Neuroendocrinología de la reproducción: de las neuronas GnRH a las kisspeptinas

La función rerpoductiva está controlado primariamente por aprpximadamente 1500 neuronas GnRH del hipotálamo. Son muchos los factores ambientales que afectan al eje regulador Hipootálamo-Hipófisi-Gónadas, así como factores internos, como son las señales provenientes del tejido adiposo. Actualmente se sabe que las neuronas GnRH actúan bajo el control de dos núcleos neuronales que producen Kissopeptina. Las Kisspeptinas modulan positivamente la actividad de los núcleos GnRH. Los núcleos Kisspeptina responden a las señales de los estrógenos segregados por las gónadas, de manera que uno de ellos responde activándose y por tanto estimulando la secreción de GnRH, y el otro responde inhibíendose, por lo que disminuye la expresión de GnRH. Esto explica el hecho de que en el ciclo reproductivo fememnino, se de la paradoja de que unos altos niveles de estrógenos en sangre provoquen un pico de LH.Vicerrectorado de Investigación y transferencia. Plan Propio. Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tec

Extrahypothalamic Control of Energy Balance and Its Connection with Reproduction: Roles of the Amygdala

Body energy and metabolic homeostasis are exquisitely controlled by multiple, often overlapping regulatory mechanisms, which permit the tight adjustment between fuel reserves, internal needs, and environmental (e.g., nutritional) conditions. As such, this function is sensitive to and closely connected with other relevant bodily systems, including reproduction and gonadal function. The aim of this mini-review article is to summarize the most salient experimental data supporting a role of the amygdala as a key brain region for emotional learning and behavior, including reward processing, in the physiological control of feeding and energy balance. In particular, a major focus will be placed on the putative interplay between reproductive signals and amygdala pathways, as it pertains to the control of metabolism, as complementary, extrahypothalamic circuit for the integral control of energy balance and gonadal function

Dissecting the Roles of Gonadotropin-Inhibitory Hormone in Mammals: Studies Using Pharmacological Tools and Genetically Modified Mouse Models

Reproduction is essential for perpetuation of the species and, hence, is controlled by a sophisticated network of regulatory factors of central and peripheral origin that integrate at the hypothalamic-pituitary-gonadal (HPG) axis. Among the central regulators of reproduction, kisspeptins, as major stimulatory drivers of gonadotropin-releasing hormone (GnRH) neurosecretion, have drawn considerable interest in the last decade. However, the dynamic, if not cyclic (in the female), nature of reproductive function and the potency of kisspeptins and other stimulatory signals of the HPG axis make tenable the existence of counterbalance inhibitory mechanisms, which may keep stimulation at check and would allow adaptation of reproductive maturation and function to different endogenous and environmental conditions. In this context, discovery of the gonadotropin-inhibitory hormone (GnIH) in birds, and its mammalian homolog, RFRP, opened up the exciting possibility that this inhibitory signal might operate centrally to suppress, directly or indirectly, GnRH/gonadotropin secretion, thus reciprocally cooperating with other stimulatory inputs in the dynamic regulation of the reproductive hypothalamic pituitary unit. After more than 15 years of active research, the role of GnIH/RFRP in the control of the HPG axis has been documented in different species. Yet, important aspects of the physiology of this system, especially regarding its relative importance and actual roles in the control of key facets of reproductive function, remain controversial. In the present work, we aim to provide a critical review of recent developments in this area, with special attention to studies in rodent models, using pharmacological tools and functional genomics. In doing so, we intend to endow the reader with an updated view of what is known (and what is not known) about the physiological role of GnIH/RFRP signaling in the control of mammalian reproduction

Expression of leptin and adiponectin in the rat oviduct

SUMMARY In mammals, the oviduct is an important source of factors that play key roles in reproductive and developmental events. The major components of oviduct fluid are oviductspecific glycoproteins, but other proteins are synthesized and secreted by the oviduct epithelium. Leptin and adiponectin are two hormones originally identified in adipocytes that play a critical role not only in the control of energy balance and metabolism but also in diverse functions such as reproduction. This study investigates the presence and distribution of leptin and adiponectin in the rat oviduct through a combination of immunohistochemistry and reverse transcription–polymerase chain reaction techniques. Using both techniques, it has been detected that the oviduct of cycling rats expresses leptin and adiponectin. Immunoreactivity for both adipokines appears in the apical region of the secretory epithelial cells, only in the isthmus and ampulla. The immunostain is stronger in the isthmus and changes throughout the estrous cycle in the ampulla, increasing from proestrous to estrous. The results presented here are a further contribution to the identification of leptin and adiponectin produced and secreted by the oviduct epithelium, which must be taken into account for a better understanding of the reproductive events that take place in this organ

Extrahypothalamic Control of Energy Balance and Its Connection with Reproduction: Roles of the Amygdala

Body energy and metabolic homeostasis are exquisitely controlled by multiple, often overlapping regulatory mechanisms, which permit the tight adjustment between fuel reserves, internal needs, and environmental (e.g., nutritional) conditions. As such, this function is sensitive to and closely connected with other relevant bodily systems, including reproduction and gonadal function. The aim of this mini-review article is to summarize the most salient experimental data supporting a role of the amygdala as a key brain region for emotional learning and behavior, including reward processing, in the physiological control of feeding and energy balance. In particular, a major focus will be placed on the putative interplay between reproductive signals and amygdala pathways, as it pertains to the control of metabolism, as complementary, extrahypothalamic circuit for the integral control of energy balance and gonadal function

Metabolic dysfunction in polycystic ovary syndrome: Pathogenic role of androgen excess and potential therapeutic strategies

Background: Polycystic ovary syndrome (PCOS) is the most common endocrinopathy among reproductive age women. Although its cardinal manifestations include hyperandrogenism, oligo/anovulation, and/or polycystic ovarian morphology, PCOS women often display also notable metabolic comorbidities. An array of pathogenic mechanisms have been implicated in the etiology of this heterogeneous endocrine disorder; hyperandrogenism at various developmental periods is proposed as a major driver of the metabolic and reproductive perturbations associated with PCOS. However, the current understanding of the pathophysiology of PCOS-associated metabolic disease is incomplete, and therapeutic strategies used to manage this syndrome's metabolic complications remain limited.Scope of review: This study is a systematic review of the potential etiopathogenic mechanisms of metabolic dysfunction frequently associated with PCOS, with special emphasis on the metabolic impact of androgen excess on different metabolic tissues and the brain. We also briefly summarize the therapeutic approaches currently available to manage metabolic perturbations linked to PCOS, highlighting current weaknesses and future directions.Major conclusions: Androgen excess plays a prominent role in the development of metabolic disturbances associated with PCOS, with a discernible impact on key peripheral metabolic tissues, including the adipose, liver, pancreas, and muscle, and very prominently the brain, contributing to the constellation of metabolic complications of PCOS, from obesity to insulin resistance. However, the current understanding of the pathogenic roles of hyperandrogenism in metabolic dysfunction of PCOS and the underlying mechanisms remain largely incomplete. In addition, the development of more efficient, even personalized therapeutic strategies for the metabolic management of PCOS patients persists as an unmet need that will certainly benefit from a better comprehension of the molecular basis of this heterogeneous syndrome. </div

Perturbation of hypothalamic MicroRNA expression patterns in male rats after metabolic distress: impact of obesity and conditions of negative energy balance

[Abstract] The hypothalamus plays a crucial role in body weight homeostasis through an intricate network of neuronal circuits that are under the precise regulation of peripheral hormones and central transmitters. Although deregulated function of such circuits might be a major contributing factor in obesity, the molecular mechanisms responsible for the hypothalamic control of energy balance remain partially unknown. MicroRNAs (miRNAs) have been recognized as key regulators of different biological processes, including insulin sensitivity and glucose metabolism. However, the roles of miRNA pathways in the control of metabolism have been mostly addressed in peripheral tissues, whereas the potential deregulation of miRNA expression in the hypothalamus in conditions of metabolic distress remains as yet unexplored. In this work, we used high-throughput screening to define to what extent the hypothalamic profiles of miRNA expression are perturbed in two extreme conditions of nutritional stress in male rats, namely chronic caloric restriction and high-fat diet–induced obesity. Our analyses allowed the identification of sets of miRNAs, including let-7a, mir-9*, mir-30e, mir-132, mir-145, mir-200a, and mir-218, whose expression patterns in the hypothalamus were jointly altered by caloric restriction and/or a high-fat diet. The predicted targets of these miRNAs include several elements of key inflammatory and metabolic pathways, including insulin and leptin. Our study is the first to disclose the impact of nutritional challenges on the hypothalamic miRNA expression profiles. These data will help to characterize the molecular miRNA signature of the hypothalamus in extreme metabolic conditions and pave the way for targeted mechanistic analyses of the involvement of deregulated central miRNAs pathways in the pathogenesis of obesity and related disorders.Instituto de Salud Carlos III; PI10/00088Ministerio de Economia y Competitividad; IN845B-2010/187Instituto de Salud Carlos III; PI13/00322FISXunta de Galicia; 10CSA916014PRXunta de Galicia; EM2013/011Ministerio de Ciencia e Innovación; BFU 2011-2502

A novel RGB-trichrome staining method for routine histological analysis of musculoskeletal tissues.

Morphometry and histology are essential approaches for investigation and diagnosis of musculo-skeletal disorders. Despite the advent of revolutionary methods of image analysis and high resolution three-dimensional imaging technology, basic conventional light microscopy still provides an incisive overview of the structure and tissue dynamics of the musculoskeletal system. This is crucial to both preclinical and clinical research, since several clinically relevant processes, such as bone repair, osteoarthritis, and metabolic bone diseases, display distinct, if not pathognomonic, histological features. Due to the particular characteristics of the skeletal tissues (i.e., the existence of mineralized extracellular matrices), a large number of staining methods applicable to either decalcified or undecalcified tissues are available. However, it is usually the case that several staining methods need to be sequentially applied in order to achieve the different endpoints required to fully assess skeletal tissue structure and dynamics, and to allow morphometric quantification. We describe herein a novel staining method, the RGB trichrome, amenable for application to decalcified, paraffin embedded human musculoskeletal tissues. The acronym RGB corresponds to the three primary dyes used: picrosirius Red, fast Green, and alcian Blue. Although these individual pigments are commonly used either isolated, in binary combinations, or as part of more complex polychrome staining methods, when merged in the RGB trichrome staining produce high-quality/high-contrast images, permitting not only clear identification of different tissues (i.e., the different types of cartilage, bone and fibrous connective tissue), but also discrimination between calcified and uncalcified bone and cartilage, as well as an unexpected diversity of shades of color, while displaying singular properties among polychrome staining methods, such as the unveiling of the bone osteocyte dendritic/canalicular network. Hence, we propose the RGB trichrome as simple but highly-reliable tool for the preclinical and clinical study of the musculoskeletal system

Emerging Roles of Epigenetics in the Control of Reproductive Function: Focus on Central Neuroendocrine Mechanisms

Reproduction is an essential function for perpetuation of the species. As such, it is controlled by sophisticated regulatory mechanisms that allow a perfect match between environmental conditions and internal cues to ensure adequate pubertal maturation and achievement of reproductive capacity. Besides classical genetic regulatory events, mounting evidence has documented that different epigenetic mechanisms operate at different levels of the reproductive axis to finely tune the development and function of this complex neuroendocrine system along the lifespan. In this mini-review, we summarize recent evidence on the role of epigenetics in the control of reproduction, with special focus on the modulation of the central components of this axis. Particular attention will be paid to the epigenetic control of puberty and Kiss1 neurons because major developments have taken place in this domain recently. In addition, the putative role of central epigenetic mechanisms in mediating the influence of nutritional and environmental cues on reproductive function will be discussed

Androgen action via testicular arteriole smooth muscle cells is important for leydig cell function, vasomotion and testicular fluid dynamics

Regulation of blood flow through the testicular microvasculature by vasomotion is thought to be important for normal testis function as it regulates interstitial fluid (IF) dynamics which is an important intra-testicular transport medium. Androgens control vasomotion, but how they exert these effects remains unclear. One possibility is by signalling via androgen receptors (AR) expressed in testicular arteriole smooth muscle cells. To investigate this and determine the overall importance of this mechanism in testis function, we generated a blood vessel smooth muscle cell-specific AR knockout mouse (SMARKO). Gross reproductive development was normal in SMARKO mice but testis weight was reduced in adulthood compared to control littermates; this reduction was not due to any changes in germ cell volume or to deficits in testosterone, LH or FSH concentrations and did not cause infertility. However, seminiferous tubule lumen volume was reduced in adult SMARKO males while interstitial volume was increased, perhaps indicating altered fluid dynamics; this was associated with compensated Leydig cell failure. Vasomotion was impaired in adult SMARKO males, though overall testis blood flow was normal and there was an increase in the overall blood vessel volume per testis in adult SMARKOs. In conclusion, these results indicate that ablating arteriole smooth muscle AR does not grossly alter spermatogenesis or affect male fertility but does subtly impair Leydig cell function and testicular fluid exchange, possibly by locally regulating microvascular blood flow within the testis