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See detailNeurochemical control of rapid stress-induced changes in brain aromatase activity
Dickens, Molly; Cornil, Charlotte ULg; Balthazart, Jacques ULg

in Journal of Neuroendocrinology (2013), 25(4), 329-39

In the male brain, the medial preoptic nucleus (POM) is known to be a critical relay for the activation of sexual behaviour, with the aromatisation of testosterone into 17b-oestradiol (E2) playing a key ... [more ▼]

In the male brain, the medial preoptic nucleus (POM) is known to be a critical relay for the activation of sexual behaviour, with the aromatisation of testosterone into 17b-oestradiol (E2) playing a key role. Acute stress has been shown to differentially modulate the aromatase enzyme in this and other brain nuclei in a sex-specific manner. In POM specifically, stress induces increases in aromatase activity (AA) that are both rapid and reversible. How the physiological processes initiated during an acute stress response mediate sex- and nuclei- specific changes in AA and which stress response hormones are involved remains to be determined. By examining the relative effects of corticosterone (CORT), arginine vasotocin (AVT, the avian homologue to arginine vasopressin) and corticotrophin-releasing factor (CRF), the present study aimed to define the hormone profile regulating stress-induced increases in AA in the POM. We found that CORT, AVT and CRF all appear to play some role in these changes in the male brain. In addition, these effects occur in a targeted manner, such that modulation of the enzyme by these hormones only occurs in the POM rather than in all aromatase-expressing nuclei. Similarly, in the female brain, the experimental effects were restricted to the POM but only CRF was capable of inducing the stress-like increases in AA. These data further demonstrate the high degree of specificity (nuclei-, sex- and hormone-specific effects) in this system, highlighting the complexity of the stress–aromatase link and suggesting modes through which the nongenomic modulation of this enzyme can result in targeted, rapid changes in local oestrogen concentrations. [less ▲]

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See detailRapid control of reproductive behaviour by locally synthesised oestrogens: focus on aromatase.
Cornil, Charlotte ULg; Seredynski, Aurore ULg; de Bournonville, Catherine ULg et al

in Journal of Neuroendocrinology (2013), 25(11), 1070-8

Oestrogens activate nucleus- and membrane-initiated signalling. Nucleus-initiated events control a wide array of physiological and behavioural responses. These effects generally take place within ... [more ▼]

Oestrogens activate nucleus- and membrane-initiated signalling. Nucleus-initiated events control a wide array of physiological and behavioural responses. These effects generally take place within relatively long periods of time (several hours to days). By contrast, membrane-initiated signalling affects a multitude of cellular functions in a much shorter timeframe (seconds to minutes). However, much less is known about their functional significance. Furthermore, the origin of the oestrogens able to trigger these acute effects is rarely examined. Finally, these two distinct types of oestrogenic actions have often been studied independently such that we do not exactly know how they cooperate to control the same response. The present review presents a synthesis of recent work carried out in our laboratory that aimed to address these issues in the context of the study of male sexual behaviour in Japanese quail, which is a considered as a suitable species for tackling these issues. The first section presents data indicating that 17b-oestradiol, or its membrane impermeable analogues, acutely enhances measures of male sexual motivation but does not affect copulatory behaviour. These effects depend on the activation of membrane-initiated events and local oestrogen production. The second part of this review discusses the regulation of brain oestrogen synthesis through post-translational modifications of the enzyme aromatase. Initially discovered in vitro, these rapid and reversible enzymatic modulations occur in vivo following variations in the social and environment context and therefore provide a mechanism of acute regulation of local oestrogen provision with a spatial and time resolution compatible with the rapid effects observed on male sexual behaviour. Finally, we discuss how these distinct modes of oestrogenic action (membrane- versus nucleus-initiated) acting in different time frames (short- versus long-term) interact to control different components (motivation versus performance) of the same behavioural response and improve reproductive fitness. [less ▲]

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See detailAromatase knockout mice show normal steroid-induced activation of gonadotrophin-releasing hormone neurones and luteinising hormone surges with a reduced population of kisspeptin neurones in the rostral hypothalamus.
Szymanski, L.; Bakker, Julie ULg

in Journal of Neuroendocrinology (2012), 24(9), 1222-33

We recently reported that female aromatase knockout (ArKO) mice show deficits in sexual behaviour and a decreased population of kisspeptin-immunoreactive neurones in the rostral periventricular area of ... [more ▼]

We recently reported that female aromatase knockout (ArKO) mice show deficits in sexual behaviour and a decreased population of kisspeptin-immunoreactive neurones in the rostral periventricular area of the third ventricle (RP3V), resurrecting the question of whether oestradiol actively contributes to female-typical sexual differentiation. To further address this question, we assessed the capacity of ArKO mice to generate a steroid-induced luteinising hormone (LH) surge. Adult, gonadectomised wild-type (WT) and ArKO mice were given silastic oestradiol implants s.c. and, 1 week later, received s.c. injections of either oestradiol benzoate (EB) followed by progesterone, EB alone, or no additional steroids to activate gonadotrophin-releasing hormone (GnRH) neurones and generate an LH surge. Treatment with EB and progesterone induced significant Fos/GnRH double-labelling and, consequently, an LH surge in female WT and in ArKO mice of both sexes but not in male WT mice. ArKO mice of both sexes had fewer cells expressing Kiss-1 mRNA in the RP3V compared to female WT mice but had more Kiss-1 mRNA-expressing cells compared to WT males, reflecting an incomplete sexual differentiation of this system. To determine the number of cells expressing kisspeptin, the same experimental design was repeated in Experiment 2 with the addition of groups of WT and ArKO mice that were given EB + progesterone and sacrificed 2 h before the expected LH surge. No differences were observed in the number of kisspeptin-immunoreactive cells 2 h before and at the time of the LH surge. The finding that ArKO mice of both sexes have a competent LH surge system suggests that oestradiol has predominantly defeminising actions on the GnRH/LH surge system in males and that the steroid-induced LH surge can occur in females even with a greatly reduced population of kisspeptin neurones in the RP3V. [less ▲]

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See detailKisspeptin-immunoreactivity changes in a sex- and hypothalamic-region-specific manner across rat postnatal development.
Desroziers, Elodie ULg; Mikkelsen, J. D.; Duittoz, A. et al

in Journal of Neuroendocrinology (2012), 24(8), 1154-65

Kisspeptins are potent secretagogues of gonadotrophin-releasing hormone, playing a key role in puberty onset. These peptides are produced by distinct neuronal populations of the hypothalamus located in ... [more ▼]

Kisspeptins are potent secretagogues of gonadotrophin-releasing hormone, playing a key role in puberty onset. These peptides are produced by distinct neuronal populations of the hypothalamus located in the rostral periventricular area of the third ventricle (RP3V) and arcuate nucleus (ARC). The present immunohistochemical study aimed to determine the spatiotemporal onset of kisspeptin-immunoreactivity (-IR) in the neonatal hypothalamus of male and female rats and to evaluate changes in kisspeptin-IR around puberty. Kisspeptin-IR cells and fibres could be detected from the day of birth in the ARC of both males and females. At this stage, only females displayed some kisspeptin-IR fibres in the RP3V. From postnatal day 7 to adulthood, males displayed lower levels of kisspeptin-IR than females in both regions. During infancy, kisspeptin-IR fibre density in the female decreased in the ARC, whereas it increased in the RP3V. A sex-independent decline in RP3V kisspeptin-IR fibre density was observed in the juvenile, followed by a peripubertal increase in RP3V and ARC kisspeptin-IR. These peripubertal increases in kisspeptin-IR occurred at different timings dependent on sex and region. In females specifically, the increase in kisspeptin-IR fibre density occurred first in the ARC and later in the RP3V under constant levels of circulating oestradiol. In conclusion, the present study highlights the expression of hypothalamic kisspeptins soon after birth, as well as the neonatal establishment of a strong and persisting sex difference in ARC kisspeptin-IR in rats. Moreover, a female-specific desynchronisation of the ARC and RP3V was observed with respect to the increase in kisspeptin-IR fibre density around puberty, which was not related to peripubertal variations in circulating oestradiol. [less ▲]

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See detailBrain aromatase and circulating corticosterone are rapidly regulated by combined acute stress and sexual interaction in a sex specific manner.
Dickens, Molly J.; Balthazart, Jacques ULg; Cornil, Charlotte ULg

in Journal of Neuroendocrinology (2012), 24(10), 1322-34

Neural production of 17β-oestradiol via aromatisation of testosterone may play a critical role in rapid, non-genomic regulation of physiological and behavioural processes. In brain nuclei implicated in ... [more ▼]

Neural production of 17β-oestradiol via aromatisation of testosterone may play a critical role in rapid, non-genomic regulation of physiological and behavioural processes. In brain nuclei implicated in the control of sexual behaviour, sexual or stressfull stimuli induce respectively a rapid inhibition or increase in preoptic aromatase activity (AA). Here, we tested quail that were either non-stressed or acutely stressed (15 min restraint) immediately prior to sexual interaction (5 min) with stressed or non-stressed partners. We measured nuclei-specific AA changes, corresponding behavioural output, fertilisation rates and corticosterone (CORT) concentrations. In males, sexual interaction rapidly reversed stress-induced increases of AA in the medial preoptic nucleus (POM). This time scale (<5min) highlights the dynamic potential of the aromatase system to integrate input from stimuli that drive AA in opposing directions. Moreover, acute stress had minimal effects on male behaviour suggesting that the input from the sexual stimuli on POM AA may actively preserve sexual behaviour despite stress exposure. We also found distinct sex differences in contextual physiological responses: while males did not show any effect of partner status, females responded to both their stress exposure and the male partner's stress exposure at the level of circulating CORT and AA. In addition, fertilisation rates and female CORT correlated with the male partner's exhibition of sexually aggressive behaviour suggesting that female perception of the male can affect their physiology as much as direct stress. Overall, male reproduction appears relatively simple - sexual stimuli, irrespective of stress, drives major neural changes including rapid reversal of stress-induced changes of AA. In contrast, female reproduction appears more nuanced and context specific, with subjects responding physiologically and behaviourally to stress, the male partner's stress exposure, and female-directed male behaviour. [less ▲]

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See detailMilestones on Steroids and the Nervous System: 10 Years of Basic and Translational Research.
Panzica, G. C.; Balthazart, Jacques ULg; Frye, C. A. et al

in Journal of Neuroendocrinology (2012), 24(1), 1-15

During the last 10 years, the conference on 'Steroids and Nervous System' held in Torino (Italy) has been an important international point of discussion for scientists involved in this exciting and ... [more ▼]

During the last 10 years, the conference on 'Steroids and Nervous System' held in Torino (Italy) has been an important international point of discussion for scientists involved in this exciting and expanding research field. The present review aims to recapitulate the main topics that have been presented through the various meetings. Two broad areas have been explored: the impact of gonadal hormones on brain circuits and behaviour, as well as the mechanism of action of neuroactive steroids. Relationships among steroids, brain and behaviour, the sexual differentiation of the brain and the impact of gonadal hormones, the interactions of exogenous steroidal molecules (endocrine disrupters) with neural circuits and behaviour, and how gonadal steroids modulate the behaviour of gonadotrophin-releasing hormone neurones, have been the topics of several lectures and symposia during this series of meetings. At the same time, many contributions have been dedicated to the biosynthetic pathways, the physiopathological relevance of neurosteroids, the demonstration of the cellular localisation of different enzymes involved in neurosteroidogenesis, the mechanisms by which steroids may exert some of their effects, both the classical and nonclassical actions of different steroids, the role of neuroactive steroids on neurodegeneration, neuroprotection, and the response of the neural tissue to injury. In these 10 years, this field has significantly advanced and neuroactive steroids have emerged as new potential therapeutic tools to counteract neurodegenerative events. [less ▲]

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See detailEmbryonic development of kisspeptin neurones in rat.
Desroziers, Elodie ULg; Droguerre, M.; Bentsen, A. H. et al

in Journal of Neuroendocrinology (2012), 24(10), 1284-95

Kisspeptins, encoded by the Kiss1 gene, play a key role in the regulation of reproductive function, although very little is known about the ontogenesis of this system. The present study aimed to determine ... [more ▼]

Kisspeptins, encoded by the Kiss1 gene, play a key role in the regulation of reproductive function, although very little is known about the ontogenesis of this system. The present study aimed to determine the period of arcuate nucleus (ARC) kisspeptin cell birth and the embryonic stage and neuroanatomical sites of onset of kisspeptin immunoreactivity. Bromodeoxyuridine (BrdU) was administered to female rats at various gestational stages and double immunohistochemistry against kisspeptin and BrdU was performed on brain sections from their offspring. The period of neurogenesis of ARC kisspeptin neurones begun between embryonic day (E) 12.5 and E13.5, reached its peak at E15.5 and was not completely over at E17.5. Kiss1 mRNA was detected in mediobasal hypothalamic punches of embryos aged E14.5, E16.5, E18.5 and E22.5 by real-time reverse transcriptase-polymerase chain reaction. Accordingly, kisspeptin-immunoreactive (-IR) cells were consistently detected in the embryonic ARC from E14.5 and their number increased until E18.5 to reach approximately half the level observed in adults. Between E18.5 and E22.5, the number of kisspeptin-IR cells and hypothalamic Kiss1 expression significantly decreased, regardless of sex, and this decrease persisted until birth. Taken together, these results demonstrate that rat ARC kisspeptin neurones are born locally during an extended embryonic period and are able to synthesise kisspeptins rapidly after their birth, consistent with the hypothesis of a role during embryonic activation of the hypothalamic-hypophyseal-gonadal axis. A sex-independent decrease of kisspeptin-IR cell numbers was observed during the perinatal period, suggestive of important regulations of kisspeptin neurones around birth. [less ▲]

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See detailRapid effects of aggressive interactions on aromatase activity and oestradiol in discrete brain regions of wild male white-crowned sparrows
Charlier, Thierry ULg; Newman, Amy EM; Heimovics, Sarah A et al

in Journal of Neuroendocrinology (2011), 23

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See detailSex differences in the rapid control of aromatase activity in the quail preoptic area.
Konkle, A. T. M.; Balthazart, Jacques ULg

in Journal of Neuroendocrinology (2011), 23(5), 424-34

Adult male quail show high levels of aromatase activity in the preoptic area-hypothalamus (POA-HYP), which parallels the high number of aromatase-immunoreactive cells and elevated mRNA concentrations ... [more ▼]

Adult male quail show high levels of aromatase activity in the preoptic area-hypothalamus (POA-HYP), which parallels the high number of aromatase-immunoreactive cells and elevated mRNA concentrations detected in this brain region by in situ hybridisation. Interestingly, females display considerably lower aromatase activity than males but have almost equal numbers of aromatase-immunoreactive cells and express similar levels of aromatase mRNA. Aromatase activity in the male POA-HYP can be rapidly regulated by calcium-dependent phosphorylations, in the absence of changes in enzyme concentration. In the present study, we investigated whether aromatase activity is differentially regulated by phosphorylations in males and females. A linear increase in accumulation of aromatisation products was observed in both sexes as a function of time but the rate of conversion was slower in females. Saturation analysis confirmed the lower maximum velocities (V(max) ) in females but indicated a similar affinity (K(m) ) in both sexes. Aromatase activity in females reacted differentially to manipulations of intracellular calcium. In particular, chelating calcium with ethylene glycol tetraacetic acid (EGTA) resulted in a larger increase of enzymatic activity in males than in females, especially in the presence of ATP. A differential reaction to kinase inhibitors was also observed between males and females (i.e. a larger increase in aromatase activity in females than in males after exposure to specific inhibitors). These findings suggest that the nature of aromatase is conserved between the sexes, although the control of its activity by calcium appears to be different. Additional characterizations of intracellular calcium in both sexes would therefore be appropriate to better understand aromatase regulation. [less ▲]

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See detailSex differences in adolescent depression: do sex hormones determine vulnerability?
Naninck, E. F. G.; Lucassen, P. J.; Bakker, Julie ULg

in Journal of Neuroendocrinology (2011), 23(5), 383-92

Depression is one of the most common, costly and severe psychopathologies worldwide. Its incidence, however, differs significantly between the sexes, and depression rates in women are twice those of men ... [more ▼]

Depression is one of the most common, costly and severe psychopathologies worldwide. Its incidence, however, differs significantly between the sexes, and depression rates in women are twice those of men. Interestingly, this sex difference emerges during adolescence. Although the adolescent period is characterised by major physical and behavioural transformations, it is unclear why the incidence of depression increases so dramatically in girls during this otherwise generally healthy developmental period. Although psychological and environmental factors are also involved, we discuss the neuroendocrinological factors determining adolescent vulnerability to depression. In particular, we address the role of sex steroids in mood regulation, hypothalamic-pituitary-adrenal axis maturation and sexual differentiation of the brain, with a focus on hippocampal plasticity. [less ▲]

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See detailMapping of kisspeptin fibres in the brain of the pro-oestrous rat.
Desroziers, Elodie ULg; Mikkelsen, J.; Simonneaux, V. et al

in Journal of Neuroendocrinology (2010), 22(10), 1101-12

Kisspeptins are a family of small peptides that play a key role in the neuroendocrine regulation of the reproductive function through neural pathways that have not yet been completely identified. The ... [more ▼]

Kisspeptins are a family of small peptides that play a key role in the neuroendocrine regulation of the reproductive function through neural pathways that have not yet been completely identified. The present study aimed to investigate the distribution of kisspeptin neurone fibres in the female rat brain by comparing precisely the immunoreactive pattern obtained with two antibodies: one specifically directed against kisspeptin-52 (Kp-52), the longest isoform, and the other directed against kisspeptin-10 (Kp-10), whose sequence is common to all putative mature isoforms. With both antibodies, immunoreactive cell bodies were exclusively observed in the arcuate nucleus, and immunoreactive fibres were confined to the septo-preoptico-hypothalamic continuum of the brain. Fibres were observed in the preoptic area, the diagonal band of Broca, the septohypothalamic area, the anteroventral periventricular, suprachiasmatic, supraoptic, paraventricular and periventricular nuclei, the dorsal border of the ventromedian nucleus, the dorsomedial and arcuate nuclei, and the median eminence. In the latter structure, varicose fibres were mainly distributed in the internal layer and were detected to a lesser extent throughout the external layer, including around the deeper part of the infundibular recess. Most regions of immunoreactive cells and fibres matched perfectly for the two antibodies. However, fibres in the dorsolateral septum, anterior fornix, accumbens nucleus and the lateral bed nucleus of the stria terminalis were only recognised by antibody anti-Kp-10, suggesting that anti-Kp-10 may recognise a wider range of kisspeptin isoforms than anti-Kp-52 or cross-react with molecules other than kisspeptin in rat tissue. Overall, these results illustrate the variety of projection sites of kisspeptin neurones in the rat and suggest that these peptides play a role in different functions. [less ▲]

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See detailSex differences in the expression of sex steroid receptor mRNA in the quail brain.
Voigt, C.; Ball, G. F.; Balthazart, Jacques ULg

in Journal of Neuroendocrinology (2009)

Abstract In Japanese quail, males will readily exhibit the full sequence of male-typical sexual behaviors but females never show this response even after ovariectomy and treatment with male-typical ... [more ▼]

Abstract In Japanese quail, males will readily exhibit the full sequence of male-typical sexual behaviors but females never show this response even after ovariectomy and treatment with male-typical concentrations of exogenous testosterone. Testosterone aromatization plays a key-limiting role in the activation of this behavior but the higher aromatase activity in the brain of males compared to females is not sufficient to explain the behavioral sex difference. The cellular and molecular bases of this prominent sex difference in the functional consequences of testosterone have not been identified so far. We hypothesized that the differential expression of sex steroid receptors in specific brain areas could mediate this behavioral sex difference and therefore quantified by radioactive in situ hybridization histochemistry the expression of the mRNA coding for the androgen receptor (AR) and the estrogen receptors (ER) of the alpha and beta sub-types. All three receptors were expressed in an anatomically discrete manner in various nuclei of the hypothalamus and limbic system and, at usually lower densities, in a few other brain areas. In both sexes, the intensity of the hybridization signal for all steroid receptors was highest in the medial preoptic nucleus (POM), a major site of testosterone action related to the activation of male sexual behavior. Although no sex difference in the optical density of the AR hybridization signal could be found in POM, the area covered by AR mRNA was significantly larger in males than in females, indicating a higher overall degree of AR expression in this region in males. In contrast, females tended to have significantly higher levels of AR expression than males in the lateral septum. ERalpha was more densely expressed in females than males throughout the medial preoptic and hypothalamic areas (including the POM and the medio-basal hypothalamus [MBH)], an area implicated in the control of female receptivity) and in the mesencephalic nucleus intercollicularis. ERbeta was more densely expressed in the medio-basal hypothalamus of females but a difference in the reverse direction (males>females) was observed in the nucleus taeniae of the amygdala. These data suggest that a differential expression of steroid receptors in specific brain areas could mediate at least certain aspects of the sex differences in behavioral responses to testosterone but they do not appear to be sufficient to explain the complete lack of activation by testosterone of male-typical copulatory behavior in females. [less ▲]

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See detailRapid regulation of brain oestrogen synthesis: the behavioural roles of oestrogens and their fates.
Cornil, Charlotte ULg

in Journal of Neuroendocrinology (2009), 21(3), 217-26

Besides their well-known genomic actions, oestrogens also exert effects through the activation of receptors associated with the plasma membrane that are too fast to be mediated by transcriptional ... [more ▼]

Besides their well-known genomic actions, oestrogens also exert effects through the activation of receptors associated with the plasma membrane that are too fast to be mediated by transcriptional activation (nongenomic effects). Although the existence of such rapid effects of oestrogens and their involvement in various biological processes are not in doubt, questions remain about the mechanisms responsible for the rapid modulations of oestrogen production that are required to sustain their nongenomic effects. Recent data indicate that the conversion of androgens into oestrogens in the brain by the enzyme aromatase can be rapidly modulated by conformational changes of the enzyme, thus providing a possible mechanism for rapid controls of the effects of oestrogens on male sexual behaviour. In this review, the data supporting this hypothesis are described. Subsequently, a few unanswered questions are discussed, such as the mechanism of oestrogen inactivation or the potential cellular sites of action of brain-derived oestrogens on male sexual behaviour. [less ▲]

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See detailCB1 receptor blockade and its impact on cardiometabolic risk factors: overview of the RIO programme with rimonabant.
Scheen, André ULg

in Journal of Neuroendocrinology (2008), 20 Suppl 1

Rimonabant, the first selective CB(1) receptor antagonist in clinical use, has been extensively investigated in the Rimonabant in Obesity (RIO) programme, comprising four 1-2 year placebo-controlled ... [more ▼]

Rimonabant, the first selective CB(1) receptor antagonist in clinical use, has been extensively investigated in the Rimonabant in Obesity (RIO) programme, comprising four 1-2 year placebo-controlled randomised clinical trials recruiting more than 6600 overweight/obese patients with or without co-morbidities. Rimonabant 20 mg daily consistently reduced body weight, waist circumference, triglycerides, blood pressure, insulin resistance and C-reactive protein levels, and increased HDL cholesterol concentrations in both non-diabetic and type-2 diabetic overweight/obese patients. Adiponectin levels were increased, an effect that correlated with HDL cholesterol augmentation, while small dense LDL cholesterol levels were decreased in patients receiving rimonabant 20 mg compared with those receiving placebo in RIO Lipids. Furthermore, in RIO Diabetes, a 0.7% reduction in glycated haemoglobin (HbA1c) levels was observed in metformin- or sulphonylurea-treated patients with type-2 diabetes, an effect recently confirmed in the 6-month SERENADE (Study Evaluating Rimonabant Efficacy in drug-NAive DiabEtic patients) trial in drug-naive diabetic patients. Almost half of metabolic changes occurred beyond weight loss, in agreement with direct peripheral effects. The positive effects observed after 1 year were maintained after 2 years. Rimonabant was generally well-tolerated, but with a slightly higher incidence of depressed mood disorders, anxiety, nausea and dizziness compared with placebo. In clinical practice, rimonabant has to be prescribed to the right patient, i.e. overweight/obese subjects with cardiometabolic risk factors and with no major depressive illness and/or ongoing antidepressive treatment, in order to both maximise efficacy and minimise safety issues. New trials are supposed to confirm the potential role of rimonabant in patients with abdominal adiposity, atherogenic dyslipidaemia and/or type-2 diabetes, i.e. at high cardiometabolic risk. [less ▲]

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See detailExposure to oestrogen prenatally does not interfere with the normal female-typical development of odour preferences
Bakker, Julie ULg; De Mees, C.; Szpirer, J. et al

in Journal of Neuroendocrinology (2007), 19(5), 329-334

The neural mechanisms controlling mate recognition and heterosexual partner preference are sexually differentiated by perinatal actions of sex steroid hormones. We previously showed that the most ... [more ▼]

The neural mechanisms controlling mate recognition and heterosexual partner preference are sexually differentiated by perinatal actions of sex steroid hormones. We previously showed that the most important action of oestrogen during prenatal development is to defeminise and, to some extent, masculinise brain and behaviour in mice. Female mice deficient in alpha-foetoprotein (AFP) due to a targeted mutation in the Afp gene (AFP-KO) do not show any female sexual behaviour when paired with an active male because they lack the protective action of AFP against maternal oestrogens. In the present study, we investigated whether odour preferences, another sexually differentiated trait in mice, are also defeminised and/or masculinised in AFP-KO females due to their prenatal exposure to oestrogens. AFP-KO females of two background strains (CD1 and C57Bl/6j) preferred to investigate male over female odours when given the choice between these two odour stimuli in a Y-maze, and thus remained very female-like in this regard. Thus, the absence of lordosis behaviour in these females cannot be explained by a reduced motivation of AFP-KO females to investigate male-derived odours. Furthermore, the presence of a strong male-directed odour preference in AFP-KO females suggests a postnatal contribution of oestrogens to the development of preferences to investigate opposite-sex odours. [less ▲]

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See detailEffects of in vivo and in vitro administration of ghrelin, leptin and neuropeptide mediators on pulsatile gonadotrophin-releasing hormone secretion from male rat hypothalamus before and after puberty
Lebrethon, Marie-Christine; Aganina, Anastasia; Fournier, Michael et al

in Journal of Neuroendocrinology (2007), 19(3), 181-188

The present study aimed to investigate the effects of leptin and ghrelin on pulsatile pulsatile gonadotrophin-releasing hormone (GnRH) secretion in vitro with emphasis on neuropeptide mediators and ... [more ▼]

The present study aimed to investigate the effects of leptin and ghrelin on pulsatile pulsatile gonadotrophin-releasing hormone (GnRH) secretion in vitro with emphasis on neuropeptide mediators and changes between prepuberty (15 days) and sexual maturity (50 days) in the male rat. When hypothalamic explants were studied 90 min after an intraperitoneal injection of leptin, ghrelin or agouti-related protein (AgRP) at 15 days, the GnRH interpulse interval (IPI) was significantly increased by ghrelin and AgRP and decreased by leptin. At 50 days, an increase in GnRH IPI was also caused by ghrelin and AgRP. When the peptides were directly incubated with the explants, the effects of leptin and AgRP in vitro were consistent with those seen after in vivo administration. By contrast, ghrelin resulted in a reduction of GnRH IPI and this was observed at 15 days only. To delineate the neuropeptide mediators of leptin and the effects of ghrelin in the hypothalamus, various hypothalamic neuropeptides and antagonists were used in vitro. At 15 days, the GnRH IPI was significantly decreased after incubation with cocaine and amphetamine-regulated transcript (CART), alpha-melanocyte-stimulating hormone, corticotrophin-releasing factor (CRF) and neuropeptide Y (NPY). The reduction of GnRH IPI caused by leptin was partially prevented by either an anti-CART antiserum or SHU 9119, a melanocortin MC3/MC4 receptor antagonist or a CRF receptor antagonist. The NPY-Y5 receptor antagonist did not influence the effects of leptin whereas that antagonist totally prevented the decrease in GnRH IPI caused by ghrelin. The ghrelin-induced reduction of GnRH IPI was partially prevented by SHU 9119. When used alone, SHU 9119 or a CRF-receptor antagonist resulted in increased GnRH IPI at 50 days while they had no effects at 15 days. The NPY-Y5 receptor antagonist resulted in increased GnRH IPI at 15 and 50 days. In conclusion, leptin and ghrelin show opposing effects on pulsatile GnRH secretion after administration in vivo whereas they both have stimulatory effects in vitro. Such effects involve consistently the anorectic peptides CART and CRF for leptin that are mainly active at 15 days. The melanocortigenic system appears to mediate the effects of both leptin and ghrelin. The effects of ghrelin also involve NPY receptors and operate effectively before and at sexual maturity. [less ▲]

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See detailA contactin-receptor-like protein tyrosine phosphatase beta complex mediates adhesive communication between astroglial cells and gonadotropin-releasing hormone neurons
Parent, Anne-Simone ULg; Mungenast, Alison; Lomniczi, Alejandro et al

in Journal of Neuroendocrinology (2007), 19

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