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)

Metabolic hormones, such as leptin, alter the input organization of hypothalamic circuits, resulting in increased pro-opiomelanocortin (POMC) tone, followed by decreased food intake and adiposity. The gonadal steroid estradiol can also reduce appetite and adiposity, and it influences synaptic plasticity. Here we report that estradiol (E2) triggers a robust increase in the number of excitatory inputs to POMC neurons in the arcuate nucleus of wild-type rats and mice. This rearrangement of synapses in the arcuate nucleus is leptin independent because it also occurred in leptin-deficient (ob/ob) and leptin receptor-deficient (db/db) mice, and was paralleled by decreased food intake and body weight gain as well as increased energy expenditure. However, estrogen-induced decrease in body weight was dependent on Stat3 activation in the brain. These observations support the notion that synaptic plasticity of arcuate nucleus feeding circuits is an inherent element in body weight regulation and offer alternative approaches to reducing adiposity under conditions of failed leptin receptor signaling.
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PMID:Anorectic estrogen mimics leptin's effect on the rewiring of melanocortin cells and Stat3 signaling in obese animals. 1719 39

The brain hypothalamus coordinates extra-hypothalamic regions to maintain energy homeostasis through the regulation of food intake and energy expenditure. A number of anorexigenic and orexigenic molecules in the hypothalamic nuclei participate in the control of energy homeostasis. Leptin and pro-opiomelanocortin (POMC)-derived alpha-melanocyte-stimulating hormone are key anorectic molecules, and the leptin receptor and POMC gene are both expressed in the hypothalamic arcuate nucleus. Although it has been considered that melanocortin signaling is localized downstream to leptin signaling, data have accumulated to support the concept of a leptin-independent melanocortin signaling system. We focus on and review the melanocortin signaling system that functions dependently or independently of leptin signaling in the regulation of energy homeostasis.
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PMID:The leptin-dependent and -independent melanocortin signaling system: regulation of feeding and energy expenditure. 1740 Jul 97

NEFA/nucleobindin2 (NUCB2), a novel satiety molecule, is associated with leptin-independent melanocortin signaling in the central nervous system. Here, we show that systemic administration of m-chlorophenylpiperazine (mCPP), a serotonin 5-HT1B/2C receptor agonist, significantly increased the expression of hypothalamic NUCB2 in wild-type mice. The increases in hypothalamic NUCB2 expression induced by mCPP were attenuated in 5-HT2C receptor mutant mice. Systemic administration of mCPP suppressed food intake in db/db mice with leptin receptor mutation as well as lean control mice. On the other hand, the expression of hypothalamic NUCB2 and proopiomelanocortin (POMC) was significantly decreased in hyperphagic and non-obese 5-HT2C receptor mutants compared with age-matched wild-type mice. Interestingly, despite increased expression of hypothalamic POMC, hypothalamic NUCB2 expression was decreased in 5-HT2C receptor mutant mice with heterozygous mutation of beta-endorphin gene. These findings suggest that 5-HT systems upregulate the expression of hypothalamic NUCB2 via 5-HT2C receptors, and induce anorexia via a leptin-independent pathway in mice.
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PMID:Serotonin systems upregulate the expression of hypothalamic NUCB2 via 5-HT2C receptors and induce anorexia via a leptin-independent pathway in mice. 1847 67

Neuropeptide Y (NPY) conjugated with a ribosomal inactivating toxin, saporin (SAP), is a toxin that targets NPY receptor-expressing cells. Injection of NPY-SAP into the rat arcuate nucleus (Arc) and basomedial hypothalamus (BMH) destroys two populations of NPY-receptor-expressing neurons important for the control of food intake and body weight, NPY and pro-opiomelanocortin (POMC) and cocaine and amphetamine related transcript (CART) neurons, and produces profound hyperphagia and obesity. Here, we investigated the contribution of lateral hypothalamus (LHA) orexigenic peptides, orexins and melanocortin concentrating hormone (MCH), to these lesion effects. We microinjected NPY-SAP into two sites on each side of the Arc, causing a loss of NPY and POMC/CART neurons that was limited to the Arc. Lesioned rats rapidly became hyperphagic and obese. However, MCH and prepro-orexin mRNA expression were not increased in the LHA in the lesioned rats, but were decreased at some levels of the LHA or were unchanged. NPY-SAP-induced obesity therefore differs from dietary obesity and from obesity associated with leptin or leptin receptor deficiency in which MCH gene expression is increased. The Arc NPY-SAP lesion produces obesity and hyperphagia that does not require overexpression of hypothalamic neuropeptides currently considered to provide major stimulatory drive for food intake: NPY, agouti gene-related protein, MCH or orexins. The source of the seemingly unregulated stimulatory drive for feeding in these animals has not been identified, but may be associated with hindbrain or endocrine mechanisms.
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PMID:Hyperphagia and obesity produced by arcuate injection of NPY-saporin do not require upregulation of lateral hypothalamic orexigenic peptide genes. 1857 7

Leptin acts within the hypothalamus to diminish food intake. In Brandt's voles (Lasiopodomys brandtii), both circulating leptin levels and food intake are elevated during pregnancy, suggesting an ineffectiveness of leptin to reduce food intake. Diminished hypothalamic leptin receptors and impaired leptin signal transduction are characteristic of central leptin resistance. The present study aimed to determine whether these characteristic modulations of leptin sensitivity occurred in pregnant Brandt's voles. The mRNA expression of the long form of the leptin receptor (Ob-Rb), suppressor-of-cytokine-signalling 3 (SOCS3), neuropeptide Y (NPY), agouti-related protein (AgRP), pro-opiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART) in the hypothalamus were examined on dioestrous, day 5, day 10 and day 18 of pregnancy. Compared to controls, there was no significant change in hypothalamic Ob-Rb mRNA during the pregnancy. SOCS3 mRNA was increased significantly by 68% on day 10% and 93% on day 18 of pregnancy compared to controls. Despite elevated leptin levels, POMC mRNA was decreased significantly by 60% on day 18 of pregnancy, whereas no differences were found in the mRNA expression of NPY, AgRP and CART in pregnant voles compared to controls. The elevation of SOCS3 mRNA together with disrupted leptin regulation of neuropeptides in the hypothalamus suggests that leptin resistance may develop in pregnant Brandt's voles.
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PMID:Hypothalamic suppressor-of-cytokine-signalling 3 mRNA is elevated and pro-opiomelanocortin mRNA is reduced during pregnancy in Brandt's voles (Lasiopodomys brandtii ). 1863 26

Human and animal studies suggest that obesity in adulthood may have its origins partly during prenatal development. One of the underlying causes of obesity is the perturbation of hypothalamic mechanisms controlling appetite. We determined mRNA levels of genes that regulate appetite, namely neuropeptide Y (NPY), pro-opiomelanocortin (POMC) and the leptin receptor isoform Ob-Rb, in the hypothalamus of adult mouse offspring from pregnant dams fed a protein-restricted diet, and examined whether mismatched post-weaning high-fat diet altered further expression of these gene transcripts. Pregnant MF1 mice were fed either normal protein (C, 18% casein) or protein-restricted (PR, 9% casein) diet throughout pregnancy. Weaned offspring were fed to adulthood a high-fat (HF; 45% kcal fat) or standard chow (21% kcal fat) diet to generate the C/HF, C/C, PR/HF and PR/C groups. Food intake and body weight were monitored during this period. Hypothalamic tissues were collected at 16 weeks of age for analysis of gene expression by real time RT-PCR. All HF-fed offspring were observed to be heavier vs. C groups regardless of the maternal diet during pregnancy. In the PR/HF males, but not in females, daily energy intake was reduced by 20% vs. the PR/C group (p<0.001). In PR/HF males, hypothalamic mRNA levels were lower vs. the PR/C group for NPY (p<0.001) and Ob-Rb (p<0.05). POMC levels were similar in all groups. In females, mRNA levels for these transcripts were similar in all groups. Our results suggest that adaptive changes during prenatal development in response to maternal dietary manipulation may have long-term sex-specific consequences on the regulation of appetite and metabolism following post-weaning exposure to an energy-rich nutritional environment.
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PMID:Appetite regulatory mechanisms and food intake in mice are sensitive to mismatch in diets between pregnancy and postnatal periods. 1875 69

Leptin produced by adipocytes acts through leptin receptors in the hypothalamus to control appetite and food intake and thus communicates information about degree of fatness. It is thought that a degree of body fat is required for initiation of puberty and maintenance of reproductive function in mammals. The objective of this study was to determine whether polymorphisms in the leptin (LEP), leptin receptor (LEPR), paired box 5 (PAX5), aldo-keto reductase (AKR), and pro-opiomelanocortin (POMC) genes were associated with age, leptin concentration, backfat as an indicator of body condition, or BW at puberty in 3 lines of gilts and to characterize genetic relationships among these traits. The first 2 lines, born in 2001, were formed by crossing maternal White Cross (Yorkshire x Maternal Landrace) gilts to Duroc (n = 210) or (lean) Landrace (n = 207) boars. The remaining line (n = 507), born in 2002, was formed by crossing progeny of the Duroc- and Landrace-sired lines. At first estrus, age, BW (BWP), and backfat (BFP) at puberty were recorded and blood was collected for leptin assays. Nine SNP were detected in candidate genes/regions: 1 in LEP, 3 in LEPR, 1 in PAX5, 2 in AKR, and 2 in POMC. Animals were genotyped for each of the SNP; genotypes were validated using GenoProb. The association model included fixed effects of farrowing group, covariates of SNP genotypic probabilities (from GenoProb), and random additive polygenic effects to account for genetic similarities between animals not explained by SNP. Variance components for polygenic effects and error were estimated using MTDFREML. Leptin concentrations were logarithmically transformed for data analysis. All 4 traits were moderately to highly heritable (0.38 to 0.48). Age and leptin at puberty had a significant (P < 0.01) genetic correlation at -0.63 +/- 0.097, and the genetic correlation between BWP and age at puberty was 0.65 +/- 0.083 (P < 0.01). Significant additive associations (a; P < 0.05) were detected at PAX5 for age at puberty (a = 3.2 d) and for BFP (a = 0.61 mm). One SNP in LEPR was associated with leptin concentration (a = 0.31 log units; P < 0.05). The associations from PAX5 correspond to a QTL peak for age at puberty detected on SSC1. Although not necessarily the causative mutation, this result implies that a QTL that can decrease age at puberty without increasing BFP and BWP at puberty may exist in this region in commercial pigs.
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PMID:Genetic relationships of body composition, serum leptin, and age at puberty in gilts. 1884 93

Epidemiological studies show a link between low birthweight and increased obesity. In contrast, slow growth during the lactation period reduces obesity risk. The present study investigates the potential underlying mechanisms of these observations. Rats were established as follows: (i) control animals [offspring of control dams fed a 20% (w/v) protein diet], (ii) recuperated animals [offspring of dams fed an isocaloric low-protein (8%, w/v) diet during pregnancy and nursed by control dams], and (iii) postnatal low protein animals (offspring of control dams nursed by low-protein-fed dams). Serum and brains were collected from fed and fasted animals at weaning. Expression of hypothalamic energy balance genes was assessed using in situ hybridization. Recuperated pups were smaller at birth, but caught up with controls by day 21 and gained more weight than controls between weaning and 12 weeks of age (P<0.05). At 21 days, they were hypoleptinaemic compared with controls in the fed state, with generally comparable hypothalamic gene expression. Postnatal low protein offspring had significantly lower body weights than controls at weaning and 12 weeks of age (P<0.001). At 21 days, they were hypoglycaemic, hypoinsulinaemic and hypoleptinaemic. Leptin receptor gene expression in the arcuate nucleus was increased in postnatal low protein animals compared with controls. Consistent with hypoleptinaemia, hypothalamic gene expression for the orexigenic neuropeptides NPY (neuropeptide Y) and AgRP (Agouti-related peptide) was increased, and that for the anorexigenic neuropeptides POMC (pro-opiomelanocortin) and CART (cocaine- and amphetamine-regulated transcript) was decreased. These results suggest that the early nutritional environment can affect the development of energy balance circuits and consequently obesity risk.
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PMID:Programming of hypothalamic neuropeptide gene expression in rats by maternal dietary protein content during pregnancy and lactation. 1915 6

Hypothalamic neuropeptides, neurotrophins, and systemic hormones modulate food intake and body composition. Although advances toward elucidating these interactions have been made, many aspects of the underlying mechanisms remain vague. Hypothalami from fat and lean chicken lines were assessed for differential expression of anabolic/orexigenic and catabolic/anorexigenic genes. Effects of triiodothyronine (T(3)), corticosterone (Cort), and brain-derived neurotrophic factor (BDNF) on expression of anabolic/orexigenic and catabolic/anorexigenic genes were tested in cultures of hypothalamic neurons. From this, we found that BDNF increased and T(3) decreased gene expression for BDNF, leptin receptor (LEPR), pro-opiomelanocortin (POMC), thyrotropin releasing hormone (TRH), and agouti-related protein (AGRP). Thyroid hormone levels were manipulated during development to show that T(3) inhibited BDNF, TRH, and BDNF receptor gene expression. Delivery of T(3), Cort, T(3) plus Cort, or vehicle in vivo continuously for 72 h indicated that Cort and T(3) have overlapping roles in regulating TRH, LEPR, and POMC gene expression and that Cort and T(3) regulate BDNF, neuropeptide Y, and AGRP in opposite directions. Collectively, these findings suggest that interactions between the neuropeptide BDNF and the hormones T(3) and/or Cort may constitute a homeostatic mechanism that links hypothalamic energy regulation controlling body composition.
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PMID:Effects of BDNF, T3, and corticosterone on expression of the hypothalamic obesity gene network in vivo and in vitro. 1915 10

A study was undertaken in Corriedale ewes to test the lipostat theory using data obtained from a model of seasonal change in food intake and body composition. The theory predicts adipose-derived factors signal to the brain and vice versa, to maintain homeostasis. It is held that leptin acts on cells in the brain to regulate food intake and energy expenditure, through "first order" neurons in the arcuate nucleus (ARC). These cells are thought to receive information that is relayed to "second order" neurons, to regulate food intake and other functions. In this study, groups (n=4-5) of ovariectomized ewes were maintained under natural conditions and sampled at various points across the year. Food intake, body composition and indices of metabolic function were measured prior to collection of brains for in situ hybridization analysis. Expression of genes encoding for neuropeptide Y (NPY), pro-opiomelanocortin (POMC), orexin (ORX), melanin concentrating hormone (MCH) and leptin receptor (ObRb) was quantified. NPY gene expression was high when food intake was also high but, across the year, changes in NPY and POMC gene expression did not correspond predictably to plasma leptin levels or leptin receptor gene expression. Negative correlation was found between adiposity (omental and whole body fat) and gene expression of MCH and ORX, suggesting that changes in expression of genes for "second order" orexigenic peptides are closely linked to changes of metabolic state, even when similar relationships cannot be shown for expression of genes in "first order" neurons. These data provide support for the lipostat theory.
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PMID:A test of the lipostat theory in a seasonal (ovine) model under natural conditions reveals a close relationship between adiposity and melanin concentrating hormone expression. 1917 37


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