UNIPROT:P01189 - FACTA Search

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Query: UNIPROT:P01189 (beta-endorphin)
21,003 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

Hypoglycaemia induced by insulin injection is a powerful stimulus to the hypothalamic-pituitary-adrenal (HPA) axis and drives the secretion of corticotropin-releasing hormone and vasopressin from the neurones in the paraventricular nucleus (PVN), as well as the downstream hormones, adrenocorticotropic hormone and corticosterone. In some brain regions, hypoglycaemia also provokes increases in extracellular fluid concentrations of glutamate. Regulation of glutamatergic mechanisms could be involved in the control of the HPA axis during hypoglycaemic stress and one potential site of regulation might be at the receptors for glutamate, which are expressed in the PVN. Insulin (2.0 IU/kg, i.p.) or saline was administered to adult male Sprague-Dawley rats and the animals were sacrificed 30 min, 180 min and 24 h after injection. The amount of several kainic acid-preferring glutamate receptor mRNAs (i.e. KA2, GluR5 and GluR6) were assessed in the PVN by in situ hybridisation histochemistry. Injection of insulin induced a rapid fall in plasma glucose concentrations, which was mirrored by an increase in plasma corticosterone concentrations. KA2 and GluR5 mRNAs are highly expressed within the rat PVN, and responded to hypoglycaemia with robust increases in expression that endured beyond the period of hypoglycaemia itself. However, GluR6 mRNA is expressed in the areas adjacent to the PVN and hypoglycaemic stress failed to alter expression of this mRNA. These experiments suggest that kainic acid-preferring glutamate receptors are responsive to changes in plasma glucose concentrations and may participate in the activation of the PVN neurones during hypoglycaemic stress.
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PMID:Provocation of kainic acid receptor mRNA changes in the rat paraventricular nucleus by insulin-induced hypoglycaemia. 1579 62

Insulin action in the central nervous system regulates energy homeostasis and glucose metabolism. To define the insulin-responsive neurons that mediate these effects, we generated mice with selective inactivation of the insulin receptor (IR) in either pro-opiomelanocortin (POMC)- or agouti-related peptide (AgRP)-expressing neurons of the arcuate nucleus of the hypothalamus. While neither POMC- nor AgRP-restricted IR knockout mice exhibited altered energy homeostasis, insulin failed to normally suppress hepatic glucose production during euglycemic-hyperinsulinemic clamps in AgRP-IR knockout (IR(DeltaAgRP)) mice. These mice also exhibited reduced insulin-stimulated hepatic interleukin-6 expression and increased hepatic expression of glucose-6-phosphatase. These results directly demonstrate that insulin action in POMC and AgRP cells is not required for steady-state regulation of food intake and body weight. However, insulin action specifically in AgRP-expressing neurons does play a critical role in controlling hepatic glucose production and may provide a target for the treatment of insulin resistance in type 2 diabetes.
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PMID:Insulin action in AgRP-expressing neurons is required for suppression of hepatic glucose production. 1755 Jul 79

The alpha-melanocyte-stimulating hormone (alpha-MSH) has been shown to interact with various cells of the immune and inflammatory systems and down-regulate either the production or the action of proinflammatory cytokines. In this study, we investigated the potential of alpha-MSH to prevent pancreatic islet cells from cytotoxic injury by inflammatory cytokines released from peripheral blood mononuclear cells (PBMCs) in rats. Pancreatic islets were cocultured with PBMCs in a transwell system during stimulation by phorbol myristic acid and ionomycin. alpha-MSH (50 nmol/L) was added to PBMCs for 2 hours before coculture. Viability and apoptosis of islets were observed by the 3-(4,5-dimethylthiazole-2-yl)-, 5-diphenyltrazolium bromide assay and flow cytometry. We measured inflammatory cytokines and nitric oxide (NO). Insulin release from islets cocultured with mononuclear cells was checked as the metric of islet function. In comparison to the control group, the viability of islets with alpha-MSH-treated mononuclear cells was increased and apoptosis reduced significantly. Inflammatory cytokines, such as tumor necrosis factor-alpha and interleukin-1beta, were significantly reduced among the alpha-MSH-treated group. NO production in the alpha-MSH-treated group was decreased significantly. Insulin secretory function of the islets recovered in conditions of alpha-MSH treatment. This study demonstrated that alpha-MSH protected pancreatic islet cells from PBMC-mediated cytotoxicity and preserved insulin secretory function. This treatment may have the potential to improve graft survival in clinical islet transplantation.
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PMID:Protective effect of alpha-melanocyte-stimulating hormone on pancreas islet cell against peripheral blood mononuclear cell-mediated cytotoxicity in vitro. 1758 Jan 98

Insulin- and leptin-stimulated phosphatidylinositol-3 kinase (PI3K) activation has been demonstrated to play a critical role in central control of energy homeostasis. To delineate the importance of pathways downstream of PI3K specifically in pro-opiomelanocortin (POMC) cell regulation, we have generated mice with selective inactivation of 3-phosphoinositide-dependent protein kinase 1 (PDK1) in POMC-expressing cells (PDK1(DeltaPOMC) mice). PDK1(DeltaPOMC) mice initially display hyperphagia, increased body weight, and impaired glucose metabolism caused by reduced hypothalamic POMC expression. On the other hand, PDK1(DeltaPOMC) mice exhibit progressive, severe hypocortisolism caused by loss of POMC-expressing corticotrophs in the pituitary. Expression of a dominant-negative mutant of FOXO1 specifically in POMC cells is sufficient to ameliorate positive energy balance in PDK1(DeltaPOMC) mice but cannot restore regular pituitary function. These results reveal important but differential roles for PDK1 signaling in hypothalamic and pituitary POMC cells in the control of energy homeostasis and stress response.
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PMID:PDK1 deficiency in POMC-expressing cells reveals FOXO1-dependent and -independent pathways in control of energy homeostasis and stress response. 1839 35

Insulin and signalling through the vagus nerve act in concert to regulate metabolic homeostasis and ingestive behaviour. Our previous studies using streptozotocin (STZ)-diabetic rats have shown that hepatic branch vagotomy (HV), gastroduodenal branch vagotomy (GV) and capsaicin treatment of the common hepatic branch that selectively destroys afferent fibres (CapV), all promote lard, but not total, caloric intake to levels similar to those achieved with insulin treatment. Because hypothalamic and limbic mRNA expression of neuropeptides linked to energy balance is altered by STZ-diabetes and HV, we examined the role(s) of insulin and the common hepatic and gastroduodenal branches of the vagus nerve and hepatic afferent fibres in the regulation of these neuropeptides in rats with high, steady-state corticosterone levels. STZ-diabetic rats were prepared with osmotic minipumps containing either saline or insulin and were compared with nondiabetic counterparts: half of each group received a vagal manipulation, the other half were sham operated. Five days after surgery, rats were offered the choice of lard and chow to consume for another 5 days, when brains were collected and processed for in situ hybridisation. Paraventricular nucleus corticotrophin-releasing factor (CRF) mRNA was elevated by STZ treatment, an effect prevented by either insulin treatment or GV. By contrast, CRF mRNA expression in the central nucleus of the amygdala and bed nuclei of the stria terminalis was unaffected by STZ treatment, but HV and CapV manipulations elevated expression in the nondiabetic, but not STZ-diabetic groups. Arcuate nucleus neuropeptide Y, but not pro-opiomelanocortin, mRNA expression was elevated by STZ treatment and all vagal manipulations; however, exogenous insulin treatment failed to prevent this, in keeping with their previously documented elevated caloric intake. These results strongly suggest that the gastroduodenal branch and hepatic branch proper, which merge to form the common hepatic branch, differentially interact with prevailing insulin levels to regulate hypothalamic and limbic neuropeptide mRNA expression.
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PMID:Insulin and the constituent branches of the hepatic vagus interact to modulate hypothalamic and limbic neuropeptide mRNA expression differentially. 1863 24

Hyperglycemic crises of diabetic ketoacidosis and nonketotic hyperglycemia are associated with elevation of counterregulatory hormones and proinflammatory cytokines, markers of lipid peroxidation, and oxidative stress. To investigate if other conditions besides hyperglycemia could evoke such a prompt increase in cytokine levels, lipid peroxidation, and oxidative stress markers, we induced hypoglycemic stress by standard insulin tolerance test and measured proinflammatory cytokines, markers of lipid peroxidation, reactive oxygen species (ROS), and counterregulatory hormones. Insulin tolerance test was performed in 13 healthy male subjects with no history of infection, cardiovascular risk factors, or abnormal glucose. At baseline and at 30, 45, 60, 120, and 240 minutes after insulin injection, the following parameters were measured: glucose, cortisol, corticotropin, epinephrine (EP), norepinephrine (NE), growth hormone, tumor necrosis factor (TNF)-alpha, interleukin (IL) 1beta, IL-6, IL-8, free fatty acids, white blood cells, lipid peroxidation markers by thiobarbituric acid assay, and ROS by dichlorofluorescein method. The peak value of white blood cell count at 120 minutes was significantly associated with the peak values of NE at 30 minutes and cortisol at 60 minutes. By comparing the area under the curve of measured parameters, EP emerged as significant predictor of TNF-alpha (P = .05) and IL-8 (P = .027). Cortisol emerged as predictor of IL-1beta significantly (P = .05). Corticotropin predicted area under the curve of IL-6 with borderline significance (P = .06). In the present study, insulin-induced hypoglycemia in nondiabetic male subjects is associated with increased proinflammatory cytokines (TNF-alpha, IL-1beta, IL-6, and IL-8), markers of lipid peroxidation, ROS, and leukocytosis. Elevations of NE, EP, corticotropin, and cortisol in hypoglycaemia are associated with the elevation of the proinflammatory cytokines and leukocytosis.
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PMID:Proinflammatory cytokines in response to insulin-induced hypoglycemic stress in healthy subjects. 1930 62

Reduced food intake brings about an adaptive decrease in energy expenditure that contributes to the recidivism of obesity after weight loss. Insulin and leptin inhibit food intake through actions in the central nervous system that are partly mediated by the transcription factor FoxO1. We show that FoxO1 ablation in pro-opiomelanocortin (Pomc)-expressing neurons in mice (here called Pomc-Foxo1(-/-) mice) increases Carboxypeptidase E (Cpe) expression, resulting in selective increases of alpha-melanocyte-stimulating hormone (alpha-Msh) and carboxy-cleaved beta-endorphin, the products of Cpe-dependent processing of Pomc. This neuropeptide profile is associated with decreased food intake and normal energy expenditure in Pomc-Foxo1(-/-) mice. We show that Cpe expression is downregulated by diet-induced obesity and that FoxO1 deletion offsets the decrease, protecting against weight gain. Moreover, moderate Cpe overexpression in the arcuate nucleus phenocopies features of the FoxO1 mutation. The dissociation of food intake from energy expenditure in Pomc-Foxo1(-/-) mice represents a model for therapeutic intervention in obesity and raises the possibility of targeting Cpe to develop weight loss medications.
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PMID:The obesity susceptibility gene Cpe links FoxO1 signaling in hypothalamic pro-opiomelanocortin neurons with regulation of food intake. 1976 34

Previously, we reported that central (but not peripheral) administration of beta-endorphin to rat pups decreases basal ornithine decarboxylase (ODC; a growth-associated enzyme) activity throughout the body. This finding is consistent with the view that CNS beta-endorphin is an important regulator of postnatal development. Insulin is a hormone that markedly affects liver growth and evidence indicates that this occurs, in part, through its ability to regulate ODC expression. The current study examines the effects of intracisternal injection of beta-endorphin on the response of liver ODC to subcutaneous administration of insulin. Insulin (20 IU/kg body wt), markedly increased liver ODC activity in 2-, 4-, 6-, 10-, 18-, and 30-day-old rats. Intracisternal injection of beta-endorphin (1.5 mug/g brain wt) inhibited this response to insulin in 2-, 4-, 6-, 10-, and 18-day-old rats, but not in 30-day-old animals. This inhibition by beta-endorphin was not reversed by naloxone, indicating that the effect is not mediated by brain mu or delta opioid receptors. Centrally administered beta-endorphin also blocked the increases in liver ODC activity evoked by subcutaneous administration of cAMP. The results from these studies suggest that the postulated regulation of postnatal development by CNS beta-endorphin may occur through actions on both basal ODC activity and tissue ODC sensitivity to "classical" trophic factors. The modulation by beta-endorphin of liver ODC expression apparently occurs distally to cAMP-generating mechanisms.
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PMID:CNS beta-endorphin regulation of insulin-induced ornithine decarboxylase expression in liver of neonatal rats. 1991 77

Short-term pharmacological melanocortin activation deters diet-induced obesity (DIO) effectively in rodents. However, whether central pro-opiomelanocortin (POMC) gene transfer targeted to the hypothalamus or hindbrain nucleus of the solitary track (NTS) can combat chronic dietary obesity has not been investigated. Four-weeks-old Sprague-Dawley rats were fed a high fat diet for 5 months, and then injected with either the POMC or control vector into the hypothalamus or NTS, and body weight and food intake recorded for 68 days. Insulin sensitivity, glucose metabolism and adrenal indicators of central sympathetic activation were measured, and voluntary wheel running (WR) assessed. Whereas the NTS POMC-treatment decreased cumulative food consumption and caused a sustained weight reduction over 68 days, the hypothalamic POMC-treatment did not alter cumulative food intake and produced weight loss only in the first 25 days. At death, only the NTS-POMC rats had a significant decrease in fat mass. They also displayed enhanced glucose tolerance, lowered fasting insulin and increased QUICK value, and elevated adrenal indicators of central sympathetic activation. Moreover, the NTS-POMC animals exhibited a near 20% increase in distance ran relative to the respective controls, but the ARC-POMC rats did not. In conclusion, POMC gene transfer to the NTS caused modest anorexia, persistent weight loss, improved insulin sensitivity, and increased propensity for WR in DIO rats. These metabolic improvements may involve stimulation of energy expenditure via centrally regulated sympathetic outflow. The similar POMC treatment in the hypothalamus had minimal long-term physiological or metabolic impact. Thus, melanocortin activation in the brainstem NTS region effectively ameliorates chronic dietary obesity whilst that in the hypothalamus fails to do so.
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PMID:Pro-opiomelanocortin gene transfer to the nucleus of the solitary track but not arcuate nucleus ameliorates chronic diet-induced obesity. 2053 45

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