Rescue of Obesity-Induced Infertility in Female Mice due to a Pituitary-Specific Knockout of the Insulin Receptor

Wu, Sheng; DiVall, Sara A.; Messmer, Marcus; Kahn, C. Ronald; Miller, Ryan S.; Radovick, Sally; Wondisford, Fredric E.; Wolfe, Andrew

doi:10.1016/j.cmet.2010.06.010

Cited by 143 publications

(163 citation statements)

References 41 publications

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“…At 7 weeks on HFD, when LR Δα females achieved similar body weight to α fl controls on regular chow diet (Supplemental Figure 5C), estrous cycles were monitored for another 7 weeks. The increase in body weight did not restore normal cyclicity in LR Δα females, but it induced longer estrous cycles in control α fl mice ( Figure 4H), as demonstrated previously in wild-type mice (32).…”

Section: -L)supporting

confidence: 61%

PI3Kα inactivation in leptin receptor cells increases leptin sensitivity but disrupts growth and reproduction

García-Galiano¹,

Borges²,

Donato³

et al. 2017

JCI Insight

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Section: -L)supporting

confidence: 61%

PI3Kα inactivation in leptin receptor cells increases leptin sensitivity but disrupts growth and reproduction

García-Galiano¹,

Borges²,

Donato³

et al. 2017

JCI Insight

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“…a, b Means with different letters are signifi cantly different, P < 0.05. ( 39,40 ). The hyperinsulinemia might disturb the release of sex steroids, leading to an abnormal follicular development ( 41 ).…”

Section: Gc-induced Decrease In Laying Performance Resulting From Thementioning

confidence: 99%

Corticosterone regulation of ovarian follicular development is dependent on the energy status of laying hens

Wang¹,

Li²,

Song³

et al. 2013

Journal of Lipid Research

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This article is available online at http://www.jlr.org secretion of gonadotropin-releasing hormone (GnRH) from the hypothalamus stimulates the release of the pituitary gonadotropins, luteinizing hormone (LH), and folliclestimulating hormone (FSH), which in turn activate gonadal development and release of sex steroids, including estradiol (E2) and testosterone. Stress is a common problem disrupting breeding in either wild birds or domestic chickens ( 1 ). Glucocorticoids (GC), as the fi nal effectors of the hypothalamic-pituitary-adrenal axis, participate in the control of whole body homeostasis and the arousal of stress responses. GCs transmit information about environmental conditions to the HPG axis, which ultimately infl uences the timing of breeding.Female kittiwakes with low baseline LH levels and elevated levels of baseline corticosterone (CORT), the main form of GCs in avians, were more likely to skip breeding ( 2 ). An experimental reduction of CORT release during the prelaying period was associated with an advancement of egg laying in female kittiwakes ( 3 ). In domestic chickens, an acute infusion of CORT resulted in a pause in laying and a severely reduced ovarian weight ( 4 ). Chronic and repeated exposure to CORT during the rearing phrase suppressed reproductive performance, resulting in a delay of fi rst egg laid and a reduction of egg production ( 5 ).In avians, the development of ovarian follicles is accompanied by the deposition of a large amount of yolk. During a laying cycle, follicular development is matched with a supply of yolk precursors. Triacylglycerols (TG), the main

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“…Excess insulin signaling may directly impact gonadotroph function as well. In a previous study, we showed that obese, hyperinsulinemic mice have elevated LH levels and female infertility that can be corrected with selective loss of insulin signaling in the gonadotroph (2). It remains to be determined, however, if insulin is able to activate Lhb expression in the gonadotroph via CBP phosphorylation.…”

Section: Discussionmentioning

confidence: 99%

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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Rescue of Obesity-Induced Infertility in Female Mice due to a Pituitary-Specific Knockout of the Insulin Receptor

Cited by 143 publications

References 41 publications

PI3Kα inactivation in leptin receptor cells increases leptin sensitivity but disrupts growth and reproduction

PI3Kα inactivation in leptin receptor cells increases leptin sensitivity but disrupts growth and reproduction

Corticosterone regulation of ovarian follicular development is dependent on the energy status of laying hens

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

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