Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Prader-Willi syndrome (PWS) is a complex genetic disorder characterized by hyperphagia, obesity and hypogonadotrophic hypogonadism, all highly suggestive of hypothalamic dysfunction. The NDN gene, encoding the MAGE family protein, necdin, maps to the PWS chromosome region and is highly expressed in mature hypothalamic neurons. Adult mice lacking necdin have reduced numbers of gonadotropin-releasing hormone (GnRH) neurons, but the mechanism for this reduction is unknown. Herein, we show that, although necdin is not expressed in an immature, migratory GnRH neuronal cell line (GN11), high levels are present in a mature GnRH neuronal cell line (GT1-7). Furthermore, overexpression of necdin activates GnRH transcription through cis elements bound by the homeodomain repressor Msx that are located in the enhancer and promoter of the GnRH gene, and knock-down of necdin expression reduces GnRH gene expression. In fact, overexpression of Necdin relieves Msx repression of GnRH transcription through these elements and necdin co-immunoprecipitates with Msx from GnRH neuronal cells, indicating that necdin may activate GnRH gene expression by preventing repression of GnRH gene expression by Msx. Finally, necdin is necessary for generation of the full complement of GnRH neurons during mouse development and extension of GnRH axons to the median eminence. Together, these results indicate that lack of necdin during development likely contributes to the hypogonadotrophic hypogonadal phenotype in individuals with PWS.
 ...
PMID:Necdin, a Prader-Willi syndrome candidate gene, regulates gonadotropin-releasing hormone neurons during development. 1893 Sep 56

Previous evidence suggests that the testicular negative feedback control of gonadotropin-releasing hormone-luteinizing hormone (LH) secretion may change as men age, and may thereby contribute to the hypogonadism that occurs as men grow older. To pursue this idea, we analyzed the results for 35 men with primary hypogonadism who were participants in an open-label multicenter study of testosterone replacement. LH, sex hormone-binding globulin (SHBG), and total and free testosterone and estradiol concentrations were measured in blood samples at baseline and after 2% testosterone gel was applied daily for 2 weeks. A 24-hour pharmacokinetic profile for testosterone and estradiol was obtained at the end of week 2. Age was a strong predictor of LH suppression during testosterone replacement (r = -0.46), and the effect could not be explained by obesity, SHBG, or higher levels of total or non-SHBG testosterone or estradiol during treatment. In fact, both LH and non-SHBG testosterone levels were lower (P < .05) in older men receiving testosterone treatment. In addition, the strongest association overall was between the percentage decline in LH and non-SHBG estradiol concentrations (r = -0.39). These data provide further evidence that suppression of LH secretion during testosterone treatment is greater as men age, and are consistent with the hypothesis that the hypogonadism of aging men is partly due to a change in gonadotropin negative feedback regulation. These results further suggest that estrogen receptor signaling might contribute to this effect.
 ...
PMID:LH and non-SHBG testosterone and estradiol levels during testosterone replacement of hypogonadal men: further evidence that steroid negative feedback increases as men grow older. 1995 27

Polycystic ovary syndrome (PCOS) is a very common endocrine disorder characterized by chronic anovulation, clinical and/or biochemical hyperandrogenism, and/or polycystic ovaries. But most experts consider that hyperandrogenism is the main characteristic of PCOS. Several theories propose different mechanisms to explain PCOS manifestations: (1) a primary enzymatic default in the ovarian and/or adrenal steroidogenesis; (2) an impairment in gonadotropin releasing hormone (GnRH) secretion that promotes luteal hormone (LH) secretion; or (3) alterations in insulin actions that lead to insulin resistance with compensatory hyperinsulinemia. However, in the past 20 years there has been growing evidence supporting that defects in insulin actions or in the insulin signalling pathways are central in the pathogenesis of the syndrome. Indeed, most women with PCOS are metabolically insulin resistant, in part due to genetic predisposition and in part secondary to obesity. But some women with typical PCOS do not display insulin resistance, which supports the hypothesis of a genetic predisposition specific to PCOS that would be revealed by the development of insulin resistance and compensatory hyperinsulinemia in most, but not all, women with PCOS. However, these hypotheses are not yet appropriately confirmed, and more research is still needed to unravel the true pathogenesis underlying this syndrome. The present review thus aims at discussing new concepts and findings regarding insulin actions in PCOS women and how it is related to hyperandrogenemia.
 ...
PMID:Insulin and hyperandrogenism in women with polycystic ovary syndrome. 2003 27

Hypogonadism occurs commonly in men with type 2 diabetes (T2DM) and severe obesity. Current evidence points to a decreased secretion of gonadotropin-releasing hormone (GnRH) from the hypothalamus and thereby decreased secretion of gonadotropins from the pituitary gland as a central feature of the pathophysiology in these men. Hyperglycaemia, inflammation, leptin and oestrogen-related feedback have been proposed to make aetiological contributions to the hypogonadotropic hypogonadism of T2DM. However, the neuroendocrine signals that link these factors with modulation of GnRH neurons have yet to be identified. Kisspeptins play a central role in the modulation of GnRH secretion and, thus, downstream regulation of gonadotropins and testosterone secretion in men. Inactivating mutations of the kisspeptin receptor have been shown to cause hypogonadotropic hypogonadism in man, whilst an activating mutation is associated with precocious puberty. Data from studies in experimental animals link kisspeptin expression with individual factors known to regulate GnRH secretion, including hyperglycaemia, inflammation, leptin and oestrogen. We therefore hypothesise that decreased endogenous kisspeptin secretion is the common central pathway that links metabolic and endocrine factors in the pathology of testosterone deficiency seen in men with obesity and T2DM. We propose that the kisspeptin system plays a central role in integrating a range of metabolic inputs, thus constituting the link between energy status with the hypothalamic-pituitary-gonadal axis, and put forward potential clinical studies to test the hypothesis.
 ...
PMID:Hypothesis: kisspeptin mediates male hypogonadism in obesity and type 2 diabetes. 2062 62

Obesity is associated with insulin resistance in metabolic tissues such as adipose, liver, and muscle, but it is unclear whether nonclassical target tissues, such as those of the reproductive axis, are also insulin resistant. To determine if the reproductive axis maintains insulin sensitivity in obesity in vivo, murine models of diet-induced obesity (DIO) with and without intact insulin signaling in pituitary gonadotrophs were created. Diet-induced obese wild-type female mice (WT DIO) were infertile and experienced a robust increase in luteinizing hormone (LH) after gonadotropin-releasing hormone (GnRH) or insulin stimulation. By contrast, both lean and obese mice with a pituitary-specific knockout of the insulin receptor (PitIRKO) exhibited reproductive competency, indicating that insulin signaling in the pituitary is required for the reproductive impairment seen in DIO and that the gonadotroph maintains insulin sensitivity in a setting of peripheral insulin resistance.
 ...
PMID:Rescue of obesity-induced infertility in female mice due to a pituitary-specific knockout of the insulin receptor. 2081 95

Pelvic ultrasound evaluation of girls presenting with secondary sex characteristics before the age of 8 years may help to differentiate precocious puberty from premature thelarche, functioning ovarian cyst, and obesity. However, although uterine and ovarian measurements are significantly higher in girls with true precocious puberty than controls, there is a significant overlap of normal prepubertal and early pubertal values. In girls with precocious puberty treated with gonadotropin-releasing hormone analogue, ultrasound is a valid tool for monitoring ovarian suppression.
 ...
PMID:Role of pelvic ultrasound in girls with precocious puberty. 2122 61

Close to 30 forms of gonadotropin releasing hormone (GnRH) and at least five GnRH receptors have been identified in a wide variety of vertebrates and some invertebrates. One form, now called GnRH II, has the broadest distribution and the most ancient and conserved phylogeny. The distribution of the neurons that produce this peptide are completely nonoverlapping with any other GnRH forms. Fibers that project from these neurons overlap with GnRH I cells and/or fibers in a few regions, but are primarily divergent. The musk shrew (Suncus murinus) continues to be the most tractable mammalian species to use for studies of the function of GnRH II. The brain of the musk shrew has two GnRH genes (I and II), two GnRH receptors (types-1 and -2), and two different behaviors can be influenced by central infusion of GnRH II, but not by GnRH I; receptivity and feeding. Here, we summarize research on the musk shrew relative to the behavioral functions of GnRH II. First, female musk shrews are continually sexually receptive by virtue of their lack of an ovarian and/or behavioral estrus cycle. This feature of their reproductive ecology may be related to their semi-tropical distribution and their breeding season is highly dependent on changes in the availability of food. When food is not abundant, females stop mating, but brief bouts of feeding reinstate reproductive behavior. Likewise, intake of food is related to GnRH II mRNA and peptide content in the brain; after mild food restriction both decline. When GnRH II is infused centrally, at times when its content is low, it can both enhance receptivity and inhibit food intake. Simultaneous administration of a type-1 antagonist does not change the effect of GnRH II and use of an analog (135-18) that is a specific GnRH II agonist as well as a type-1 antagonist has the same effect as the endogenous GnRH II peptide. We propose that GnRH II plays a critical role by orchestrating the coordination of reproduction with the availability of nutritional support for these activities. Humans are bombarded with copious nutritional opportunities and at present obesity is a larger threat to health in many parts of the world than is under nutrition. It is our hope that understanding neuropeptides such as GnRH II that regulate food intake can ultimately lead to products that may curb appetite and thus decrease obesity and related risks to health.
 ...
PMID:Gonadotropin-releasing hormone II: a multi-purpose neuropeptide. 2166 18

Cytokines encompass a broad class of peptides that mediate signals in a broad range of physiological situations including inflammation, infection, and obesity. The cytokine receptor-associated tyrosine kinase, Jak2, is one of the most important proteins mediating cytokine signaling pathway activation. Recently, our group has demonstrated that Jak2 signaling in the gonadotropin-releasing hormone (GnRH) neuron plays a critical role in fertility in males and females, implicating cytokine activation of the neuron in GnRH neuronal development and function. To date, the specific cytokine(s) essential for activating Jak2 during neuroendocrine development are not known. In this article, we review the evidence for the role of several class 1 cytokines in regulating GnRH neuronal development, GnRH secretion, and GnRH expression.
 ...
PMID:Signaling of cytokines is important in regulation of GnRH neurons. 2216 98

Polycystic ovarian syndrome (PCOS) is a common disorder characterized by ovulatory dysfunction and hyperandrogenemia (HA). Neuroendocrine abnormalities including increased gonadotropin-releasing hormone (GnRH) pulse frequency, increased luteinizing hormone (LH) pulsatility, and relatively decreased follicle stimulating hormone contribute to its pathogenesis. HA reduces inhibition of GnRH pulse frequency by progesterone, causing rapid LH pulse secretion and increasing ovarian androgen production. The origins of persistently rapid GnRH secretion are unknown but appear to evolve during puberty. Obese girls are at risk for HA and develop increased LH pulse frequency with elevated mean LH by late puberty. However, even early pubertal girls with HA have increased LH pulsatility and enhanced daytime LH pulse secretion, indicating the abnormalities may begin early in puberty. Decreasing sensitivity to progesterone may regulate normal maturation of LH secretion, potentially related to normally increasing levels of testosterone during puberty. This change in sensitivity may become exaggerated in girls with HA. Many girls with HA-especially those with hyperinsulinemia-do not exhibit normal LH pulse sensitivity to progesterone inhibition. Thus, HA may adversely affect LH pulse regulation during pubertal maturation leading to persistent HA and the development of PCOS.
 ...
PMID:Neuroendocrine dysfunction in polycystic ovary syndrome. 2217 93

Androgen deprivation therapy (ADT) is the most effective systemic treatment for prostate cancer. ADT has been shown to have a high rate of response and to improve overall survival in patients with metastatic prostate cancer. In addition, multiple studies have shown that adding ADT to external beam radiation therapy leads to improvement in cure rates and overall survival in prostate cancer patients. The most commonly used ADT is gonadotropin-releasing hormone (GnRH) agonist therapy. Although GnRH agonist therapy has significant benefits for patients with prostate cancer, it has also been shown to have significant side effects, including fatigue, hot flashes, decreased libido, decreased quality of life, obesity, diabetes mellitus, coronary artery disease, decreased bone mineral density, and increased risk of fractures. Therefore, it is crucial that the benefits of ADT be weighed against its potential adverse effects before its use.
 ...
PMID:Efficacy and safety of gonadotropin-releasing hormone agonists used in the treatment of prostate cancer. 2227 15


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>