Gonadotropin-Releasing Hormone Secretion from Hypothalamic Neurons: Stimulation by Insulin and Potentiation by Leptin

Burcelin, Rémy; Thorens, Bernard; Glauser, M. P.; Gaillard, Rolf C.; Pralong, François P.

doi:10.1210/en.2003-0457

Cited by 150 publications

(111 citation statements)

References 59 publications

(73 reference statements)

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“…In vitro, low concentrations of insulin that do not activate the IGF-1R have been shown to increase GnRH gene expression (14) in GnRH-secreting immortalized cell lines. Insulin also increases GnRH pulsatile secretion (16), suggesting that insulin pathways can be activated in the GnRH neuron. Although the dose of insulin used to achieve this effect may cause activation of the IGF-1R, IGF-1 infusion did not cause GnRH secretion in the protocol used.…”

Section: Discussionmentioning

confidence: 99%

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Divergent roles of growth factors in the GnRH regulation of puberty in mice

et al. 2010

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Pubertal onset, initiated by pulsatile gonadotropin-releasing hormone (GnRH), only occurs in a favorable, anabolic hormonal milieu. Anabolic factors that may signal nutritional status to the hypothalamus include the growth factors insulin and IGF-1. It is unclear which hypothalamic neuronal subpopulation these factors affect to ultimately regulate GnRH neuron function in puberty and reproduction. We examined the direct role of the GnRH neuron in growth factor regulation of reproduction using the Cre/lox system. Mice with the IR or IGF-1R deleted specifically in GnRH neurons were generated. Male and female mice with the IR deleted in GnRH neurons displayed normal pubertal timing and fertility, but male and female mice with the IGF-1R deleted in GnRH neurons experienced delayed pubertal development with normal fertility. With IGF-1 administration, puberty was advanced in control females, but not in females with the IGF-1R deleted in GnRH neurons, in control males, or in knockout males. These mice exhibited developmental differences in GnRH neuronal morphology but normal number and distribution of neurons. These studies define the role of IGF-1R signaling in the coordination of somatic development with reproductive maturation and provide insight into the mechanisms regulating pubertal timing in anabolic states.

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Section: Discussionmentioning

confidence: 99%

“…GnRH neurons contain both insulin receptors (IRs) and IGF-1 receptors (IGF-1Rs) (11)(12)(13). In vitro stimulation of GnRH neurons with insulin increases GnRH expression and release (11,(14)(15)(16). IGF-1 stimulation also increases GnRH expression (17,18) and release (19) in vitro.…”

Section: Introductionmentioning

confidence: 99%

Divergent roles of growth factors in the GnRH regulation of puberty in mice

et al. 2010

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“…These mice have a phenotype very similar to that of mice lacking a functional leptin receptor with hyperphagic obesity and central hypogonadism secondary to functional GnRH deficiency. Using rat primary hypothalamic neurons in cell culture, Burcelin et al could demonstrate that insulin stimulates in vitro both the expression and the secretion of GnRH (Burcelin et al, 2003). Both insulin receptor mRNA and protein are expressed in a clonal cell line expressing GnRH (Salvi et al, 2006).…”

Section: Peripubertal Food Restrictionmentioning

confidence: 99%

Developmental variations in environmental influences including endocrine disruptors on pubertal timing and neuroendocrine control: Revision of human observations and mechanistic insight from rodents

Parent

Franssen

Fudvoye

et al. 2015

Frontiers in Neuroendocrinology

160

140

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Puberty presents remarkable individual differences in timing reaching over 5 years in humans. We put emphasis on the two edges of the age distribution of pubertal signs in humans and point to an extended distribution towards earliness for initial pubertal stages and towards lateness for final pubertal stages. Such distortion of distribution is a recent phenomenon. This suggests changing environmental influences including the possible role of nutrition, stress and endocrine disruptors. Our ability to assess neuroendocrine effects and mechanisms is very limited in humans. Using the rodent as a model, we examine the impact of environmental factors on the individual variations in pubertal timing and the possible underlying mechanisms. The capacity of environmental factors to shape functioning of the neuroendocrine system is thought to be maximal during fetal and early postnatal life and possibly less important when approaching the time of onset of puberty.

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“…However, despite initial reports showing expression of LepRs in immortalized GnRH cell lines, it is now recognized that GnRH neurons do not physiologically express LepRs (14,38,49). Instead, leptin is believed to act indirectly via interneurons impinging on GnRH-secreting cells in the hypothalamus (24,90), although the identity of such interneurons is unclear.…”

Section: Circulating Leptin and Insulin Affect Fertilitymentioning

confidence: 99%

Hypothalamic pathways linking energy balance and reproduction

Hill

Elmquist²,

Elias

2008

American Journal of Physiology-Endocrinology and Metabolism

302

218

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During periods of metabolic stress, animals must channel energy toward survival and away from processes such as reproduction. The reproductive axis, therefore, has the capacity to respond to changing levels of metabolic cues. The cellular and molecular mechanisms that link energy balance and reproduction, as well as the brain sites mediating this function, are still not well understood. This review focuses on the best characterized of the adiposity signals: leptin and insulin. We examine their reproductive role acting on the classic metabolic pathways of the arcuate nucleus, NPY/AgRP and POMC/CART neurons, and the newly identified kisspeptin network. In addition, other hypothalamic nuclei that may play a role in linking metabolic state and reproductive function are discussed. The nature of the interplay between these elements of the metabolic and reproductive systems presents a fascinating puzzle, whose pieces are just beginning to fall into place.gonadotropin-releasing hormone; leptin; insulin; kisspeptin SINCE ANIMALS UNDER METABOLIC STRESS must invest energy in survival first and reproduction second, the reproductive axis has the capacity to respond to changes in caloric status. Indeed, every level of the reproductive axis, the hypothalamus, pituitary gland, and gonad, has the capacity to respond to metabolic cues. In humans, anorexia, cachexia, and excessive exercise can all shut down reproductive cyclicity and the secretion of gonadal steroids that are essential for the health of many organs and tissues (28,57). On the opposite end of the spectrum, obesity and diabetes can also negatively affect fertility (74,92). The mechanisms regulating these processes are not well understood, but recent work has begun to yield new insights.While long recognized, the exact nature of the relationship between energy stores and fertility has been somewhat controversial. Work in rodent models (55) and human subjects (40, 41) gave rise to the idea that a female's fat reserves must exceed a critical threshold for ovulation to occur. However, it has now become clear that the body allocates energy based on current energy balance as opposed to the absolute amount of stored adipose tissue. Ovulation is suppressed when a mammal is in negative energy balance whether that state is caused by inadequate food intake, excessive locomotor activity, or heavy thermoregulatory costs. In the mouse, ovulation occurs whenever extant energetic conditions permit, unless the process is blocked by nonmetabolic stress, social cues, or a predictive seasonal cue such as photoperiod. Mice in the wild often continue to ovulate and become pregnant during seasons of famine despite lacking the energy reserves to carry a litter to term (12). In the human, menstrual irregularities, amenorrhea, and infertility can result from inadequate food intake to compensate for energy demands; for instance, when a severe athletic training schedule is relaxed, luteinizing hormone (LH) pulses and menstrual cycles resume without a significant increase in body fat content (2...

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Gonadotropin-Releasing Hormone Secretion from Hypothalamic Neurons: Stimulation by Insulin and Potentiation by Leptin

Cited by 150 publications

References 59 publications

Divergent roles of growth factors in the GnRH regulation of puberty in mice

Divergent roles of growth factors in the GnRH regulation of puberty in mice

Developmental variations in environmental influences including endocrine disruptors on pubertal timing and neuroendocrine control: Revision of human observations and mechanistic insight from rodents

Hypothalamic pathways linking energy balance and reproduction

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