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)

Leptin, the protein product of the obese (ob) gene, has been suggested to play a role in the regulation of food intake. As depressive episodes are frequently characterized by loss of appetite, reduced food intake and weight loss, altered leptin secretion might also be expected in patients with depression. Therefore, we examined nocturnal (10.00 p.m. to 7.00 a.m.) secretion of leptin, cortisol, ACTH and growth hormone (GH) in a group of 15 patients with depression and age- and sex-matched controls (age range 23-71 years). In addition, the effects of pulsatile administration of growth hormone-releasing hormone (GHRH), thought to be an endogenous antagonist of corticotropin-releasing hormone (CRH), which in turn is believed to play a critical role for the pathophysiology of depression, on nocturnal hormone secretion were assessed. Patients with depression showed a trend towards elevated nocturnal cortisol secretion (F = 3.8, p < 0.05). Nocturnal serum leptin was significantly higher in patients, despite a reported weight loss (F = 8, p < 0.05), but showed the same sexual dimorphism as in controls (F = 20.9, p < 0.01). No significant differences were seen between patients and controls with regard to plasma GH and ACTH. GHRH treatment increased GH secretion in both patients and controls, while the other hormones were not affected. Furthermore, serum leptin was correlated with body mass index (BMI) in controls, but not in patients with depression, supporting an altered regulation of leptin secretion in depressive illness. Finally, we provide some evidence that in young female patients the normal nocturnal leptin surge is blunted. As glucocorticoids can prevent the fasting-induced decline in serum leptin, we propose that hypercortisolism in depression might counteract the reduction in leptin secretion caused by decreased food intake and weight loss. Elevated serum leptin in depression might in turn further promote CRH release, as shown in animals and, hence, contribute to HPA system hyperactivity seen in depression.
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PMID:Elevated nocturnal profiles of serum leptin in patients with depression. 984 57

The major effects of leptin, an adipostatic hormone produced in fat tissue, are exerted through the hypothalamic-pituitary-adrenal axis and the systemic sympathetic/adrenomedullary system at the level of the central nervous system. Here, we examined the direct effects of leptin on the adrenal gland, a peripheral end organ of both the hypothalamic-pituitary-adrenal axis and the sympathetic/adrenomedullary system. As cortical and chromaffin tissues are intermingled in the human adrenal, we employed the novel technique of laser capture microdissection to analyze these systems separately. Functional full-length leptin receptor messenger ribonucleic acid and all human isoforms Ob219.1-3 were demonstrated by RT-PCR in both cortical and medullary tissue. Immunohistochemical staining of leptin receptor protein, however, demonstrated a strong signal only in the adrenal cortex, whereas there was weak positive staining in the medulla. Corticotropin (ACTH)-induced adrenal aldosterone, cortisol, and dehydroepiandrosterone secretion was inhibited by leptin in a concentration-dependent manner, whereas this hormone had no significant effect on catecholamine release by primary cultures of human adrenal chromaffin cells. Leptin itself was not expressed in human adrenal tissue, excluding a local paracrine or autocrine function of this peptide. In conclusion, this is the first report identifying functional leptin receptor in human adrenal tissue and showing a differential action of leptin on human adrenocortical and chromaffin hormone production. This peripheral action of leptin on the adrenal gland provides an additional important link between the human stress response and body weight regulation.
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PMID:Expression of Ob receptor in normal human adrenals: differential regulation of adrenocortical and adrenomedullary function by leptin. 985 94

Bacterial-derived products [e.g., lipopolysaccharide (LPS) from Gram-negative and muramyl dipeptide (MDP) from Gram-positive bacteria] are proposed to play a pivotal role in the generation of neurological and neuroinflammatory/immunological responses during bacterial infections of the nervous system. LPS and MDP may act through cytokines; cytokine-neuropeptide interactions may also be involved. Here, we investigated cytokine and neuropeptide mRNA profiles in specific brain regions in response to the intracerebroventricular administration of LPS and MDP. IL-beta1 system components (ligand, signalling receptor, receptor accessory proteins, receptor antagonist), TNF-alpha, TGF-beta1, glycoprotein 130 (IL-6 receptor signal transducer), OB protein (leptin) receptor, neuropeptide Y, Y5 receptor, and pro-opiomelanocortin (opioid peptide precursor) mRNAs were analyzed. The same brain region sample was assayed for all components. LPS and MDP administration induced significantly different behavioral and molecular profiles. LPS was significantly more potent than MDP in inducing anorexia and in up-regulating pro-inflammatory cytokines (IL- beta1 and TNF-alpha mRNAs in the cerebellum, hippocampus and hypothalamus; MDP was more potent in up-regulating anti-inflammatory cytokine (IL-1 receptor antagonist and TGF-beta1) mRNAs. LPS and MDP also modulated hypothalamic IL-1 receptor mRNA components, but did not affect any of the neuropeptide-related components examined. The results suggest that the magnitude of neurological manifestations induced by LPS and MDP may involve the ratio between stimulatory and inhibitory cytokines, and this ratio may have implications for the neuroinflammatory/neurotoxic events associated with bacterial infections of the central nervous system.
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PMID:Gram-negative and gram-positive bacterial products induce differential cytokine profiles in the brain: analysis using an integrative molecular-behavioral in vivo model. 985 41

Alterations of hypothalamic neuropeptide Y(NPY) and melanocortinergic functions in diet-induced obese (DIO) C57BL/6J mice were investigated by in situ hybridization. Compared with controls, the DIO mice displayed a profound induction (approximately 40-fold) of NPY expression in the dorsomedial (DMH) and ventromedial (VMH) hypothalamic nuclei, whereas the level of NPY mRNA in the arcuate nucleus (ARC) was reduced by 44%. The expression of pro-opiomelanocortin (POMC) and agouti-related protein was not significantly altered in the ARC of obese mice. Both excess body weight gain and altered hypothalamic NPY expression were reversible. We propose that the highly induced NPY expression in DMH and/or VMH may be a contributing etiological factor for the development of obesity and leptin resistance in the DIO mice.
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PMID:Induction of neuropeptide Y expression in dorsomedial hypothalamus of diet-induced obese mice. 985 91

Leptin is proposed to control food intake at least in part by regulating hypothalamic neuropeptide Y (NPY), a stimulator of food intake, and corticotropin-releasing hormone (CRH), an inhibitor of food intake. Ob/ob mice are leptin-deficient and would thus be expected to exhibit alterations in hypothalamic NPY and CRH. We therefore measured concentrations of NPY and CRH in discrete regions of the hypothalamus (i.e., ARC, arcuate nucleus; PVN, paraventricular nucleus; VMH, ventromedial nucleus; DMH, dorsomedial nucleus; and SCN, suprachiasmatic nucleus) of 6.5-7-wk-old ob/ob and lean mice with free access to stock diet, 24 h after food deprivation, and 1 h after refeeding. Fed ob/ob mice had 55-75% higher concentrations of NPY in the ARC, VMH and SCN than lean mice. Food deprivation increased NPY concentrations approximately 70% in the ARC, PVN and VMH of lean mice, and refeeding lowered NPY concentrations approximately 70% in the PVN of these mice. NPY in these hypothalamic regions of ob/ob mice was unresponsive to food deprivation or refeeding. The most pronounced change in CRH concentrations within the regions examined (i.e., ARC, PVN and VMH) occurred in the ARC of lean mice where refeeding lowered CRH concentrations by 75% without influencing ARC CRH concentrations in ob/ob mice. The hypothalamic concentrations of two neuropeptides involved in body weight regulation (i.e., NPY and CRH) in leptin-deficient ob/ob mice respond abnormally to abrupt changes in nutritional status.
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PMID:Neuropeptide Y and corticotropin-releasing hormone concentrations within specific hypothalamic regions of lean but not ob/ob mice respond to food-deprivation and refeeding. 986 2

Feeding is influenced by hypothalamic neuropeptides that promote (orexigenic peptides) or inhibit feeding. Of these, neuropeptide Y (NPY) in the arcuate nucleus and melanin-concentrating hormone (MCH) and orexins/hypocretins in the lateral hypothalamus have received attention because their expression is increased during fasting and because they promote feeding when administered centrally. Surprisingly, absence of the orexigenic neuropeptide NPY fails to alter feeding or body weight in normal mice. As deficiency of a single component of the pathway that limits food intake (such as leptin or receptors for melanocortin-4) causes obesity, it has been suggested that orexigenic signals are more redundant than those limiting food intake. To define further the physiological role of MCH and to test the redundancy of orexigenic signals, we generated mice carrying a targeted deletion of the MCH gene. MCH-deficient mice have reduced body weight and leanness due to hypophagia (reduced feeding) and an inappropriately increased metabolic rate, despite their reduced amounts of both leptin and arcuate nucleus pro-opiomelanocortin messenger RNA. Our results show that MCH is a critical regulator of feeding and energy balance which acts downstream of leptin and the melanocortin system, and that deletion of a gene encoding a single orexigenic peptide can result in leanness.
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PMID:Mice lacking melanin-concentrating hormone are hypophagic and lean. 987 14

The decline of leptin (Ob protein) concentrations during fasting is implicated as a signal for increasing the expression of the orexigenic peptide neuropeptide Y (NPY) in the hypothalamus. To test the hypothesis that the effects of food intake on arcuate nucleus NPY activation are mediated by leptin, we performed simultaneous triple in situ hybridization colocalization studies to determine whether the subset of NPY neurons that are activated by fasting preferentially expresses the long form of the leptin receptor (Ob-Rb). Thus, mRNAs encoding NPY and pro-opiomelanocortin (POMC) were colocalized in the arcuate nucleus of fed and fasted rats by fluorescence in situ hybridization in combination with isotopic in situ hybridization for Ob-Rb mRNA. In fed animals, 47% of arcuate nucleus neurons containing NPY mRNA also contained Ob-Rb mRNA, compared with 79% of POMC neurons (P < 0.01). After a 2-day fast, the number of arcuate nucleus neurons with NPY mRNA increased 50% (P < 0.05); the number of these that coexpressed Ob-Rb increased twofold (P = 0.013). Furthermore, Ob-Rb mRNA hybridization in individual NPY neurons increased by 64% (P < 0.02). In contrast, the number of POMC neurons that coexpressed Ob-Rb was unchanged. A significant interpretation of these findings is that the NPY neurons that do not express detectable levels of Ob-Rb mRNA are not activated by fasting, whereas the NPY neurons that are activated by fasting are the ones that express Ob-Rb. These data demonstrate a significant physiological difference between NPY neurons that express Ob-Rb and those that do not. The results support the conclusion that the effect of food intake on NPY neurons is mediated by the direct action of leptin via Ob-Rb receptors expressed by these NPY cells. The results also indicate that expression of Ob-Rb is a defining phenotypic characteristic of the subset of arcuate nucleus NPY neurons that are activated by fasting and play a central role in the adaptive response to negative energy balance.
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PMID:Leptin receptor mRNA identifies a subpopulation of neuropeptide Y neurons activated by fasting in rat hypothalamus. 1010

Anorexia nervosa is a syndrome of unknown etiology. It is associated with multiple endocrine abnormalities. Hypothalamic monoamines (especially serotonin), neuropeptides (especially neuropeptide Y and cholecystokinin) and leptin are involved in the regulation of human appetite, and in several ways they are changed in anorexia nervosa. However, it remains to be clarified whether the altered appetite regulation is secondary or etiologic. Increased secretion of corticotropin-releasing hormone and proopiomelanocortin seems to be secondary to starvation, however, there is evidence that it may maintain and intensify anorexia, excessive physical activity and amenorrhea. Hypothalamic amenorrhea, which is a diagnostic criterion in anorexia nervosa, is not solely related to the low body weight and exercise. Growth hormone resistance with low production of insulin-like growth factor I and high growth hormone secretion reflect the nutritional deprivation. The nutritional therapy of patients with anorexia nervosa might be improved by administering an anabolic agent such as growth hormone or insulin-like growth factor I. So far none of the endocrine abnormalities have proved to be primary, however, there is increasing evidence that some of these might participate in a vicious circle.
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PMID:A review of endocrine changes in anorexia nervosa. 1022 46

To investigate whether brain leptin involves neuropeptidergic pathways influencing ingestion, metabolism, and gastrointestinal functioning, leptin (3.5 micrograms) was infused daily into the third cerebral ventricular of rats for 3 days. To distinguish between direct leptin effects and those secondary to leptin-induced anorexia, we studied vehicle-infused rats with food available ad libitum and those that were pair-fed to leptin-treated animals. Although body weight was comparably reduced (-8%) and plasma glycerol was comparably increased (142 and 17%, respectively) in leptin-treated and pair-fed animals relative to controls, increases in plasma fatty acids and ketones were only detected (132 and 234%, respectively) in pair-fed rats. Resting energy expenditure (-15%) and gastrointestinal fill (-50%) were reduced by pair-feeding relative to the ad libitum group, but they were not reduced by leptin treatment. Relative to controls, leptin increased hypothalamic mRNA for corticotropin-releasing hormone (CRH; 61%) and for proopiomelanocortin (POMC; 31%) but did not reduce mRNA for neuropeptide Y. These results suggest that CNS leptin prevents metabolic/gastrointestinal responses to caloric restriction by activating hypothalamic CRH- and POMC-containing pathways and raise the possibility that these peripheral responses to CNS leptin administration contribute to leptin's anorexigenic action.
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PMID:Metabolic, gastrointestinal, and CNS neuropeptide effects of brain leptin administration in the rat. 1023 36

We have examined the effects of underfeeding and obesity on the density of hypothalamic melanocortin MC3 and MC4 receptors (MC3-R and MC4-R, respectively), which may mediate the hypophagic effects of alpha-melanocyte-stimulating hormone (MSH) in the rat. MC3-R and MC4-R were measured by quantitative autoradiography in brain sections using 125I-labeled Nle4-D-Phe7-alpha-MSH (125I-NDP-MSH) and discriminated by masking MC3-R with excess unlabelled gamma2-MSH. High densities of MC4-R occurred in the ventromedial (VMH) and arcuate (ARC) nuclei, median eminence (ME), and medial habenular nucleus (MHb), with lower densities in the dorsomedial hypothalamus (DMH) and forebrain regions. MC3-R were confined to the VMH, ARC, and MHb. After 10-days of food restriction (14% weight loss), density of MC4-R was significantly increased by 20-65% in the VMH, ARC, ME, and DMH, with no changes elsewhere. Similarly, obese (fa/fa) Zucker rats showed 43-98% increases in MC4-R in the same regions. By contrast, rats with diet-induced obesity (18% heavier than controls) showed significantly decreased binding to MC4-R, especially in the VMH, ARC, and ME. MC3-R showed no significant alterations in any model. We suggest that increased density of MC4-R with food restriction and in obese Zucker rats reflects receptor upregulation secondary to decreased release of alpha-MSH, consistent with increased hunger in these models. Conversely, downregulation of MC4-R in diet-induced obesity may indicate increased alpha-MSH secretion in an attempt to limit overeating. This alpha-MSH/MC4-R system may be inhibited by leptin and/or insulin. MC3-R are not apparently involved in regulating feeding.
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PMID:Altered energy balance causes selective changes in melanocortin-4(MC4-R), but not melanocortin-3 (MC3-R), receptors in specific hypothalamic regions: further evidence that activation of MC4-R is a physiological inhibitor of feeding. 1033


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