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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    • "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.
    Metabolism: clinical and experimental 10/2014; 64(1). DOI:10.1016/j.metabol.2014.10.013 · 3.89 Impact Factor
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    • "Much of the initial interest in leptin was related to its involvement in the control of energy homeostasis, where it acts through leptin receptors (LepR) expressed on the hypothalamus (Fruhbeck, 2006; Margetic et al., 2002). Leptin-mediated signaling in mammals is involved in a range of physiological functions, including regulation of food intake (Banks et al., 2004; Pelleymounter et al., 1995), reproduction (Elias and Purohit, 2013; Moschos et al., 2002; Zieba et al., 2005), "
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    ABSTRACT: The first studies that identified leptin and its receptor (LepR) in mammals were based on mutant animals that displayed dramatic changes in body-weight and regulation of energy homeostasis. Subsequent studies have shown that a deficiency of leptin or LepR in homoeothermic mammals results in hyperphagia, obesity, infertility and a number of other abnormalities. The physiological roles of leptin-mediated signaling in ectothermic teleosts are still being explored. Here, we produced medaka with homozygous LepR gene mutation using the targeting induced local lesions in a genome method. This knockout mutant had a point mutation of cysteine for stop codon at the 357th amino acid just before the leptin-binding domain. The evidence for loss of function of leptin-mediated signaling in the mutant is based on a lack of response to feeding in the expression of key appetite-related neuropeptides in the diencephalon. The mutant lepr−/− medaka expressed constant up-regulated levels of mRNA for the orexigenic neuropeptide Ya and agouti-related protein and a suppressed level of anorexigenic proopiomelanocortin 1 in the diencephalon independent of feeding, which suggests that the mutant did not possess functional LepR. Phenotypes of the LepR-mutant medaka were analyzed in order to understand the effects on food intake, growth, and fat accumulation in the tissues. The food intake of the mutant medaka was higher in post-juveniles and adult stages than that of wild-type (WT) fish. The hyperphagia led to a high growth rate at the post-juvenile stage, but did not to significant alterations in final adult body size. There was no additional deposition of fat in the liver and muscle in the post-juvenile and adult mutants, or in the blood plasma in the adult mutant. However, adult LepR mutants possessed large deposits of visceral fat, unlike in the WT fish, in which there were none. Our analysis confirms that LepR in medaka exert a powerful influence on the control on food intake. Further analyses using the mutant will contribute to a better understanding of the role of leptin in fish. This is the first study to produce fish with leptin receptor deficiency.
    General and Comparative Endocrinology 02/2014; 195:9–20. DOI:10.1016/j.ygcen.2013.10.008 · 2.47 Impact Factor
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    • "A paradigmatic example of a target area for the reproductive effects of leptin outside Kiss1 - enriched hypothalamic nuclei is the PMV . In - deed , this nucleus had been pointed out as node for the transmission of environmental cues to the reproductive centers well before the iden - tification of the roles of leptin and kisspeptins ( Elias and Purohit , 2013 ) . "
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    ABSTRACT: This article is part of a Special Issue "Puberty and Adolescence". Reproduction is an energy-demanding function. Accordingly, puberty is metabolically gated, as a means to prevent fertility in conditions of energy insufficiency. In addition, obesity has been shown to impact the timing of puberty and may be among the causes for the earlier trends of pubertal age reported in various countries. The metabolic control of puberty in such a spectrum of situations, ranging from energy deficit to extreme overweight, is the result of the concerted action of different peripheral hormones and central transmitters that sense the metabolic state of the organism and transmit this information to the various elements of the reproductive axis, mainly the GnRH neurons. Among the peripheral signals involved, the adipose hormone, leptin, is known to play an essential role in the regulation of puberty, especially in females. Yet, although it is clear that the effects of leptin on puberty onset are predominantly permissive and mainly conducted at central (hypothalamic) levels, the primary sites and mechanisms of action of leptin within the reproductive brain remain unsolved. In this context, neurons expressing kisspeptins, the products of the Kiss1 gene that have emerged recently as essential upstream regulators of GnRH neurons, operate as key sensors of the metabolic state and funnel of the reproductive effects of leptin. Yet, much debate has arisen recently on whether the putative actions of leptin on the Kiss1 system are actually indirect and/or may primarily target Kiss1-independent pathways, such as those originating from the ventral premmamilary nucleus. Moreover, evidence has been presented for extra-hypothalamic or peripheral actions of leptin, including direct gonadal effects, which may contribute to the metabolic control of reproduction in extreme body weight conditions. In this work, we will critically review the experimental evidence supporting a role of leptin, kisspeptin and putatively related pathways in the concerted control of puberty by energy balance and metabolism.
    Hormones and Behavior 07/2013; 64(2):187-94. DOI:10.1016/j.yhbeh.2013.01.014 · 4.63 Impact Factor
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