Leptin signaling and circuits in puberty and fertility. Cell Mol Life Sci

Division of Hypothalamic Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Y6-220B, Dallas, TX, 75390-9077, USA, .
Cellular and Molecular Life Sciences CMLS (Impact Factor: 5.81). 08/2012; 70(5). DOI: 10.1007/s00018-012-1095-1
Source: PubMed


Leptin is an adipocyte-derived hormone involved in a myriad of physiological process, including the control of energy balance and several neuroendocrine axes. Leptin-deficient mice and humans are obese, diabetic, and display a series of neuroendocrine and autonomic abnormalities. These individuals are infertile due to a lack of appropriate pubertal development and inadequate synthesis and secretion of gonadotropins and gonadal steroids. Leptin receptors are expressed in many organs and tissues, including those related to the control of reproductive physiology (e.g., the hypothalamus, pituitary gland, and gonads). In the last decade, it has become clear that leptin receptors located in the brain are major players in most leptin actions, including reproduction. Moreover, the recent development of molecular techniques for brain mapping and the use of genetically modified mouse models have generated crucial new findings for understanding leptin physiology and the metabolic influences on reproductive health. In the present review, we will highlight the new advances in the field, discuss the apparent contradictions, and underline the relevance of this complex physiological system to human health. We will focus our review on the hypothalamic circuitry and potential signaling pathways relevant to leptin's effects in reproductive control, which have been identified with the use of cutting-edge technologies of molecular mapping and conditional knockouts.

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    • "The results indicate that such variation is not a common cause of these extreme phenotypes and suggest that the primary role of LIN28B may be in regulating the timing of puberty within the general population. In contrast to other studies using more severely affected animals (Good et al. 1997, Corradi et al. 2003, Seminara et al. 2003, Pask et al. 2005, Brill & Moenter 2009, DeBoer et al. 2010, Deboer & Li 2011, Elias & Purohit 2013), all three strains of our mice were healthy and fertile and were thus a good model for studying genes that affect timing of puberty in the general population. Similarly, the two-day delay detected in our transgenic male mice is of comparable magnitude to studies of litter-size and diet manipulations in male mice (DeBoer et al. 2010, Smith & Spencer 2012, SanchezGarrido et al. 2013). "
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    ABSTRACT: Growth and pubertal timing differ in boys and girls. Variants in/near LIN28B associate with age at menarche (AAM) in genome-wide association studies and some AAM-related variants associate with growth in a sex-specific manner. Sex-specific growth patterns in response to Lin28b perturbation have been detected in mice, and overexpression of Lin28a has been shown to alter pubertal timing in female mice. To investigate further how Lin28a and Lin28b affect growth and puberty in both males and females, we evaluated Lin28b loss-of-function (LOF) mice and Lin28a gain-of-function (GOF) mice. Because both Lin28a and Lin28b can act via the conserved microRNA let-7, we also examined let-7 GOF mice. As reported previously, Lin28b LOF led to lighter body weights only in male mice while Lin28a GOF yielded heavier mice of both sexes. Let-7 GOF mice weighed less than controls, and males were more affected than females. Timing of puberty was assessed by vaginal opening (VO) and preputial separation (PS). Male Lin28b LOF and male let-7 GOF, but not female, mice displayed alteration of pubertal timing, with later PS than controls. In contrast, both male and female Lin28a GOF mice displayed late onset of puberty. Together, these data point toward a complex system of regulation by Lin28a, Lin28b, and let-7, in which Lin28b and let-7 can impact both puberty and growth in a sex-specific manner, raising the possibility that this pathway may contribute to differential regulation of male and female growth and puberty in humans.
    No preview · Article · Dec 2015 · Journal of Endocrinology
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    • "It acts both centrally through the hypothalamus, and peripherally (Allison and Myers, 2014). Additional roles for leptin include development of adipocytes for energy storage (adipogenesis), modulating metabolism of both lipids and glucose, and playing an active part in many reproductive processes (Wang et al., 2012;Elias and Purohit, 2013;Mantzoros, 2006). Little is actually known regarding normal, expected methylation patterns in healthy humans or the specific relevance of the methylation patterns to nutritional phenotypes of populations from diverse climates , food chains, and cultures (Bouchard et al., 2010: Bock et al., 2008).Stöger (2008) "
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    ABSTRACT: Epigenetic mechanisms have been widely studied for the past several decades, yet despite a surfeit of literature examining animal models and extensive human research associating these mechanisms with pathology, little is known regarding the normal variation among populations or the phenotypic relevance of that variation. Moreover, no one is certain of the evolutionary significance these mechanisms and their underlying machinery. Their structure and function are highly dependent upon dietary intake of indispensable nutrients, yet nutrient profiles vary across populations and generations in an ongoing manner and energy intake can fluctuate dramatically. Here, we examine how the DNA methylation might archive ancestral dietary patterns and discuss the initial findings in a pilot study on population variation in DNA methylation patterns in four maternal/offspring duos from three continents (n = 88). This pilot examined DNA methylation patterns across the core promoter of the metabolic gene leptin (LEP), a leading regulator of energy homeostasis and adipogenesis. Remarkably similar overall mean patterns were present across 7 CpG sites which include the C/EBPα transcription binding site, and two sites proximal to the TATA. Findings suggest a stable and conserved DNA methylation pattern in this region of the (LEP) promoter across populations consuming diets from varying food chains.
    Full-text · Article · Nov 2015
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    • "Because of its paramount importance in the central control of reproduction, quite some attention has been paid to evaluate the potential role of Kiss1 neurons in the metabolic control of GnRH neurons and in transmitting the effects of leptin. For sake of concision, the reader is referred to recent reviews on the major features of kisspeptins, the product of the Kiss1 gene, as major gatekeepers of puberty and fertility in general, and in the metabolic control of the HPG axis [3] [9] [12] [47]. As a means of introduction, we stress here that Kiss1 neurons in the brain, which in rodents are prominently located in the hypothalamic ARC and AVPV areas, are known to potently stimulate GnRH neurosecretory activity and likely mediate the influence of numerous endogenous and exogenous cues, ranging from sex steroids to light/dark cycles, on the GnRH system [3] [47] [68] [69]. "
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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.
    Full-text · Article · Oct 2014 · Metabolism: clinical and experimental
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