Leptin’s effect on puberty in mice is relayed by the ventral premammillary nucleus and does not require signaling in Kiss1 neurons. J Clin Invest

Department of Internal Medicine, Division of Hypothalamic Research, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9077, USA.
The Journal of clinical investigation (Impact Factor: 13.22). 01/2011; 121(1):355-68. DOI: 10.1172/JCI45106
Source: PubMed


Studies in humans and rodents indicate that a minimum amount of stored energy is required for normal pubertal development. The adipocyte-derived hormone leptin is a key metabolic signal to the neuroendocrine reproductive axis. Humans and mice lacking leptin or the leptin receptor (LepR) (ob/ob and db/db mice, respectively) are infertile and fail to enter puberty. Leptin administration to leptin-deficient subjects and ob/ob mice induces puberty and restores fertility, but the exact site or sites of leptin action are unclear. Here, we found that genetic deletion of LepR selectively from hypothalamic Kiss1 neurons in mice had no effect on puberty or fertility, indicating that direct leptin signaling in Kiss1 neurons is not required for these processes. However, bilateral lesions of the ventral premammillary nucleus (PMV) of ob/ob mice blunted the ability of exogenous leptin to induce sexual maturation. Moreover, unilateral reexpression of endogenous LepR in PMV neurons was sufficient to induce puberty and improve fertility in female LepR-null mice. This LepR reexpression also normalized the increased hypothalamic GnRH content characteristic of leptin-signaling deficiency. These data suggest that the PMV is a key site for leptin's permissive action at the onset of puberty and support the hypothesis that the multiple actions of leptin to control metabolism and reproduction are anatomically dissociated.

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Available from: Michael M Scott, Jan 13, 2014
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    • "In spite of the suggestive evidence summarized above, experimental data gathered in the last few years have questioned the hypothesis of a predominant or exclusive direct mode of action of leptin on Kiss1 neurons. Thus, elimination of LepR selectively from Kiss1 cells has been shown not to interfere with normal puberty onset and fertility [63]. As call of caution, this approach involved the congenital ablation of LepR from Kiss1-expressing cells; hence, it is possible that such manipulation might have induced compensatory changes that might mask the phenotypic impact of elimination of LepR in this neuronal population. "
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    ABSTRACT: As an essential function for perpetuation of species, reproduction, including puberty onset, is sensitive to the size of body energy stores and the metabolic state of the organism. Accordingly, impaired energy homeostasis, ranging from extreme leanness, such as in anorexia or cachexia, to morbid obesity has an impact on the timing of puberty and is often associated to fertility problems. The neuroendocrine basis for such phenomenon is the close connection between numerous metabolic hormones and nutritional cues with the various elements of the so-called hypothalamic-pituitary-gonadal (HPG) axis. Yet, despite previous fragmentary knowledge, it was only the discovery of the adipose-hormone, leptin, in 1994 what revolutionized our understanding on how metabolic and reproductive systems closely interplay and allowed the definition of the neurohormonal causes of perturbations of puberty and fertility in conditions of impaired body energy homeostasis. In this article, we aim to provide a synoptic view of the mechanisms whereby leptin engages in the regulation of different elements of the HPG axis, with special attention to its effects and mechanisms of action on the different elements of the reproductive brain and its proven direct effects in the gonads. In addition, we will summarize the state-of-the-art regarding the putative roles of leptin during gestation, including its potential function as placental hormone. Finally, comments will be made on the eventual leptin alterations in reproductive disorders, with special attention to the polycystic ovary syndrome (PCOS), a disease in which reproductive, metabolic and neuroendocrine alterations are commonly observed. All in all, we intend to provide an updated account of our knowledge on the physiological roles of leptin in the metabolic regulation of the reproductive axis and its eventual pathophysiological implications in prevalent reproductive disorders, such as PCOS. Copyright © 2014 Elsevier Inc. All rights reserved.
    Metabolism: clinical and experimental 10/2014; 64(1). DOI:10.1016/j.metabol.2014.10.013 · 3.89 Impact Factor
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    • "Likewise, circuits involving the PMV participate also in this phenomenon (Elias, 2012). In fact, studies from Elias and co-workers have documented the importance of PMV in transmitting the reproductive effects of leptin (Donato et al., 2011), and recent analyses unveiled alterations of the Kiss1 system following PMV lesions (Donato et al., 2013). In good agreement, neuroanatomical studies have shown that neurons from the PMV apparently innervate Kiss1 and GnRH neurons. "
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    ABSTRACT: It is well established that pubertal activation of the reproductive axis and maintenance of fertility are critically dependent on the magnitude of body energy reserves and the metabolic state of the organism. Hence, conditions of impaired energy homeostasis often result in deregulation of puberty and reproduction, whereas gonadal dysfunction can be associated with the worsening of the metabolic profile and, eventually, changes in body weight. While much progress has taken place in our knowledge about the neuroendocrine mechanisms linking metabolism and reproduction, our understanding of how such dynamic interplay happens is still incomplete. As paradigmatic example, much has been learnt in the last two decades on the reproductive roles of key metabolic hormones (such as leptin, insulin and ghrelin), their brain targets and the major transmitters and neuropeptides involved. Yet, the molecular mechanisms whereby metabolic information is translated and engages into the reproductive circuits remain largely unsolved. In this work, we will summarize recent developments in the characterization of the putative central roles of key cellular energy sensors, such as mTOR, in this phenomenon, and will relate these with other molecular mechanisms likely contributing to the brain coupling of energy balance and fertility. In doing so, we aim to provide an updated view of an area that, despite still underdeveloped, may be critically important to fully understand how reproduction and metabolism are tightly connected in health and disease.
    Molecular and Cellular Endocrinology 10/2014; 397(1-2). DOI:10.1016/j.mce.2014.09.027 · 4.41 Impact Factor
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    • "Incomplete restoration of Kiss1 mRNA expression suggests that other mediators are involved in inhibiting kisspeptin signalling in leptin deficiency. Furthermore, mice with selective deletion of leptin receptor from kisspeptin neurones display normal pubertal development, sexual maturation and fertility, demonstrating that leptin action on kisspeptin neurones is not obligatory for these processes (Donato et al., 2011). "
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    ABSTRACT: BACKGROUND The discovery of kisspeptin as key central regulator of GnRH secretion has led to a new level of understanding of the neuroendocrine regulation of human reproduction. The related discovery of the kisspeptin-neurokinin B-dynorphin (KNDy) pathway in the last decade has further strengthened our understanding of the modulation of GnRH secretion by endocrine, metabolic and environmental inputs. In this review, we summarize current understanding of the physiological roles of these novel neuropeptides, and discuss the clinical relevance of these discoveries and their potential translational applications.METHODSA systematic literature search was performed using PUBMED for all English language articles up to January 2014. In addition, the reference lists of all relevant original research articles and reviews were examined. This review focuses mainly on published human studies but also draws on relevant animal data.RESULTSKisspeptin is a principal regulator of the secretion of gonadotrophins, and through this key role it is critical for the onset of puberty, the regulation of sex steroid-mediated feedback and the control of adult fertility. Although there is some sexual dimorphism, both neuroanatomically and functionally, these functions are apparent in both men and women. Kisspeptin acts upstream of GnRH and, following paracrine stimulatory and inhibitory inputs from neurokinin B and dynorphin (KNDy neuropeptides), signals directly to GnRH neurones to control pulsatile GnRH release. When administered to humans in different isoforms, routes and doses, kisspeptin robustly stimulates LH secretion and LH pulse frequency. Manipulation of the KNDy system is currently the focus of translational research with the possibility of future clinical application to regulate LH pulsatility, increasing gonadal sex steroid secretion in reproductive disorders characterized by decreased LH pulsatility, including hypothalamic amenorrhoea and hypogonadotropic hypogonadism. Conversely there may be scope to reduce the activity of the KNDy system to reduce LH secretion where hypersecretion of LH adds to the phenotype, such as in polycystic ovary syndrome.CONCLUSIONS Kisspeptin is a recently discovered neuromodulator that controls GnRH secretion mediating endocrine and metabolic inputs to the regulation of human reproduction. Manipulation of kisspeptin signalling has the potential for novel therapies in patients with pathologically low or high LH pulsatility.
    Human Reproduction Update 03/2014; 20(4). DOI:10.1093/humupd/dmu009 · 10.17 Impact Factor
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