Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01189 (beta-endorphin)
 21,003 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Epidemiological studies suggest that maternal undernutrition predisposes the offspring to development of energy balance metabolic pathologies in adulthood. Using a model of a prenatal maternal 70% food-restricted diet (FR30) in rats, we evaluated peripheral parameters involved in nutritional regulation, as well as the hypothalamic appetite-regulatory system, in nonfasted and 48-h-fasted adult offspring. Despite comparable glycemia in both groups, mild glucose intolerance, with a defect in glucose-induced insulin secretion, was observed in FR30 animals. They also exhibited hyperleptinemia, despite similar visible fat deposits. Using semiquantitative RT-PCR, we observed no basal difference of hypothalamic proopiomelanocortin (POMC) and neuropeptide Y (NPY) gene expression, but a decrease of the OB-Rb and an increase of insulin receptor mRNA levels, in FR30 animals. These animals also exhibited basal hypercorticosteronemia and a blunted increase of corticosterone in fasted compared with control animals. After fasting, FR30 animals showed no marked reduction of POMC mRNA levels or intensity of beta-endorphin-immunoreactive fiber projections. By contrast, NPY gene expression and immunoreactive fiber intensity increased. FR30 rats also displayed subtle alterations of food intake: body weight-related food intake was higher and light-dark phase rhythm and refeeding time course were modified after fasting. At rest, in the morning, hyperinsulinemia and a striking increase in the number of c-Fos-containing cells in the arcuate nucleus were observed. About 30% of the c-Fos-expressing cells were POMC neurons. Our data suggest that maternal undernutrition differently programs the long-term appetite-regulatory system of offspring, especially the response of POMC neurons to energy status and food intake rhythm.
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PMID:Maternal prenatal undernutrition alters the response of POMC neurons to energy status variation in adult male rat offspring. 1908 53

Long-term morbidity for children with low-grade glioma (LGG) requires exposure-specific characterization. Overall survival (OS) and progression-free survival (PFS) were estimated for 361 children diagnosed with LGG between 1985 and 2007 at a single institution. Five-year survivors (n = 240) received risk-based clinical assessment. Cumulative incidence of late effects 15 years from diagnosis were estimated. Risk factors for adverse health were identified using Fine and Gray's approach to Cox's proportional hazards model, accounting for death as a competing risk. OS at 15 years was 86% (95% confidence interval [CI] 82%-90%), and PFS was 55% (95% CI 51%-58%). Among the 240 5-year survivors, the 5-, 10-, and 15-year cumulative incidence of adverse outcomes included blindness: 10%, 13%, and 18%, respectively; hearing loss: 8%, 14%, and 22%; obesity/overweight: 18%, 35%, and 53%; hyperinsulinism: 1%, 5%, and 24%; growth hormone deficiency: 13%, 27%, and 29%;thyroid hormone deficiency: 16%, 28%, and 33%; and adrenocorticotropic hormone (ACTH) deficiency: 12%, 22%, and 26%. Multivariable models demonstrated radiation therapy to be a significant independent predictor of hearing loss, growth hormone deficiency, abnormal thyroid function, and ACTH deficiency. Diencephalic location was a statistically significant independent risk factor for blindness, growth hormone deficiency, abnormal thyroid function, and ACTH deficiency. Among the 182 5-year survivors assessed for intellectual function, 34% had an intelligence quotient (IQ) below average (<85), associated with younger age at diagnosis, epilepsy, and shunt placement. Survivors of childhood LGG experience substantial long-term adverse effects that continue to increase well beyond the 5-year survival time point.
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PMID:Survival and long-term health and cognitive outcomes after low-grade glioma. 2117 81

Physiological responses to hypoglycemia, hyperinsulinemia, and hyperglycemia include a critical adrenocortical component that is initiated by hypothalamic control of the anterior pituitary and adrenal cortex. These adrenocortical responses ensure appropriate long-term glucocorticoid-mediated modifications to metabolism. Despite the importance of these mechanisms to disease processes, how hypothalamic afferent pathways engage the intracellular mechanisms that initiate adrenocortical responses to glycemia-related challenges are unknown. This study explores these mechanisms using network- and cellular-level interventions in in vivo and ex vivo rat preparations. Results show that a hindbrain-originating catecholamine afferent system selectively engages a MAP kinase pathway in rat paraventricular hypothalamic CRH (corticotropin-releasing hormone) neuroendocrine neurons shortly after vascular insulin and 2-deoxyglucose challenges. In turn, this MAP kinase pathway can control both neuroendocrine neuronal firing rate and the state of CREB phosphorylation in a reduced ex vivo paraventricular hypothalamic preparation, making this signaling pathway an ideal candidate for coordinating CRH synthesis and release. These results establish the first clear structural and functional relationships linking neurons in known nutrient-sensing regions with intracellular mechanisms in hypothalamic CRH neuroendocrine neurons that initiate the adrenocortical response to various glycemia-related challenges.
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PMID:MAP kinases couple hindbrain-derived catecholamine signals to hypothalamic adrenocortical control mechanisms during glycemia-related challenges. 2217 Oct 49

A 3-year-old girl with Graves' disease developed a generalized convulsion as a result of hypoglycemia (25 mg/dL). At the time of the hypoglycemic seizure, her plasma adrenocorticotropin (ACTH) level (1460 pg/mL) was extremely high, but her serum cortisol level (28.4 microg/dL) was relatively low given the severe stress. The cortisol-releasing hormone (CRH) provocation test done after thyroid function had improved revealed normal ACTH and cortisol responses. Since there was no other cause of hypoglycemia, such as hyperinsulinemia, long-term starvation, suddenly advanced emaciation, or prolonged fasting, it was suspected that the transient adrenal hyporesponsiveness was the main cause of hypoglycemia.
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PMID:A 3-year-old girl with Graves' disease with hypoglycemia following transient adrenal hyporesponsiveness. 2230 63

The aim of this study was to clarify the hypothalamic neuropeptides that are associated with hyperphagic feeding in Tsumura Suzuki Obese Diabetes (TSOD) mice, a model of type 2 diabetes with polygenic abnormalities. TSOD mice showed an increase in body weight and hyperleptinemia from 1 month of age and hyperphagic feeding, hyperglycemia, hyperlipidemia and hyperinsulinemia from 3 to 12 months of age compared with age-matched non-diabetic control Tsumura Suzuki Non Obesity (TSNO) mice. The mRNA level of nucleobindin-2 (NUCB2), the precursor of the anorexigenic neuropeptide nesfatin-1, was significantly decreased in the hypothalamus of TSOD mice compared with that in TSNO mice from 3 to 12 months of age. The protein level of NUCB2 was significantly decreased in the hypothalamus of TSOD mice compared with that in TSNO mice at 3 months of age. The mRNA levels of galanin, melanin-concentrating hormone, neuropeptide Y, and pro-opiomelanocortin were significantly changed in the hypothalamus in TSOD mice at several time points. Another model of type 2 diabetes, db/db mice, which is a mutant mouse that lacks a functional leptin receptor, showed hyperphagic feeding but no change in hypothalamic NUCB2 mRNA compared with non-diabetic control db/+ mice. The results suggest that the disrupted control of hypothalamic NUCB2-mediated signaling may contribute to hyperphagic feeding in TSOD mice. In addition, the mechanism for the development of hyperphagic feeding in TSOD mice is different than that in db/db mice.
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PMID:Possible involvement of hypothalamic nucleobindin-2 in hyperphagic feeding in Tsumura Suzuki obese diabetes mice. 2303 68

6-Fluoro-((18)F)-L-3,4-dihydroxyphenylalanine (FDOPA) is an amino acid analogue for positron emission tomography (PET) imaging which has been registered since 2006 in several European Union (EU) countries and by several pharmaceutical firms. Neuroendocrine tumour (NET) imaging is part of its registered indications. NET functional imaging is a very competitive niche, competitors of FDOPA being two well-established radiopharmaceuticals for scintigraphy, (123)I-metaiodobenzylguanidine (MIBG) and (111)In-pentetreotide, and even more radiopharmaceuticals for PET, including fluorodeoxyglucose (FDG) and somatostatin analogues. Nevertheless, there is no universal single photon emission computed tomography (SPECT) or PET tracer for NET imaging, at least for the moment. FDOPA, as the other PET tracers, is superior in diagnostic performance in a limited number of precise NET types which are currently medullary thyroid cancer, catecholamine-producing tumours with a low aggressiveness and well-differentiated carcinoid tumours of the midgut, and in cases of congenital hyperinsulinism. This article reports on diagnostic performance and impact on management of FDOPA according to the NET type, emphasising the results of comparative studies with other radiopharmaceuticals. By pooling the results of the published studies with a defined standard of truth, patient-based sensitivity to detect recurrent medullary thyroid cancer was 70 % [95 % confidence interval (CI) 62.1-77.6] for FDOPA vs 44 % (95 % CI 35-53.4) for FDG; patient-based sensitivity to detect phaeochromocytoma/paraganglioma was 94 % (95 % CI 91.4-97.1) for FDOPA vs 69 % (95 % CI 60.2-77.1) for (123)I-MIBG; and patient-based sensitivity to detect midgut NET was 89 % (95 % CI 80.3-95.3) for FDOPA vs 80 % (95 % CI 69.2-88.4) for somatostatin receptor scintigraphy with a larger gap in lesion-based sensitivity (97 vs 49 %). Previously unpublished FDOPA results from our team are reported in some rare NET, such as small cell prostate cancer, or in emerging indications, such as metastatic NET of unknown primary (CUP-NET) or adrenocorticotropic hormone (ACTH) ectopic production. An evidence-based strategy in NET functional imaging is as yet affected by a low number of comparative studies. Then the suggested diagnostic trees, being a consequence of the analysis of present data, could be modified, for some indications, by a wider experience mainly involving face-to-face studies comparing FDOPA and (68)Ga-labelled peptides.
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PMID:18F-fluorodihydroxyphenylalanine vs other radiopharmaceuticals for imaging neuroendocrine tumours according to their type. 2341 99

Adipocyte-derived leptin is a hormone associated with the regulation of energy homeostasis, including glucose metabolism. Hyperleptinemia, induced by the consumption of energy-enriched diets, inhibits leptin transport across the blood-brain barrier, and thereby produces leptin insufficiency in the hypothalamus. As a result of sustained leptin insufficiency, the hypothalamic restraint on pancreatic insulin secretion is lost. Additionally, both glucose metabolism and energy expenditure are also diminished, and both type 1 and type 2 diabetes are induced. A replication-deficient recombinant adeno-associated virus vector engineered to encode the leptin gene (rAVV-LEP) has been used in models of diabetes as a novel therapeutic approach. After rAVV-LEP injection in ob/ob mice, hypothalamic leptin expression was increased, body weight was suppressed, and hyperinsulinemia was ameliorated. Additionally injection of rAVV-LEP into the hypothalamus suppressed the expression of orexigenic neuropeptide Y (NPY) and enhanced anorexigenic pro-opiomelanocortin (POMC) in the arcuate nucleus (ARC) in rats. It is proposed that central leptin gene therapy should be tested clinically to reduce the worldwide epidemic of obesity, diabetes, and shortened life span. In this article, the information has been assembled from published review articles on this topic.
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PMID:Long-term correction of type 1 and 2 diabetes by central leptin gene therapy independent of effects on appetite and energy expenditure. 2356 90

Energy and glucose homeostasis are regulated by central serotonin 2C receptors. These receptors are attractive pharmacological targets for the treatment of obesity; however, the identity of the serotonin 2C receptor-expressing neurons that mediate the effects of serotonin and serotonin 2C receptor agonists on energy and glucose homeostasis are unknown. Here, we show that mice lacking serotonin 2C receptors (Htr2c) specifically in pro-opiomelanocortin (POMC) neurons had normal body weight but developed glucoregulatory defects including hyperinsulinemia, hyperglucagonemia, hyperglycemia, and insulin resistance. Moreover, these mice did not show anorectic responses to serotonergic agents that suppress appetite and developed hyperphagia and obesity when they were fed a high-fat/high-sugar diet. A requirement of serotonin 2C receptors in POMC neurons for the maintenance of normal energy and glucose homeostasis was further demonstrated when Htr2c loss was induced in POMC neurons in adult mice using a tamoxifen-inducible POMC-cre system. These data demonstrate that serotonin 2C receptor-expressing POMC neurons are required to control energy and glucose homeostasis and implicate POMC neurons as the target for the effect of serotonin 2C receptor agonists on weight-loss induction and improved glycemic control.
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PMID:Serotonin 2C receptors in pro-opiomelanocortin neurons regulate energy and glucose homeostasis. 2417 24

Loss of pancreatic islet function and insulin-producing beta cell mass is a central hallmark in the pathogenesis of both type 1 and type 2 diabetes. While in type 1 diabetes this phenomenon is due to an extensive destruction of beta cells caused by an autoimmune process, the mechanisms resulting in beta cell failure in type 2 diabetes are different and less clear. Also, beta cell destruction in type 1 diabetes occurs early and is the initial step in the pathogenetic process, while beta cell loss in type 2 diabetes after an initial phase of hyperinsulinemia due to the underlying insulin resistance occurs relatively late and it is less pronounced. Since diabetes mellitus is the most frequent endocrine disease, with an increasing high prevalence worldwide, huge efforts have been made over the past many decades to identify predisposing genetic, environmental, and nutritional factors in order to develop effective strategies to prevent the disease. In parallel, extensive studies in different cell systems and animal models have helped to elucidate our understanding of the physiologic function of islets and to gain insight into the immunological and non-immunological mechanisms of beta cell destruction and failure. Furthermore, currently emerging concepts of beta cell regeneration (e.g., the restoration of the beta cell pool by regenerative, proliferative and antiapoptotic processes, and recovery of physiologic islet function) apparently is yielding the first promising results. Recent insights into the complex endocrine and paracrine mechanisms regulating the physiologic function of pancreatic islets, as well as beta cell life and death, constitute an essential part of this new and exciting area of diabetology. For example, understanding of the physiological role of glucagon-like peptide 1 has resulted in the successful clinical implementation of incretin-based therapies over the last years. Further, recent data suggesting paracrine effects of growth hormone-releasing hormone and corticotropin-releasing hormone on the regulation of pancreatic islet function, survival, and proliferation as well as on local glucocorticoid metabolism provide evidence for a potential role of the pancreatic islet-stress axis in the pathophysiology of diabetes mellitus. In this chapter, we provide a comprehensive overview of current preventive and regenerative concepts as a basis for the development of novel therapeutic approaches to the treatment of diabetes mellitus. A particular focus is given on the potential of the pancreatic islet-stress axis in the development of novel regenerative strategies.
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PMID:Modulation of the pancreatic islet-stress axis as a novel potential therapeutic target in diabetes mellitus. 2455 19

Earlier, we showed that rearing of newborn rats on a high-carbohydrate (HC) milk formula resulted in the onset of hyperinsulinemia, its persistence in the post-weaning period and adult-onset obesity. DNA methylation of CpG dinucleotides in the proximal promoter region and modifications in the N-terminal tail of histone 3 associated with the neuropeptide Y (Npy) and pro-opiomelanocortin (Pomc) genes were investigated to decipher the molecular mechanisms supporting the development of obesity in HC females. Although there were no differences in the methylation status of CpG dinucleotides in the proximal promoter region of the Pomc gene, altered methylation of specific CpG dinucleotides proximal to the transcription start site was observed for the Npy gene in the hypothalami of 16- and 100-day-old HC rats compared with their methylation status in mother-fed (MF) rats. Investigation of histone tail modifications on hypothalamic chromatin extracts from 16-day-old rats indicated decreased acetylation of lysine 9 in histone 3 (H3K9) for the Pomc gene and increased acetylation for the same residue for the Npy gene, without changes in histone methylation (H3K9) in both genes in HC rats. These findings are consistent with the changes in the levels of Npy and Pomc mRNAs in the hypothalami of HC rats compared with MF animals. Our results suggest that epigenetic modifications could contribute to the altered gene expression of the Npy and Pomc genes in the hypothalami of HC rats and could be a mechanism leading to hyperphagia and the development of obesity in adult female HC rats.
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PMID:Epigenetic changes in hypothalamic appetite regulatory genes may underlie the developmental programming for obesity in rat neonates subjected to a high-carbohydrate dietary modification. 2492 27


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