Insulin: Its role in the central control of reproduction

Śliwowska, Joanna H.; Fergani, Chrysanthi; Gawałek, Monika; Skowrońska, Bogda; Fichna, Piotr; Lehman, Michael N.

doi:10.1016/j.physbeh.2014.05.021

Cited by 80 publications

(62 citation statements)

References 178 publications

(182 reference statements)

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“…Drivers of GnRH1 include energy balance indicated by insulin. 27 Insulin increases IHD risk. 28 Insulin raises testosterone 29 30 providing a pathway from GnRH1 to IHD.…”

Section: Discussionmentioning

confidence: 99%

Reproduction and longevity A Mendelian randomization study of gonadotropin-releasing hormone and ischemic heart disease

Schooling

2018

Preprint

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BackgroundAccording to well-established evolutionary biology theory reproduction trades-off against longevity, implying that upregulating the reproductive axis might drive major diseases. We assessed whether the central driver of reproduction gonadotropin-releasing hormone 1 (GnRH1) had a causal effect on the leading cause of global morbidity and mortality, i.e. ischemic heart disease (IHD). As a contrast we similarly examined the role of GnRH2 because it is more a driver of female sexual behavior.MethodsWe applied strong (p-value <5×10−6) and independent genetic predictors of GnRH1 and GnRH2 to an extensively genotyped IHD case (n=76,014) - control (n=264,785) study using multiplicative random effects inverse variance weighted (IVW), weighted median, MR-Egger and MR-PRESSO estimates.ResultsGnRH1, predicted by 11 genetic variants, was positively associated with IHD (IVW odds ratio (OR) 1.04 per effect size, 95% confidence interval (CI) 1.01 to 1.08), but GnRH2, predicted by 15 genetic variants, was not (IVW OR 0.98, 95% CI 0.95 to 1.02).ConclusionsGnRH1 is a potential IHD genetic target. Apart from demonstrating a central tenet of evolutionary biology in humans, our study suggests that existing treatments and environmental factors targeting GnRH1, its drivers or consequences could be re-purposed to prevent and treat IHD. Given, the importance of reproduction to the human species, many such exposures likely exist.

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“…Drivers of GnRH1 include energy balance indicated by insulin. 27 Insulin increases IHD risk. 28 Insulin raises testosterone 29 30 providing a pathway from GnRH1 to IHD.…”

Section: Discussionmentioning

confidence: 99%

Reproduction and longevity A Mendelian randomization study of gonadotropin-releasing hormone and ischemic heart disease

Schooling

2018

Preprint

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“…In contrast, prenatal T-treatment decreases the percentage of KNDy neurons that colocalize the beta subunit of insulin receptor (IRβ) and co-administration of flutamide fails to prevent this change in female sheep, indicating that this alteration is programmed likely by estrogenic actions of T [57]. Because KNDy neurons are believed to mediate in part the stimulatory effects of insulin on GnRH and LH release [58, 59], alterations in IRβ expression in this cell population may contribute to defects in reproductive functions seen in this animal model.…”

Section: Neuroendocrine Disruptionsmentioning

confidence: 99%

Steroidogenic versus Metabolic Programming of Reproductive Neuroendocrine, Ovarian and Metabolic Dysfunctions

2015

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The susceptibility of the reproductive system to early exposure to steroid hormones has become a major concern in our modern societies. Human fetuses are at risk of abnormal programming via exposure to endocrine disrupting chemicals, inadvertent use of contraceptive pills during pregnancy, as well as from excess exposure to steroids due to disease states. Animal models provide an unparalleled resource to understand the developmental origin of diseases. In female sheep, prenatal exposure to testosterone excess results in an array of adult reproductive disorders that recapitulate those seen in women with polycystic ovary syndrome (PCOS), including disrupted neuroendocrine feedback mechanisms, increased pituitary sensitivity to gonadotropin-releasing hormone, luteinizing hormone excess, functional hyperandrogenism, and multifollicular ovarian morphology culminating in early reproductive failure. Prenatal testosterone treatment also leads to fetal growth retardation, insulin resistance, and hypertension. Mounting evidence suggests that developmental exposure to an improper steroidal/metabolic environment may mediate the programming of adult disorders in prenatal testosterone-treated females, and these defects are maintained or amplified by the postnatal sex steroid and metabolic milieu. This review addresses the steroidal and metabolic contributions to the development and maintenance of the PCOS phenotype in the prenatal testosterone-treated sheep model, including the effects of prenatal and postnatal treatment with an androgen antagonist or insulin sensitizer as potential strategies to prevent/ameliorate these dysfunctions. Insights obtained from these intervention strategies on the mechanisms underlying these defects are likely to have translational relevance to human PCOS.

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“…NKB acts as a positive regulator and DYN is a negative regulator in this neuronal circuit, whereas kisspeptin is considered as an output of the neuronal circuit because KNDy neurones do not express the kisspeptin receptor . Additionally, the ARC is a site for the integration of reproductive and metabolic signals and KNDy neurones are influenced by both a negative (undernutrition) and positive (overnutrition) energy balance . Our recent data indicate that type 2 diabetes (DM2), but not obesity, alters the number of kisspeptin‐immunoreactive (‐IR), NKB‐IR and DYN‐IR neurones in male rats .…”

Section: Introductionmentioning

confidence: 99%

High‐fat diet and type 2 diabetes induced disruption of the oestrous cycle and alteration of hormonal profiles, but did not affect subpopulations of KNDy neurones in female rats

Ziarniak

Kołodziejski

Pruszyńska‐Oszmałek

et al. 2018

J Neuroendocrinology

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Apart from the primary metabolic symptoms of obesity and/or diabetes, there are numerous secondary problems, including disruptions of the reproductive system. The KNDy neurones, which express kisspeptin, neurokinin B and dynorphin A and are located in the arcuate nucleus of the hypothalamus (ARC), are important regulators of reproduction. Their functions are highly influenced by metabolic and hormonal status. We have previously shown that, in male rats with experimentally‐induced diabetes type 2 (but not with high‐fat diet‐induced obesity), there are alterations in the number of these cells. In the present study, we hypothesised that a high‐fat diet (HFD) and/or diabetes type 2 (DM2) in female rats affect the oestrous cycle, hormonal profiles and the number of kisspeptin‐immunoreactive, neurokinin B‐immunoreactive and/or dynorphin A‐immunoreactive neurones in the ARC. Rats were assigned to one of three groups: a control group fed a regular chow diet, a high‐fat diet group (HFD) and a diabetic group (DM2), with both of the latter two groups receiving a high calorie diet (50% of energy from lard). The third group was additionally treated with streptozotocin to induce DM2. Their oestrous cycles was monitored and their metabolic and hormonal status were assessed. We found that HFD and DM2 female rats, despite having significant alterations in their metabolic and hormonal profiles, as well as disruptions of the oestrous cycle, showed no changes in the number of the kisspeptin‐immunoreactive, neurokinin B‐immunoreactive and/or dynorphin A‐immunoreactive neurones in the ARC. However, slight differences in the rostrocaudal distribution of these neurones among groups were reported. In conclusion, the data from the present study, together with our previously published results in males, indicate sex differences in the response of KNDy neurones to DM2 but not to HFD conditions.

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Insulin: Its role in the central control of reproduction

Cited by 80 publications

References 178 publications

Reproduction and longevity A Mendelian randomization study of gonadotropin-releasing hormone and ischemic heart disease

Reproduction and longevity A Mendelian randomization study of gonadotropin-releasing hormone and ischemic heart disease

Steroidogenic versus Metabolic Programming of Reproductive Neuroendocrine, Ovarian and Metabolic Dysfunctions

High‐fat diet and type 2 diabetes induced disruption of the oestrous cycle and alteration of hormonal profiles, but did not affect subpopulations of KNDy neurones in female rats

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