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)

Organisms respond to infection in a complex manner involving bidirectional interactions between the neuroendocrine and immune systems. Many of the bioactive endocrine/immune factors are synthesized in a precursor form and are expected to be activated by prohormone convertases (PCs). Since patients with both type 1 and type 2 diabetes have an increased incidence and severity of infections, we hypothesized that in a condition of hyperglycemia, these processing enzymes would be activated in an immune tissue, the spleen. To test this hypothesis, we treated rats with intraperitoneal streptozotocin (STZ) (50 mg/kg/day) daily for 5 days and measured splenic PC1 and PC2 mRNA by ribonuclease protection assay. We found that PC1 mRNA was increased 6.0+/-0.02-fold (P<0.05) and PC2 mRNA was increased 1.80+/-0.01-fold (P<0.005) in the spleen of rats that received STZ compared to rats that received vehicle. Western blot indicated that the 75-kDa form of PC1 was the only form of PC1 present in the spleen and that this form increased with STZ treatment. Immunohistochemistry revealed that PC1 was found in both the white pulp (T-lymphocytes) and red pulp (monocytes and macrophages) and that its increase in immunoreactivity occurred primarily in the white pulp. PC2 and pro-opiomelanocortin (POMC, a possible splenic substrate for PC1/PC2) immunoreactivity was found predominantly in the red pulp. STZ induced an increase in splenic PC1 and POMC, but not PC2 protein levels. We conclude that in the STZ model of diabetes, splenic PCs are induced, which could lead to an increased activation of many immune-derived hormones. We speculate that this up-regulation of prohormone converting enzymes may be related to the increased infections seen in patients with both type 1 and type 2 diabetes.
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PMID:Up-regulation of splenic prohormone convertases PC1 and PC2 in diabetic rats. 1173 Sep 86

The fatty acid synthase inhibitor, C75, acts centrally to reduce food intake and body weight in mice. Here we report the effects of C75 on the expression of key orexigenic [neuropeptide Y (NPY), agouti-related protein (AgRP), and melanin-concentrating hormone] and anorexigenic [pro-opiomelanocortin (POMC) and cocaine-amphetamine-related transcript (CART)] neuropeptide messages in the hypothalami of lean and obese (ob/ob) mice. In lean mice, C75 rapidly and almost completely blocked food intake and prevented fasting-induced up-regulation of hypothalamic AgRP and NPY mRNAs, as well as down-regulation of CART and POMC mRNAs. Thus, in lean mice C75 seems to interrupt the fasting-induced signals that activate expression of NPY and AgRP and suppression of POMC and CART. In obese mice, C75 rapidly suppressed food intake, reduced body weight, and normalized obesity-associated hyperglycemia and hyperinsulinemia. Like its effect in lean mice, C75 prevented the fasting-induced increase of hypothalamic NPY and AgRP mRNAs in obese mice, but had no effect on the expression of POMC and CART mRNAs. The suppressive effect of C75 on food intake in lean mice seems to be mediated both by NPY/AgRP and POMC/CART neurons, whereas in obese mice the effect seems to be mediated primarily by NPY/AgRP neurons. In both lean and obese mice, C75 markedly increased expression of melanin-concentrating hormone and its receptor in the hypothalamus.
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PMID:Effect of a fatty acid synthase inhibitor on food intake and expression of hypothalamic neuropeptides. 1175 83

Opioid plays an important role in the regulation of glucose homeostasis in diabetic rats lacking insulin. The present study investigated the changes of beta-endorphin biosynthesis in the adrenal medulla of streptozotocin-induced diabetic rats (STZ-diabetic rats) by determination of the gene expression of pro-opiomelanocortin (POMC) and the amount of beta-endorphin. Expression of the distinct mRNA that encodes proteins of POMC was studied using reverse transcription combined with polymerase chain reaction (RT-PCR). Results of RT-PCR demonstrated that the mRNA level of POMC in the adrenal gland markedly increased in STZ-diabetic rats as compared with that in normal rats. The content of beta-endorphin-like immunoreactivity (BER) in the adrenal medulla, determined by enzyme-linked immunosorbent assay, was actually higher in diabetic rats with insulin deficiency. Normalization of the plasma glucose concentration in STZ-diabetic rats with exogenous insulin or phlorizin, an inhibitor of the renal tubular glucose transport, reversed the mRNA level of POMC in the adrenal gland after 4 days of treatment. A similar decrease of BER amount also observed in the adrenal medulla of STZ-diabetic rats received the same treatment with exogenous insulin or phlorizin. Therefore, correction of hyperglycemia in STZ-diabetic rats could reverse the higher gene expression of POMC in the adrenal gland. These results suggest that hyperglycemia is responsible for the increase of POMC gene expression to enhance beta-endorphin biosynthesis in the adrenal gland of STZ-diabetic rats.
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PMID:Increase of beta-endorphin biosynthesis in the adrenal gland of streptozotocin-induced diabetic rats. 1179 85

Melanocortin-4 Receptor (MC4R) plays an important role in the regulation of human obesity. It can cooperate with leptin, neuropeptide Y(NPY) and melanocyte-stimulating hormone (MSH) to regulate body weight and feeding. Inactivation of this receptor by gene targeting in mice results in a maturity onset obesity syndrome associated with hyperphagic, hyperinsulinemia, hyperglycemia, as well as decreased linear growth and adult obesity. Multiple alignments of the sequences from individuals of several pig lines identified a single nucleotide substitution(G-->A) at position 298 of the seventh transmembrane domain. In present study, polymorphism distribution of MC4R gene fragment in resource population was studied using PCR-RFLP method based on the enzyme Taq I. The genotype was analyzed with the phenotype of the slaughtered individuals. The results showed that the frequencies of MC4R genotype varied in different breeds. The correlation analysis demonstrated the genotype of MC4R was in significant relation with back-fat thickness on thorax-waist, buttock and the average back-fat thickness, as well as with the width and area of longissmus dorsi (LD), and the percentage of skin. MC4R gene plays a role mainly in the pattern of dominant effect, and all the additive effects were not significant.
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PMID:[Molecular screening of MC4R gene and association with fat traits in pig resource family]. 1209 26

Neuronal plasticity during the critical postnatal period of development seems to promote a change in the function of the hypothalamic regulatory system of body weight. Rats raised in small litters (SL) of only three pups per mother compared to ten or twelve in control litters (CL) gain significantly more weight than normal rats till weaning and are overweight also in later life. These rats are known to express hyperleptinemia, hyperglycemia and hyperinsulinemia. The review summarizes the results of action of leptin and insulin as well as of several feeding-relevant neuropeptides on neuronal activity of hypothalamic regulatory centres in overweight SL rats compared to controls. The study was performed on brain slices perfused with solution containing 10 mM glucose. Whereas a normally inhibitory action of leptin and insulin on medial arcuate neurons (ArcM) is reduced in SL rats and partly replaced by activation, the normally activating effect of these hormones on ventromedial (VMH) neurons is altered to predominant inhibition. Inhibition of ArcM neurons may decrease the release of the orexigenic neuropeptide Y (NPY) and agouti gene-related protein (AGRP). Thus, the negative feedback by leptin and insulin on food intake is replaced by diminished response and partly positive feedback processes in SL rats. The action of NPY and AGRP as well as of the orexigenic melanin-concentrating hormone on paraventricular (PVH) and VMH neurons is also shaped from activation or bimodal effects to predominant inhibition. Such inhibition of PVH and VMH might lead to reduced energy expenditure in small litter rats. Also the anorexigenic melanocortin alpha-MSH seems to contribute into increased energy storage. These altered responses of hypothalamic neurons in overweight small litter rats might reflect a general mechanism of neurochemical plasticity and "malprogramming" of hypothalamic neuropeptidergic systems leading to a permanently altered regulatory function.
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PMID:Altered neuronal responses to feeding-relevant peptides as sign of developmental plasticity in the hypothalamic regulatory system of body weight. 1465 33

We examined the effect of six doses of dexamethasone (Dex) administered daily (2-7 days of age) to postnatal rats on body weight gain, food and water intake, peripheral hormonal/metabolic milieu, and hypothalamic neuropeptides that regulate food intake. We observed a Dex-induced acute (3 days of age) suppression of endogenous corticosterone and an increase in circulating leptin concentrations that were associated with a decrease in body weight in males and females. Followup during the suckling, postsuckling, and adult stages (7-120 days of age) revealed hypoleptinemia in males and females, and hypoinsulinemia, a relative increase in the glucose-to-insulin ratio, and a larger increase in skeletal muscle glucose transporter (GLUT 4) concentrations predominantly in the males, reflective of a catabolic state associated with a persistent decrease in body weight gain. The increase in the glucose-to-insulin ratio and hyperglycemia was associated with an increase in water intake. In addition, the changes in the hormonal/metabolic milieu were associated with an increase in hypothalamic neuropeptide Y content in males and females during the suckling phase, which persisted only in the 120-day-old female with a transient postnatal decline in alpha-melanocyte-stimulating hormone and corticotropin-releasing factor. This increase in neuropeptide Y (NPY) during the suckling phase in males and females was associated with a subsequent increase in adult food intake that outweighed the demands of body weight gain. In contrast to the adult hypothalamic findings, cerebral ventricular dilatation was more prominent in adult males. We conclude that postnatal Dex treatment causes permanent sex-specific changes in the adult phenotype, setting the stage for future development of diabetes (increased glucose:insulin ratio), obesity (increased NPY and food intake), and neurological impairment (loss of cerebral volume).
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PMID:Postnatal glucocorticoid exposure alters the adult phenotype. 1500 31

We investigated the effect of daily intracerebroventricular (ICV) leptin administration (neonatal age 2-7 days) on hypothalamic neuropeptides (neuropeptide Y, alpha-melanocyte-stimulating hormone) that regulate food intake, body weight (BW) gain, and the metabolic/hormonal profile in suckling (8 and 21 days) and adult rat (35, 60, 90, and 120 days). ICV leptin (0.16 mug.g BW(-1).dose(-1); n = 70) led to a postnatal decline in BW (P = 0.0002) that persisted only in the adult females (P = 0.002). The postnatal decline in BW due to leptin was associated with a decline in food intake (P = 0.01) and hypothalamic leptin receptor (P = 0.008) and neuropeptide Y (P = 0.008) immunoreactivities and an increase in alpha-melanocyte-stimulating hormone (P = 0.008) immunoreactivity. In addition, hyperinsulinemia (P = 0.01) with hypocorticosteronemia (P = 0.007) occurred during the postnatal period with hypercorticosteronemia (P = 0.007) and hypoleptinemia (P = 0.008) and an increase in leutinizing hormone (P = 0.01) in the adult male and female progeny. Persistent hyperinsulinemia (P = 0.015) with hyperglycemia (P = 0.008) and glucose intolerance (P = 0.001) were observed only in the adult female. We conclude that postnatal leptin administration alters the adult female phenotype and speculate that this may relate to retention of leptin sensitivity resulting in a lipoatrophic state.
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PMID:Postnatal intracerebroventricular exposure to leptin causes an altered adult female phenotype. 1531 6

Endocrinopathy during sepsis can manifest as hyperglycemia and insulin resistance or as insufficient production of either adrenal corticosteroids or vasopressin. The results of a recent large clinical trial have demonstrated that tight glycemic control with insulin can confer survival benefit to selected intensive care unit patients. Relative impairment of adrenocortical reserve has been suggested to be an important contributor to the pathogenesis of shock in sepsis. Replacement doses of glucocorticoids and mineralocorticoids have been associated with improved survival in the subset of patients with blunted results on adrenocorticotropin hormone stimulation tests. Posterior pituitary production of vasopressin is diminished in septic shock while sensitivity to its vasopressor effects is enhanced. Clinical trials are underway to determine whether administration of vasopressin can improve outcomes in patients with septic shock. Whether the euthyroid sick syndrome represents an adaptive or a maladaptive response to severe illness remains unclear.
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PMID:The endocrine system during sepsis. 1548 39

Epinephrine, norepinephrine, and corticosterone responses to hypoglycemia are impaired in diabetic rats. Recurrent hypoglycemia further diminishes epinephrine responses. This study examined the sympathoadrenal system and hypothalamo-pituitary-adrenal axis for molecular adaptations underlying these defects. Groups were normal (N) and diabetic (D) rats and diabetic rats exposed to 4 days of 2 episodes/day of hyperinsulinemic hypoglycemia (D-hypo) or hyperinsulinemic hyperglycemia (D-hyper). D-hypo and D-hyper rats differentiated effects of hypoglycemia and hyperinsulinemia. Adrenal tyrosine hydroxylase (TH) mRNA was reduced (P < 0.05 vs. N) 25% in all diabetic groups. Remarkably, mRNA for phenylethanolamine N-methyltransferase (PNMT), which converts norepinephrine to epinephrine, was reduced (P < 0.05 vs. all) 40% only in D-hypo rats. Paradoxically, dopamine beta-hydroxylase mRNA was elevated (P < 0.05 vs. D, D-hyper) in D-hypo rats. Hippocampal mineralocorticoid receptor (MR) mRNA was increased (P < 0.05 vs. N) in all diabetic groups. Hippocampal glucocorticoid receptor (GR), hypothalamic paraventricular nucleus (PVN) GR and corticotropin-releasing hormone (CRH), and pituitary GR and proopiomelanocortin (POMC) mRNA levels did not differ. We conclude that blunted corticosterone responses to hypoglycemia in diabetic rats are not due to altered basal expression of GR, CRH, and POMC in the hippocampus, PVN, and pituitary. The corticosterone defect also does not appear to be due to increased hippocampal MR, since we have reported normalized corticosterone responses in D-hypo and D-hyper rats. Furthermore, impaired epinephrine counterregulation in diabetes is associated with reduced adrenal TH mRNA, whereas the additional epinephrine defect after recurrent hypoglycemia is associated with decreases in both TH and PNMT mRNA.
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PMID:Effects of diabetes and recurrent hypoglycemia on the regulation of the sympathoadrenal system and hypothalamo-pituitary-adrenal axis. 1549 9

Recently, we established that hypothalamo-pituitary-adrenal (HPA) and counterregulatory responses to insulin-induced hypoglycemia were impaired in uncontrolled streptozotocin (STZ)-diabetic (65 mg/kg) rats and insulin treatment restored most of these responses. In the current study, we used phloridzin to determine whether the restoration of blood glucose alone was sufficient to normalize HPA function in diabetes. Normal, diabetic, insulin-treated, and phloridzin-treated diabetic rats were either killed after 8 days or subjected to a hypoglycemic (40 mg/dl) glucose clamp. Basal: Elevated basal ACTH and corticosterone in STZ rats were normalized with insulin but not phloridzin. Increases in hypothalamic corticotrophin-releasing hormone (CRH) and inhibitory hippocampal mineralocorticoid receptor (MR) mRNA with STZ diabetes were not restored with either insulin or phloridzin treatments. Hypoglycemia: In response to hypoglycemia, rises in plasma ACTH and corticosterone were significantly lower in diabetic rats compared with controls. Insulin and phloridzin restored both ACTH and corticosterone responses in diabetic animals. Hypothalamic CRH mRNA and pituitary pro-opiomelanocortin mRNA expression increased following 2 h of hypoglycemia in normal, insulin-treated, and phloridzin-treated diabetic rats but not in untreated diabetic rats. Arginine vasopressin mRNA was unaltered by hypoglycemia in all groups. Interestingly, hypoglycemia decreased hippocampal MR mRNA in control, insulin-, and phloridzin-treated diabetic rats but not uncontrolled diabetic rats, whereas glucocorticoid receptor mRNA was not altered by hypoglycemia. In conclusion, despite elevated basal HPA activity, HPA responses to hypoglycemia were markedly reduced in uncontrolled diabetes. We speculate that defects in the CRH response may be related to a defective MR response. It is intriguing that phloridzin did not restore basal HPA activity but it restored the HPA response to hypoglycemia, suggesting that defects in basal HPA function in diabetes are due to insulin deficiency, but impaired responsiveness to hypoglycemia appears to stem from chronic hyperglycemia.
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PMID:Hyperglycemia does not increase basal hypothalamo-pituitary-adrenal activity in diabetes but it does impair the HPA response to insulin-induced hypoglycemia. 1577 66


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