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

The mechanism underlying the leptin-induced increased sympathetic nerve activity and cardiovascular tone was investigated in normal rats. The melanocortin (MC) peptides and other fragments derived from proopiomelancortin (POMC) have a diverse array of biological activities and have been implicated in mediating the feeding behavioral responses to leptin. In this study we evaluated the possible involvement of two major products of POMC, alpha-melanocyte stimulating hormone (alpha-MSH) and beta-endorphin, in mediating the effects of leptin on sympathetic activity and mean arterial pressure (MAP) in normal rats. Intraventricular (i.c.v.) cannulas were implanted in normal rats and allowed to recover. On the day of the study the animals were anesthetized with urethane alpha-chloralose and instrumented for the recording of MAP, lumbar sympathetic nerve activity (LSNA), and heart rate (HR). To determine the correlation between the leptin response and the POMC products, alpha-MSH and beta-endorphins were also injected into the lateral ventricle. alpha-MSH acted to increase MAP and LSNA while beta-endorphin decreased these parameters. Leptin administration by i.c.v. cannula increased the MAP and LSNA in normal rats. The i.c.v. administration of agouti protein, an alpha-MSH receptor antagonist, prior to leptin infusion blocked this response. Likewise, pretreatment with naloxone a beta-endorphin receptor antagonist also blocked the response to leptin. From these studies we conclude that the acute increased LSNA and MAP in response to i.c.v. leptin may be mediated by increased POMC and its subsequent production of breakdown product alpha-MSH and/or beta-endorphin and it is the subsequent action of alpha-MSH that increases MAP and LSNA by activation of the MC4 receptor. The naloxone antagonism of the leptin response is likely due to the blockade of presynaptic opioid inhibition of the MC4 receptor-mediated pressor response.
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PMID:Leptin-induced increase in sympathetic nervous and cardiovascular tone is mediated by proopiomelanocortin (POMC) products. 1056 84

Insulin and leptin are hypothesized to be 'adiposity signals' for the long-term regulation of body weight by the brain. Accordingly, a change in the plasma levels of leptin or insulin indicates a state of altered energy homeostasis and adiposity, and the brain responds by adjusting food intake to restore adipose tissue mass to a regulated level. The candidate site for the brain's detection of leptin adiposity signaling is the hypothalamic arcuate nucleus, where leptin inhibits expression neuropeptide Y and increases expression of the pro-opiomelanocortin (POMC) precursor of alphaMSH. Insulin also inhibits arcuate nucleus expression of neuropeptide Y but its effects on other hypothalamic signaling systems are not known. Leptin-responsive neurons in the arcuate nucleus are hypothesized to project to the paraventricular nucleus and lateral hypothalamic area where they are proposed to influence the expression of peptides that regulate food intake. Future development of this model will incorporate brain pathways for integration of leptin and insulin adiposity signaling to the hypothalamus with meal-related signals that act in the caudal brainstem. Recent research showing that leptin and insulin enhance the satiety action of peripheral CCK, thereby causing meals to be terminated earlier and reducing cumulative food intake, suggests that hypothalamic pathways that are sensitive to leptin and insulin adiposity signals have anatomical connections with caudal brainstem neurons that respond to meal-related signals and regulate meal size. The recent findings that insulin alters the expression and function of neural transporters for dopamine and norepinephrine indicate that adiposity signals may influence food intake by acting on non-peptide neurotransmitter systems.
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PMID:Insulin and leptin: dual adiposity signals to the brain for the regulation of food intake and body weight. 1061 3

Orexins-A and B are two novel hypothalamic peptides, which, like leptin and neuropeptide-Y (NPY), are involved in the central regulation of feeding. Since leptin and NPY were found to modulate adrenal function, we have examined whether orexins are able to directly affect rat adrenal steroid secretion. Both orexin-A and orexin-B raised basal corticosterone secretion of dispersed rat zona fasciculata-reticularis (ZF/R) cells, their maximal effective concentration being 10(-8) M. In contrast, orexins did not affect either maximally ACTH (10(-9) M)-stimulated corticosterone production by ZF/R cells or the basal and agonist-stimulated aldosterone secretion of dispersed zona glomerulosa cells. The ACTH-receptor antagonist corticotropin-inhibiting peptide (10(-6) M) annulled corticosterone response of ZF/R cells to ACTH (10(-9) M), but not to orexins (10(-8) M). Orexins (10(-8) M) enhanced cyclic-AMP release by ZF/R cells, and the selective inhibitor of protein-kinase A (PKA) H-89 (10(-5) M) abolished corticosterone responses to both ACTH (10(-9) M) and orexins (10(-8) M). A subcutaneous injection of both orexins (5 or 10 nmol/kg) evoked a clear-cut increase in the plasma concentration of corticosterone (but not aldosterone), the effect of orexin-A being significantly more intense than that of orexin-B. Collectively, these findings suggest that orexins exert a selective and direct glucocorticoid secretagogue action on the rat adrenals, acting through a receptor-mediated activation of the adenylate cyclase/PKA-dependent signaling pathway.
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PMID:Orexins stimulate corticosterone secretion of rat adrenocortical cells, through the activation of the adenylate cyclase-dependent signaling cascade. 1062 6

Leptin is one of the key afferent signals that regulate food intake and energy expenditure by acting on specific receptors in the hypothalamus. Recently, leptin was reported to activate the peripheral immune system by acting directly on lymphocytes. To elucidate the brain-mediated participation of leptin in the modulation of peripheral immune functions, we examined the effects of intracerebroventricular (icv) injection of murine recombinant leptin on the proliferative response to Concanavalin A (ConA response) of splenic lymphocytes in rats. The ConA response of splenic lymphocytes was markedly reduced 30 min after icv injection of leptin. The suppressive effect of leptin was abolished completely either by surgical severing of the splenic nerves or by icv injection of an antibody against corticotropin-releasing hormone (CRH), but only partially by an anti-urocortin antibody. Icv injection of CRH and urocortin also suppressed the ConA response of splenic lymphocytes, and the effect of urocortin was prevented by the anti-CRH antibody, while that of CRH was not prevented by the anti-urocortin antibody. These results suggest that leptin suppresses peripheral lymphocyte functions, in contrast to the direct activating effects, indirectly through the activation of the CRH (urocortin)-sympathetic nervous system.
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PMID:Central leptin suppresses splenic lymphocyte functions through activation of the corticotropin-releasing hormone-sympathetic nervous system. 1065 Jan 50

The mechanisms by which leptin influences energy homeostasis are not entirely understood. Several observations indicate that proopiomelanocortin (POMC) is involved in the regulation of food intake and may be a mediator of leptin action. To further study this interaction, a sensitive solution hybridization assay was used to compare the levels of POMC mRNA in the medial basal hypothalamus (MBH) of lean (+/+, +/fa(f)) and obese leptin receptor-deficient (fa(f)/fa(f)) rats. POMC peptide products were also measured by RIA in the same animals. Cytoplasmic POMC RNA levels were significantly reduced by 53% in obese rats as compared with lean controls: 0.30 +/- 0.04 vs. 0.64 +/- 0.07 pg/microgram total RNA (p < 0.02). Significant reductions in mean concentrations of hypothalamic POMC-derived peptides from the same dissections were detected in the obese rats vs. lean controls: alpha-MSH 1.77 +/- 0.07 vs. 2.34 +/- 0.10; beta-EP 4.06 +/- 0.24 vs. 5.86 +/- 0.36; gamma(3)-MSH 5.32 +/- 0. 20 vs. 6.52 +/- 0.12 ng/mg protein (p < 0.001). To determine whether leptin stimulates POMC gene transcription, the acute effect of an intracerebroventricular (i.c.v.) injection of leptin (5 microgram) on POMC primary transcript was quantified in the MBH of lean rats after a 16-hour fast. There was a significant 167% increase in mean POMC hnRNA levels 3 h after i.c.v. leptin injection (1.15 +/- 0.22 pg/MBH; p < 0.02), but not after 1 h (0.76 +/- 0.08 pg/MBH), compared to saline controls (0.69 +/- 0.08 pg/MBH). 4 h after the injection of leptin, POMC hnRNA was still increased, but to a lesser extent (140%), as compared with control animals (p = 0.006). These studies demonstrate for the first time in the leptin receptor-deficient rat that there is an associated decrease in POMC gene expression and peptide levels in the MBH. Furthermore, the acute increase in the levels of POMC primary transcript in non-obese rats after a single i.c.v. injection of leptin supports a role for leptin in the regulation of POMC gene transcription. Taken together, these studies provide further evidence that POMC is an important mediator of the effects of leptin on food intake and energy expenditure.
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PMID:Regulation of hypothalamic proopiomelanocortin by leptin in lean and obese rats. 1065 30

The hypothalamic arcuate nucleus has an essential role in mediating the homeostatic responses of the thyroid axis to fasting by altering the sensitivity of prothyrotropin-releasing hormone (pro-TRH) gene expression in the paraventricular nucleus (PVN) to feedback regulation by thyroid hormone. Because agouti-related protein (AGRP), a leptin-regulated, arcuate nucleus-derived peptide with alpha-MSH antagonist activity, is contained in axon terminals that terminate on TRH neurons in the PVN, we raised the possibility that alpha-MSH may also participate in the mechanism by which leptin influences pro-TRH gene expression. By double-labeling immunocytochemistry, alpha-MSH-IR axon varicosities were juxtaposed to approximately 70% of pro-TRH neurons in the anterior and periventricular parvocellular subdivisions of the PVN and to 34% of pro-TRH neurons in the medial parvocellular subdivision, establishing synaptic contacts both on the cell soma and dendrites. All pro-TRH neurons receiving contacts by alpha-MSH-containing fibers also were innervated by axons containing AGRP. The intracerebroventricular infusion of 300 ng of alpha-MSH every 6 hr for 3 d prevented fasting-induced suppression of pro-TRH in the PVN but had no effect on AGRP mRNA in the arcuate nucleus. alpha-MSH also increased circulating levels of free thyroxine (T4) 2.5-fold over the levels in fasted controls, but free T4 did not reach the levels in fed controls. These data suggest that alpha-MSH has an important role in the activation of pro-TRH gene expression in hypophysiotropic neurons via either a mono- and/or multisynaptic pathway to the PVN, but factors in addition to alpha-MSH also contribute to the mechanism by which leptin administration restores thyroid hormone levels to normal in fasted animals.
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PMID:alpha-Melanocyte-stimulating hormone is contained in nerve terminals innervating thyrotropin-releasing hormone-synthesizing neurons in the hypothalamic paraventricular nucleus and prevents fasting-induced suppression of prothyrotropin-releasing hormone gene expression. 1066 44

We have investigated whether interactions between leptin and hypothalamic melanocortin-4 receptors (MC4-Rs) determine individual susceptibility to dietary obesity in rats. Animals with relatively high plasma leptin levels 1 week after presentation of palatable food, before weight increased significantly, subsequently showed lower food intake and weight gain after 8 weeks of palatable feeding than those with low early leptin levels. The rats with lesser weight gain also showed significantly greater down-regulation of MC4-Rs, which mediate hypophagia, in specific hypothalamic areas, namely, the arcuate, dorsomedial, and ventromedial (VMH) nuclei and the median eminence. We suggest that this reflects enhanced receptor exposure to endogenous alpha-melanocyte-stimulating hormone, an appetite-suppressing peptide produced by hypothalamic proopiomelanocortin neurones. It is striking that plasma leptin levels at 1 week were inversely correlated with MC4-R density in the VMH, suggesting that this is a key site of leptin action. The early leptin response to palatable feeding may therefore "program" subsequent feeding behaviour and weight gain by regulating neurones that project selectively to the VMH.
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PMID:Early leptin response to a palatable diet predicts dietary obesity in rats: key role of melanocortin-4 receptors in the ventromedial hypothalamic nucleus. 1069 55

We have examined the regulation of the orexigenic neurotransmitter, NPY, in hypothalamic slices of rat brain to discover whether the leptin or melanocortin receptor-4 (MCR-4) agonists, which act as satiety signals, can influence the release of this neurotransmitter. Basal and potassium-stimulated NPY release from hypothalamic slices was not significantly altered by the addition of recombinant murine leptin. However, the melanocortin-4 agonists, alpha-MSH and MT-II, significantly inhibited potassium-stimulated NPY release (p < 0.01) without significantly altering basal NPY release. However, the MCR-4 antagonist, agouti-related protein, did not significantly alter either basal or stimulated NPY release. In conclusion, hypothalamic NPY release can be attenuated by MCR-4 agonists, but not by leptin, suggesting that the activation of MCR-4 receptors leading to satiety can also further inhibit food intake through an inhibition of orexigenic NPYergic activity.
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PMID:Regulation of neuropeptide Y release from hypothalamic slices by melanocortin-4 agonists and leptin. 1070 18

Prolonged fasting is associated with a downregulation of the hypothalamo-pituitary thyroid (H-P-T) axis, which is reversed by administration of leptin. The hypothalamic melanocortin system regulates energy balance and mediates a number of central effects of leptin. In this study, we show that hypothalamic melanocortins can stimulate the thyroid axis and that their antagonist, agouti-related peptide (Agrp), can inhibit it. Intracerebroventricular (ICV) administration of Agrp (83-132) decreased plasma thyroid stimulating hormone (TSH) in fed male rats. Intraparaventricular nuclear administration of Agrp (83-132) produced a long-lasting suppression of plasma TSH, and plasma T4. ICV administration of a stable alpha-MSH analogue increased plasma TSH in 24-hour-fasted rats. In vitro, alpha-MSH increased thyrotropin releasing hormone (TRH) release from hypothalamic explants. Agrp (83-132) alone caused no change in TRH release but antagonized the effect of alpha-MSH on TRH release. Leptin increased TRH release from hypothalami harvested from 48-hour-fasted rats. Agrp (83-132) blocked this effect. These data suggest a role for the hypothalamic melanocortin system in the fasting-induced suppression of the H-P-T axis.
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PMID:The central melanocortin system affects the hypothalamo-pituitary thyroid axis and may mediate the effect of leptin. 1074 65

To explore the pathophysiological role of leptin in obesity-related hypertension, we examined cardiovascular phenotypes of transgenic skinny mice whose elevated plasma leptin concentrations are comparable to those seen in obese subjects. We also studied genetically obese KKA(y) mice with hyperleptinemia, in which hypothalamic melanocortin system is antagonized by ectopic expression of the agouti protein. Systolic blood pressure (BP) and urinary catecholamine excretion are elevated in transgenic skinny mice relative to nontransgenic littermates. The BP elevation in transgenic skinny mice is abolished by alpha(1)-adrenergic, beta-adrenergic, or ganglionic blockers at doses that do not affect BP in nontransgenic littermates. Central administration of an alpha-melanocyte-stimulating hormone antagonist causes a marked increase in cumulative food intake but no significant changes in BP. The obese KKA(y) mice develop BP elevation with increased urinary catecholamine excretion relative to control KK mice. After a 2-week caloric restriction, BP elevation is reversed in nontransgenic littermates with the A(y) allele, in parallel with a reduction in plasma leptin concentrations, but is sustained in transgenic mice overexpressing leptin with the A(y) allele, which remain hyperleptinemic. This study demonstrates BP elevation in transgenic skinny mice and obese KKA(y) mice that are both hyperleptinemic, thereby suggesting the pathophysiological role of leptin in some forms of obesity-related hypertension.
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PMID:Pathophysiological role of leptin in obesity-related hypertension. 1079 99


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