 32 publications

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“…Our sensitivity analysis, excluding girls with transient thelarche, showed similar (17). Furthermore, insulin resistance increases the levels of hyperandrogenemia (14), which in combination may facilitate the GnRH pulsatile secretion and increase pituitary secretion (37) and androgen secretion at the ovarian theca cells (16). Additionally, in adults, insulin and IGF1 stimulate breast cell division (7,8); thus, they could be involved in breast development in early puberty (9).…”

Section: Resultsmentioning

confidence: 77%

Ultrasensitive estrogen levels at 7 years of age predict earlier thelarche: evidence from girls of the growth and obesity Chilean cohort

Pereira

Uauy

Klein

et al. 2015

European Journal of Endocrinology

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Objective: Prepubertal estradiol equivalents have been inconsistently linked to age at thelarche; elucidating this relationship becomes relevant given the worldwide decline in the age of puberty onset. Thus, our aim is to assess whether prepubertal girls with higher serum levels of estradiol equivalents at age 7 have a greater risk of presenting early thelarche (ET). Design: Nested case-control study within the Growth and Obesity Cohort Study of 1196 low-middle income children (w50% girls) from Santiago, Chile. Girls were defined as cases (ET; nZ61) if breast bud appeared prior to 8 years of age; controls (nZ91) had thelarche O8 years. Methods: At 6.7 years, weight, height and waist circumference were measured and a fasting blood sample was obtained for measuring estrogen equivalent (ultrasensitive recombinant cell bioassay), DHEAS, leptin, insulin and IGF1. Beginning at 7 years old, Tanner staging was assessed prospectively twice a year and the appearance of breast bud was assessed by palpation. Results: Mean serum estradiol-equivalent at 6.7 years was 3.9G3.6 pg/ml for cases and 3.6G2.3 pg/ml for controls. Girls with ET had a higher risk of presenting elevated estradiol-equivalent (R5 pg/ml) at 7 years (ORZ2.05, 95% CI: 0.96-4.36) than controls that was borderline significant. However, after adjusting by BMI, insulin and IGF1 at age 7, the association between estradiol-equivalent and ET was significant (ORZ2.29 (95% CI: 1.05-5.01)). Conclusions: Chilean girls from low to middle socioeconomic status with ET exhibited double the risk of having high levels of estradiol-equivalent at 7 years than girls with a later age of thelarche. Whole-body adiposity and increased adrenal activity did not explain the observed prepubertal estrogen increase.

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Section: Resultsmentioning

confidence: 77%

Ultrasensitive estrogen levels at 7 years of age predict earlier thelarche: evidence from girls of the growth and obesity Chilean cohort

Pereira

Uauy

Klein

et al. 2015

European Journal of Endocrinology

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“…Phosphorylation of CBP via insulin results in dissociation of CBP from the CREB-CBP-TORC2 complex, and in gonadotrophs, it results in recruitment to the Lhb promoter and activation of Lhb gene expression. We and others have shown that insulin can increase GNRH-mediated Lhb expression and secretion with some evidence of a costimulatory effect of insulin and GNRH in L␤T2 cells via activation of AKT and extracellular signal-regulated kinase (ERK) (1,4,10,31,40). This suggests that energy-homeostatic information can be integrated at the level of the pituitary gland, possibly through CBP, to modulate reproductive function.…”

Section: Discussionmentioning

confidence: 92%

“…The Lhb promoter-luciferase reporter contains the Ϫ140 to ϩ1 fragment of the mouse Lhb gene promoter cloned into pA 3 Luc proximal to luciferase as previously described (4). The wild-type CBP and S436A mutant vectors were generated using the QuikChange site-directed mutagenesis kit (Stratagene) as previously described (56).…”

Section: Constructsmentioning

confidence: 99%

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CREB Binding Protein (CBP) Activation Is Required for Luteinizing Hormone Beta Expression and Normal Fertility in Mice

Miller

Wolfe

et al. 2012

Molecular and Cellular Biology

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Normal function of the hypothalamic-pituitary-gonadal axis is dependent on gonadotropin-releasing hormone (GNRH)-stimulated synthesis and secretion of luteinizing hormone (LH) from the pituitary gonadotroph. While the transcriptional coactivator CREB binding protein (CBP) is known to interact with Egr-1, the major mediator of GNRH action on the Lhb gene, the role of CBP in Lhb gene expression has yet to be characterized. We show that in the L␤T2 gonadotroph cell line, overexpression of CBP augmented the response to GNRH and that knockdown of CBP eliminated GNRH responsiveness. While GNRH-mediated phosphorylation of CBP at Ser436 increased the interaction with Egr-1 on the Lhb promoter, loss of this phosphorylation site eliminated GNRH-mediated Lhb expression in L␤T2 cells. In vivo, loss of CBP phosphorylation at Ser436 rendered female mice subfertile. S436A knock-in mice had disrupted estrous cyclicity and reduced responsiveness to GNRH. Our results show that GNRHmediated phosphorylation of CBP at Ser436 is required for Egr-1 to activate Lhb expression and is a requirement for normal fertility in female mice. As CBP can be phosphorylated by other factors, such as insulin, our studies suggest that CBP may act as a key regulator of Lhb expression in the gonadotroph by integrating homeostatic information with GNRH signaling. Reproductive viability in humans is dependent on normal function of the hypothalamic-pituitary-gonadal axis. Gonadotropin-releasing hormone (GNRH) is produced by hypothalamic neurosecretory cells and released in a pulsatile manner into the hypothalamo-hypophyseal portal circulation, through which the hormone is transported to the anterior pituitary gland. GNRH bound to its receptor on pituitary gonadotrophs results in an increase in GNRH receptor density and stimulates the synthesis and secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) into the circulation (14,30,41). LH and FSH are heterodimeric glycoproteins consisting of a common ␣-subunit and hormone-specific ␤-subunit encoded by the Lhb and Fshb genes, respectively. Lhb and Fshb gene expression in the anterior pituitary is dependent on pulsatile GNRH secretion. Rapid, highamplitude GNRH pulses stimulate an increase in Lhb mRNA levels, leading to an increase in LH synthesis and release from the gonadotroph (11,18,45,51).At least three major transcription factors are important for Lhb gene expression: steroidogenic factor 1 (SF-1), pituitary homeobox factor 1 (Pitx1), and early growth response factor 1 (Egr-1). GNRH stimulates the expression of Egr-1, resulting in Egr-1 binding to two conserved cis elements of the proximal Lhb promoter (5, 43, 49). Egr-1 is rapidly and markedly induced by GNRH, while SF-1 and Pitx1 expression levels are unchanged following GNRH administration (43, 49). In rat, Egr-1 expression increases in proestrous, suggesting that it may be an important signal for ovulation (39). Loss of Egr-1 in the gonadotroph, unlike loss of SF-1 or Pitx1, renders the cell unable to respond to GNRH, and Egr-1...

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“…These include insulin and fatty acids (Buggs et al 2006, Garrel et al 2014, indicating a potential role in mediating the effects of nutritional status and possibly obesity on reproductive capacity (shown in Brothers et al (2010)). In addition, there is evidence that EGR1 mediates the effects of glucocorticoids/stress at the Lhb gene promoter (Breen et al 2012).…”

Section: Introductionmentioning

confidence: 99%

Cellular distribution of Egr1 transcription in the male rat pituitary gland

Man

Wells

Carter

2014

Journal of Molecular Endocrinology

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The transcription factor gene Egr1 is necessary for female fertility; EGR1 protein is an established molecular regulator of adult female gonadotroph function where it mediates GNRH-stimulated transcription of the Lhb gene. Recent studies have also implicated pituitary EGR1 in the mediation of other physiological signals indicating an integrative function. However, the role of EGR1 in males is less well defined and this uncertainty is compounded by the absence of cellular expression data in the male pituitary gland. The aim of this study, therefore, was to define the distribution of Egr1 gene expression in the adult male rat pituitary. To further this aim, we have evaluated cellular populations in a transgenic rat model (Egr1-d2EGFP), in which we demonstrate regulated green fluorescent protein (GFP) expression in EGR1C pituitary cells. Cellular filling by GFP enabled morphological and molecular differentiation of different populations of gonadotrophs; Egr1 transcription and LHB were highly co-localised in a major population of large cells but only minimally co-localised in small GFPC cells; the latter cells were shown to be largely (80%) composed of minority populations of GHC somatotrophs (9% of total GHC) and PRLC lactotrophs (3% of total PRLC). Egr1 transcription was not found in TSHC, ACTHC or SOX2C precursor cells and was only minimally co-localised in S-100bC folliculostellate cells. Our demonstration that the Egr1 gene is actively and selectively transcribed in a major sub-population of male LHBC cells indicates a largely conserved role in gonadotroph function and has provided a basis for further defining this role.

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Insulin augments GnRH-stimulated LHβ gene expression by Egr-1

Cited by 40 publications

References 32 publications

Ultrasensitive estrogen levels at 7 years of age predict earlier thelarche: evidence from girls of the growth and obesity Chilean cohort

Ultrasensitive estrogen levels at 7 years of age predict earlier thelarche: evidence from girls of the growth and obesity Chilean cohort

CREB Binding Protein (CBP) Activation Is Required for Luteinizing Hormone Beta Expression and Normal Fertility in Mice

Cellular distribution of Egr1 transcription in the male rat pituitary gland

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