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)

Exposure to maternal gestational diabetes (GD) "programs" offspring for obesity in childhood and later life. Recent clinical data suggest that neonatal ingestion of breast milk from diabetic mothers might be crucially involved. Mediobasal hypothalamic nuclei such as the ventromedial nucleus (VMN), the paraventricular nucleus (PVN) and the arcuate nucleus (ARC) play a key role in the central nervous system regulation of food intake and body weight. In the ARC, orexigenic neuropeptides such as neuropeptide Y (NPY), galanin (GAL), and agouti-related peptide (AGRP) and anorexigenic neuropeptides such as proopiomelanocortin (POMC) and alpha-melanocyte-stimulating hormone (MSH) are expressed. We investigated the effects of neonatal exposure to milk from GD rat dams on the development of hypothalamic nuclei in weanling rats. Offspring of control (CO) rat dams cross-fostered to GD rat dams (CO-GD) developed early postnatal growth delay. On d 21 of life, CO-GD rats showed structural and functional hypothalamic "malprogramming." The ARC of CO-GD rats showed increased immunopositivity of both NPY and AGRP under basal conditions, despite normal levels of glucose, leptin, and insulin. Conversely, CO-GD rats showed decreased immunopositivity of both POMC and MSH and decreased density of immunopositive neurons, compared with offspring of control rat dams cross-fostered to control rat dams. No morphometric alterations were found in the VMN, whereas CO-GD rats showed an increased total number of neurons in the PVN. In summary, neonatal exposure to maternal diabetes through the intake of dam's milk in rats leads to a complex malprogramming of hypothalamic orexigenic and anorexigenic circuits that are critically involved in the lifelong regulation of food intake, body weight, and metabolism.
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PMID:Cross-fostering to diabetic rat dams affects early development of mediobasal hypothalamic nuclei regulating food intake, body weight, and metabolism. 1498 62

In the adult, a hypothalamic neural network acts to maintain energy balance in response to nutritional feedback from the periphery. Although there is an immediate requirement for this system to be functional at birth, it is unknown whether the components of this central neural network are expressed in the developing brain before birth. We therefore examined in the fetal sheep hypothalamus during late gestation gene expression for leptin receptor (OB-Rb) and neuropeptides that regulate energy balance in the adult. Brains were collected from fetal sheep at 110 days (n = 12) and 140 days of gestation (n = 5) (term = 150 days) and gene expression was detected in all hypothalami using in situ hybridization with radiolabelled riboprobes for OB-Rb, neuropeptide Y (NPY), agouti-related peptide, pro-opiomelanocortin and cocaine- and amphetamine-regulated transcript (CART). All mRNAs were expressed in the arcuate nucleus of fetuses at both time points. Additional sites of mRNA expression were the dorsomedial hypothalamus (DMH) for NPY, the paraventricular nucleus (PVN), ventromedial hypothalamus (VMH) and lateral hypothalamic area for CART, and the DMH, PVN and VMH for OB-Rb. We have therefore demonstrated that adult-like localization of gene expression for OB-Rb and key appetite regulatory neuropeptides is established in the ovine hypothalamus before birth. Thus, the fetus possesses a central appetite regulatory neural network with the potential to respond to changes in nutrient supply, which could impact on energy balance regulation both before and after birth.
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PMID:Appetite regulatory neuropeptides are expressed in the sheep hypothalamus before birth. 1518 24

gamma-Aminobutyric acid (GABA), the major inhibitory neurotransmitter in the brain, acts via two different type of GABA receptors. GABA(A) receptors are composed of five subunits that belong to eight different classes. Depending on their subunit composition, distinct pharmacological and electrophysiological properties are obtained. GABA is produced in certain hypothalamic neurones known to be involved in control of feeding behaviour. We report the detailed immunohistochemical localization of four GABA(A)R alpha subunits in hypothalamic regions associated with the regulation of feeding behaviour. Immunoreactive structures for all studied GABA(A)R alpha subunits were observed in the hypothalamus, but with subunit-specific staining patterns. GABA(A)R alpha(1) immunoreactivity was most prominent in the dorsomedial hypothalamic nucleus and in the lateral hypothalamic area (LHA), whereas GABA(A)R alpha(2), alpha(3) and alpha(5) subunits exhibited particularly strong immunoreactivity in the ventromedial hypothalamic nucleus. In comparison, GABA(A)R alpha subunit immunoreactivities were generally weak in the arcuate nucleus. In the ventromedial part of the arcuate nucleus, neuropeptide Y- and agouti-related peptide-containing cell bodies, which also are known to be GABAergic, were immunoreactive for only the GABA(A)R alpha(3) subunit, whereas pro-opiomelanocortin- and cocaine- and amphetamine-regulated transcript- containing cell bodies located in the ventrolateral subdivision of the arcuate nucleus, showed GABA(A)R alpha(1), alpha(2) and alpha(3) subunit immunoreactivity. In the LHA, GABA(A)R alpha(3) subunit immunoreactivity was demonstrated in both melanin-concentrating hormone (MCH) and orexin-containing neurones. In addition, MCH neurones contained GABA(A)R alpha(2) immunoreactivity. In neurones of the tuberomammillary nucleus, GABA(A)R alpha(2) and alpha(5) subunits were colocalized with histidine decarboxylase, a marker for histamine-containing neurones.
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PMID:Cellular localization of GABA receptor alpha subunit immunoreactivity in the rat hypothalamus: relationship with neurones containing orexigenic or anorexigenic peptides. 1521 62

The expression of neuropeptide Y (NPY) and agouti-related peptide (AgRP), both of which are important neuropeptides involved in regulation of energy balance and hormone secretion, is up-regulated in the arcuate nucleus during lactation in rodents. The present study tested whether reductions in circulating insulin and/or leptin that occur in lactation provide the critical signals to these systems. Lactating female rats received 3-day infusions of either bovine insulin or recombinant rat leptin via Alzet Osmotic minipumps implanted subcutaneously in regimens designed to restore serum concentrations of these hormones to the higher non-lactating level. Compared to non-lactating rats in diestrus, lactating rats displayed significantly lower serum concentrations of insulin and leptin, and significantly increased NPY peptide concentrations in the paraventricular nucleus (PVN) and median eminence, and AgRP mRNA in the arcuate nucleus. Infusion of leptin in lactating females significantly increased serum concentrations of leptin and significantly reduced NPY concentrations in the PVN and median eminence, and decreased NPY and AgRP mRNAs in the arcuate nucleus. The same effects were produced by infusion of insulin in lactating rats, which restored both insulin and leptin concentrations in serum. The levels of pro-opiomelanocortin mRNA in the arcuate nucleus were not different in non-lactating and lactating females, and were not altered by leptin or insulin treatment. These findings support the hypothesis that the reduction in circulating leptin during lactation contributes to increased expression of NPY and AgRP in hypothalamic systems involved in the behavioural and neuroendocrine adaptations to lactation.
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PMID:Role of leptin in orexigenic neuropeptide expression during lactation in rats. 1521 67

The melanocortins (alpha-melanocyte-stimulating hormone and adrenocorticotropin) act on epidermal melanocytes to increase melanogenesis, the eumelanin/pheomelanin ratio and dendricity. These actions are mediated by the heptahelical melanocortin 1 receptor (MC1R), positively coupled to adenylyl cyclase. Gain-of-function mouse Mc1r alleles are associated with a dark, eumelanic coat. Conversely, loss-of-function variants, or overexpression of agouti, a natural melanocortin antagonist, yield yellow, pheomelanic furs. In humans, loss-of-function MC1R variants are associated with fair skin, poor tanning, propensity to freckle and increased skin cancer risk. Therefore, MC1R is a key regulator of mammalian pigmentation. Several observations such as induction of constitutive pigmentation in amelanotic mouse melanoma cells following expression of MC1R indicate that the receptor might display agonist-independent activity. We report a systematic and comparative study of MC1R and Mc1r constitutive activity. We show that expression of MC1R in heterologous systems leads to an agonist-independent increase in cyclic adenosine monophophate (cAMP). Basal signalling is a function of receptor expression and is two to fourfold higher for MC1R than for Mc1r. Moreover, it is observed in human melanoma cells over-expressing the MC1R. Constitutive signalling is abolished or reduced by point mutations of MC1R impairing the response to agonists, and is only doubled by the Lys94Glu mutation, mimicking the constitutively active mouse E(so-3J) allele. Stable or transient expression of wild-type MC1R, but not of loss-of-function mutants, potently stimulates forskolin activation of adenylyl cyclase, a common feature of constitutively active Gs-coupled receptors. Therefore, human MC1R displays a strong agonist-independent constitutive activity.
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PMID:Agonist-independent, high constitutive activity of the human melanocortin 1 receptor. 1525 Sep 41

The melanocortin system is involved in regulation of food intake and energy balance. Melanocyte-stimulating hormone (alpha-MSH) is an endogenous melanocortin receptor (MC-R) agonist. It acts on MC3/4 receptors to reduce appetite and to increase energy expenditure. The production of alpha-MSH is reduced during food deprivation, but MC4-R density is increased. The net effect of reduced alpha-MSH production and increased receptor level is not clear. To address this question, responses of ventromedial hypothalamic (VMH) neurons to melanotan II (MTII; a synthetic analogue of alpha-MSH) were recorded in brain slices from fed and food-deprived rats. Responses to the highest dose MTII were observed in 61% of VMH neurons from fed rats but only 33% of VMH neurons from food-deprived rats. To assess a possible mechanism by which responsiveness to melanocortins is diminished even though receptor number is augmented during fasting, we examined the effect of agouti gene-related peptide (AGRP), an endogenous MC-R antagonist that stimulates food intake. The synthesis of AGRP increases during fasting. AGRP significantly reduced VMH responsiveness to MTII. Additionally, AGRP by itself evoked neuronal responses, in contrast to synthetic MC-R antagonists. AGRP (1 nM) induced a predominant inhibitory effect on VMH neurons in food-deprived rats but not in fed rats. In the presence of AGRP, MTII induced a significant inhibition of neuronal activity in deprived rats, but not in fed rats. Inhibition of VMH neurons reduces energy expenditure and the satiety signal. These findings suggest that although food deprivation increases MC4-R density, it nevertheless reduces the effectiveness of melanocortins on VMH neurons, possibly by the involvement of AGRP.
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PMID:Food deprivation decreases responsiveness of ventromedial hypothalamic neurons to melanocortins. 1526 29

The regulation of bodyweight is a complex process involving the interplay of neuronal circuitries controlling food intake and energy expenditure (thermogenesis) with endocrine secretions modulating the activity of the neurons making up those circuitries. The neurons controlling food intake and thermogenesis also modulate the hypothalamic-pituitary-adrenal axis, the role of which in the regulation of energy balance has been acknowledged for some time. These neurons secrete various neuromolecules or neuropeptides including endocannabinoids, neuropeptide Y, agouti-related protein, melanin-concentrating hormone, orexins (hypocretins), melanocortins, cocaine- and amphetamine-regulated transcript, thyrotropin-releasing hormone, corticotropin-releasing hormone, and urocortins. Among those peptides, neuropeptide Y, agouti-related peptide, melanin-concentrating hormone, orexins, and endocannabinoids have been classified as being anabolic molecules whereas melanocortins, cocaine- and amphetamine-regulated transcript, thyrotropin-releasing hormone, and corticotropin-releasing hormone are referred to as catabolic peptides. The expression and secretion of these neuromolecules are known to be affected by the anabolic (corticosteroids and ghrelin) and catabolic (leptin, insulin, and glucagon-like peptide 1) peripheral hormones. A link is made between the pathways regulating energy balance and those modulating the activity of the hypothalamic-pituitary-adrenal axis.
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PMID:Circuitries involved in the control of energy homeostasis and the hypothalamic-pituitary-adrenal axis activity. 1533 Jun 75

Public health efforts and current antiobesity agents have not controlled the increasing epidemic of obesity. Investigational antiobesity agents consist of 1) central nervous system agents that affect neurotransmitters or neural ion channels, including antidepressants (bupropion), selective serotonin 2c receptor agonists, antiseizure agents (topiramate, zonisamide), some dopamine antagonists, and cannabinoid-1 receptor antagonists (rimonabant); 2) leptin/insulin/central nervous system pathway agents, including leptin analogues, leptin transport and/or leptin receptor promoters, ciliary neurotrophic factor (Axokine), neuropeptide Y and agouti-related peptide antagonists, proopiomelanocortin and cocaine and amphetamine regulated transcript promoters, alpha-melanocyte-stimulating hormone analogues, melanocortin-4 receptor agonists, and agents that affect insulin metabolism/activity, which include protein-tyrosine phosphatase-1B inhibitors, peroxisome proliferator activated receptor-gamma receptor antagonists, short-acting bromocriptine (ergoset), somatostatin agonists (octreotide), and adiponectin; 3) gastrointestinal-neural pathway agents, including those that increase cholecystokinin activity, increase glucagon-like peptide-1 activity (extendin 4, liraglutide, dipeptidyl peptidase IV inhibitors), and increase protein YY3-36 activity and those that decrease ghrelin activity, as well as amylin analogues (pramlintide); 4) agents that may increase resting metabolic rate ("selective" beta-3 stimulators/agonist, uncoupling protein homologues, and thyroid receptor agonists); and 5) other more diverse agents, including melanin concentrating hormone antagonists, phytostanol analogues, functional oils, P57, amylase inhibitors, growth hormone fragments, synthetic analogues of dehydroepiandrosterone sulfate, antagonists of adipocyte 11B-hydroxysteroid dehydrogenase type 1 activity, corticotropin-releasing hormone agonists, inhibitors of fatty acid synthesis, carboxypeptidase inhibitors, indanones/indanols, aminosterols, and other gastrointestinal lipase inhibitors (ATL962). Finally, an emerging concept is that the development of antiobesity agents must not only reduce fat mass (adiposity) but must also correct fat dysfunction (adiposopathy).
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PMID:Current and investigational antiobesity agents and obesity therapeutic treatment targets. 1534 Jan

Sheep exhibit photoperiod-driven seasonal changes in appetite and body weight so that nutritional status increases in long days (LD) and decreases in short days (SD); additionally, they are reproductively active in SD and inactive in LD. We addressed the hypothesis that appetite-regulatory genes in the hypothalamus respond differently to changes in nutritional feedback induced by photoperiod as opposed to food restriction, and that responses would be influenced by gonadal steroid status. Castrated oestradiol-implanted male sheep were kept in SD (8 h light/day) or LD (16 h light/day) for 11 weeks, with ad libitum or restricted food (experiment 1; n=8/group). Rams were kept in SD or LD for 12 weeks with ad libitum or restricted food (experiment 2; n=6/group). Gene expression (by in situ hybridisation) in the hypothalamic arcuate nucleus for leptin receptor (OB-Rb), neuropeptide Y (NPY), pro-opiomelanocortin (POMC) and agouti-related peptide (AGRP) was unaffected by photoperiod treatment, but food restriction increased NPY and AGRP mRNAs, in experiment 1. In experiment 2, mRNAs for POMC and cocaine- and amphetamine-regulated transcript (CART) were up-regulated and AGRP down-regulated in SD, while food restriction increased OB-Rb mRNA, increased NPY and AGRP mRNAs only in LD and decreased POMC mRNA only in SD. Thus, gene expression responded differently to photoperiod and food restriction, and the melanocortin pathway was up-regulated in SD in reproductively activated rams but not in oestradiol-implanted castrates. These data support the hypothesis that hypothalamic appetite-regulatory pathways respond differently to changes in nutritional feedback induced by photoperiod as opposed to food restriction, with gonadal steroid feedback additionally influencing the responses.
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PMID:Effects of nutritional status and gonadal steroids on expression of appetite-regulatory genes in the hypothalamic arcuate nucleus of sheep. 1535 Jan 83

Rats normally eat about 85% of their food at night. Lactation increases food intake 3- to 4-fold, but the diurnal pattern of food intake persists. The mechanisms responsible for the diurnal and lactation-induced changes in food intake are still unresolved, hence we have further investigated the possible roles of serum leptin and hypothalamic expression of neuropeptide Y (NPY), agouti-related peptide (AgRP) and pro-opiomelanocortin (POMC) in rats. Suppressor of cytokine signalling-3 (SOCS-3) acts as a feedback inhibitor of leptin signalling in the hypothalamus, hence changes in expression of SOCS-3 were also investigated. Changes in expression of NPY, AgRP or POMC alone could not account for the diurnal changes in intake and their alteration by lactation. However, there were increased AgRP mRNA:POMC mRNA ratios at night and also during lactation, which were very similar to estimated changes in food intake. Such changes in expression may result in dominance of the orexigenic AgRP peptide over the appetite-suppressing POMC-derived peptides, and so could contribute to the hyperphagia in these states. Diurnal and lactation-related changes in the AgRP mRNA:POMC mRNA ratio and food intake are not due to changes in leptin alone. However, hypoleptinaemia, possibly through increased expression of NPY, may contribute to the hyperphagia of lactation. In the dark, expression of SOCS-3 was decreased in non-lactating rats; lactation decreased SOCS-3 expression in both light and dark phases. However, such changes are likely to enhance the ability of leptin-responsive neurones to transmit the leptin signal, and so are unlikely to contribute to either the nocturnal increase in appetite or the hyperphagia of lactation.
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PMID:Diurnal changes in hypothalamic neuropeptide and SOCS-3 expression: effects of lactation and relationship with serum leptin and food intake. 1552 85


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