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)

Body reserves (long-term) and food intake (short-term) both contribute nutritional feedback to the hypothalamus. Reproductive neuroendocrine output (GnRH/LH) is stimulated by increased food intake and not by high adiposity in sheep, but it is unknown whether appetite-regulating hypothalamic neurons show this differential response. Castrated male sheep (Scottish Blackface) with oestradiol implants were studied in two 4 week experiments. In Experiment 1, sheep were fed to maintain the initial body condition (BC) score of 2.0+/-0.00 (lower BC (LBC), n=7) or 2.9+/-0.09 (higher BC (HBC), n=9), and liveweight of 43+/-1.1 and 59+/-1.6 kg respectively. LBC and HBC sheep had similar mean plasma LH concentration, pulse frequency and amplitude, but HBC animals had higher mean plasma concentrations of insulin (P<0.01), leptin (P<0.01) and glucose (P<0.01). Gene expression (measured by in situ hybridisation) in the hypothalamic arcuate nucleus (ARC) was higher in LBC than HBC sheep for neuropeptide Y (NPY; 486% of HBC, P<0.01), agouti-related peptide (AGRP; 467%, P<0.05) and leptin receptor (OB-Rb; 141%, P<0.05), but lower for cocaine- and amphetamine-regulated transcript (CART; 92%, P<0.05) and similar between groups for pro-opiomelanocortin (POMC). In Experiment 2, sheep with initial mean BC score 2.4+/-0.03 and liveweight 55+/-0.8 kg were fed a liveweight-maintenance ration (low intake, LI, n=7) while sheep with initial mean BC score 2.0+/-0.03 and liveweight 43+/-1.4 kg were fed freely so that BC score increased to 2.5+/-0.00 and liveweight increased to 54+/-1.4 kg (high intake, HI, n=9). Compared with LI, HI sheep had higher mean plasma LH (P<0.05), baseline LH (P<0.01) and pulse amplitude (P<0.01) and showed a trend towards higher pulse frequency. Although there were no differences in final mean plasma concentrations, there were significant increases over time in mean concentrations of insulin (P<0.001), leptin (P<0.05) and glucose (P<0.001) in HI sheep. Gene expression for AGRP in the ARC was higher in HI than LI animals (453% of LI; P<0.05), but expression levels were similar for NPY, OB-Rb, CART and POMC. Thus, the hypothalamus shows differential responses to steady-state adiposity as opposed to an increase in food intake, in terms of both reproductive neuroendocrine activity and hypothalamic appetite-regulating pathways. Differences in hypothalamic gene expression were largely consistent with contemporary levels of systemic leptin and insulin feedback; however, increased nutritional feedback was stimulatory to GnRH/LH whereas constant high feedback was not. The hypothalamus therefore has the ability to retain a nutritional memory that can influence subsequent responses.
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PMID:Contrasting effects of different levels of food intake and adiposity on LH secretion and hypothalamic gene expression in sheep. 1242 36

Glucocorticoids regulate body energy balance through both peripheral and central mechanisms. In order to understand the central mechanisms that mediate these effects of glucocorticoids we studied the effects of adrenalectomy (ADX) and food deprivation on the expression of four neuropeptide genes (measured by S1 nuclease protection assay) in the medial basal hypothalamus (MBH), which are known to regulate energy balance: pro-opiomelanocortin (POMC), agouti-related peptide (AGRP), neuropeptide Y (NPY), and cocaine and amphetamine regulated transcript (CART). Adult male rats were ADX or sham operated (SHAM), and studied 1-2 weeks later. In the first study effects of ADX and corticosterone replacement on POMC and AGRP expression were determined. ADX decreased POMC and AGRP gene expression in the MBH by 27 and 38%, respectively, compared to SHAM rats. Corticosterone treatment increased the expression of POMC by 87% and AGRP by 45% in ADX rats. The second study was designed to determine if glucocorticoids are necessary for the fasting induced changes in POMC, AGRP, NPY and CART in the MBH. ADX caused a 20-30% decrease in the expression of all four neuropeptide genes in the MBH. As expected, fasting suppressed POMC and CART expression and increased AGRP and NPY expression. The fasting-induced increases in AGRP and NPY persisted after ADX but no further significant decreases in POMC or CART were noted after fasting in ADX rats. Plasma leptin and insulin declined significantly after ADX and increased with corticosterone replacement; both leptin and insulin declined further in fasted, ADX animals. In conclusion, ADX decreases both anorexigenic, POMC and CART, and orexigenic, AGRP and NPY, neuropeptide gene expression in the MBH. AGRP and NPY decrease after ADX despite the fall in plasma leptin and insulin concentrations which in other situations would increase these neuropeptides. Furthermore, glucocorticoids are not required for fasting-induced upregulation of AGRP and NPY expression.
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PMID:Effects of adrenalectomy on AGRP, POMC, NPY and CART gene expression in the basal hypothalamus of fed and fasted rats. 1246 37

The co-ordinated regulation of food intake and energy expenditure takes place in the hypothalamic regions of the brain. Current understanding of the systems involved in this regulation suggests that, in the hypothalamus, there are two major groups of neuropeptides involved in orexigenic and anorexic processes. The orexigenic neuropeptides are neuropeptide Y (NPY) and agouti-related peptide (AgRP) and the anorexic neuropeptides are alpha-melanocyte-stimulating hormone (alpha-MSH) and cocaine and amphetamine-related transcript (CART). Theneurons expressing these neuropeptides interact with each other and with signals from the periphery (such as leptin, insulin, ghrelin and glucocorticoids) to regulate feeding behaviour, energy expenditure and various endocrine axes. Although direct evidence is limited, there are examples of genetic obesity in humans which suggest that the balance between orexigenic and anorexic pathways in the hypothalamus is also pivotally important in the maintenance of energy homeostasis in humans.
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PMID:Hypothalamic regulation of energy homeostasis. 1246 11

Gamma-aminobutyric acid (GABA) interacts with hypothalamic neuronal pathways regulating feeding behaviour. GABA has been reported to stimulate feeding via both ionotropic GABA(A) and metabotropic GABA(B) receptors. The functional form of the GABA(B) receptor is a heterodimer consisting of GABA(B) receptor-1 (GABA(B)R1) and GABA(B) receptor-2 (GABA(B)R2) proteins. Within the heterodimer, the GABA-binding site is localized to GABA(B)R1. In the present study, we used an antiserum to the GABA(B)R1 protein in order to investigate the cellular localization of GABA(B)R1-immunoreactive neurones in discrete hypothalamic regions implicated in the control of body weight. The colocalization of GABA(B)R1 immunoreactivity with different chemical messengers that regulate food intake was analysed. GABA(B)R1-immunoreactive cell bodies were found in the periventricular, paraventricular (PVN), supraoptic, arcuate, ventromedial hypothalamic, dorsomedial hypothalamic, tuberomammillary nuclei and lateral hypothalamic area (LHA). Direct double-labelling showed that glutamic acid decarboxylase (GAD)-positive terminals were in close contact with GABA(B)R1-containing cell bodies located in all these regions. In the ventromedial part of the arcuate nucleus, GABA(B)R1-immunoreactive cell bodies were found to contain neuropeptide Y, agouti-related peptide (AGRP) and GAD. In the ventrolateral part of the arcuate nucleus, GABA(B)R1-immunoreactive cell bodies were shown to contain pro-opiomelanocortin and cocaine- and amphetamine-regulated transcript. In the LHA, GABA(B)R1 immunoreactivity was present in both melanin-concentrating hormone- and orexin-containing cell populations. In the tuberomammillary nucleus, GABA(B)R1-immunoreactive cell bodies expressed histidine decarboxylase, a marker for histamine-containing neurones. In addition, GAD and AGRP were found to be colocalized in some nerve terminals surrounding GABA(B)R1-immunoreactive cell bodies in the parvocellular part of the PVN. The results may provide a morphological basis for the understanding of how GABA regulates the hypothalamic control of food intake and body weight via GABA(B) receptors.
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PMID:Chemical coding of GABA(B) receptor-immunoreactive neurones in hypothalamic regions regulating body weight. 1253 64

As an incidental finding in a study of mammary tumorigenesis, two lines of genetically engineered mice were observed to develop pigmentation changes of the fur. Mice with targeted mutations of the Rb1 (Rb) and Cdkn1b (p27kip1) genes were crossed from C57BL/6 (black coat color; eumelanin) and 129Sv (wild-type agouti coat color) backgrounds, respectively, to one with a dominant yellow coat color (phaeomelanin) carrying a transgene for Agouti under a keratinocyte specific promoter. Both Rb+/- and p27-/- mice developed pituitary tumors of the pars intermedia that were associated with a switch to black (eumelanic) fur but were not observed in sibling Rb+/+ and p27+/+ mice. This phenomenon was observed first in the vibrissae and, subsequently one to two weeks later, as periorbital and dorsal patches, and was associated with pituitary lesions larger than four millimeters in the longest dimension. In Rb+/- mice, pigmentation change preceded a moribund state attributable to the tumors by two to four weeks, whereas in p27-/- mice, the pigmentation alteration was earlier, more gradual, and prolonged. The switch from phaeomelanin to eumelanin in the fur is most likely due to out-competition of the agouti gene product by alpha-melanocyte-stimulating hormone from the pituitary tumors, an effect masked in black or agouti mice.
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PMID:Switching of melanocyte pigmentation associated with pituitary pars intermedia tumors in Rb+/- and p27-/- female mice with yellow pelage. 1262 10

Research in mammals has established the existence of a neuronal network that lies within the hypothalamus and that regulates energy homeostasis. However, it is unknown whether this system has been evolutionarily conserved. The objective of the present study was therefore to examine the influence of the agouti-related peptide (AGRP), pro-opiomelanocortin (POMC), prepro-orexin, and vasoactive intestinal polypeptide (VIP) genes on energy balance in birds by quantifying the effect of a 24-h fast on their expression in the hypothalamus of the Japanese quail. In situ hybridization revealed strong signals for AGRP and POMC mRNAs in the infundibular nucleus (IN), for prepro-orexin in the lateral hypothalamic area (LHy) and periventricular hypothalamic nucleus, and for VIP in the LHy. POMC mRNA was co-localized with alpha-melanocyte-stimulating hormone-like immunoreactivity in individual IN neurons. Compared with the ad-libitum-fed state, a 24-h fast resulted in a 2.2-fold increased expression of AGRP mRNA in the IN. However, fasting did not induce changes in POMC, prepro-orexin, or VIP mRNAs. The results suggest an involvement of the central melanocortin system in the regulation of energy balance in birds, as in mammals. In contrast, orexins in birds may be primarily involved in the control of physiological functions other than energy homeostasis.
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PMID:Fasting differentially regulates expression of agouti-related peptide, pro-opiomelanocortin, prepro-orexin, and vasoactive intestinal polypeptide mRNAs in the hypothalamus of Japanese quail. 1284 20

Mice deficient in proopiomelanocortin peptides (Pomc(-/-)) generated on a 129 (A(w)/ A(w)) genetic background were back-crossed onto the C57BL/6 (a/a) genetic background. These mice exhibited most of the phenotypic characteristics previously reported on the 129 genetic background (Yaswen et al. 1999. Nat. Med. 5: 1066-1070). Adult mice became obese, their adrenals were atrophied, and they had undetectable plasma corticosterone in basal and stressed states. The partial perinatal lethality previously reported was also present on the C57BL/6 background. In addition, we found that both male and female homozygote (-/-) adults were fertile, but when homozygous males were intercrossed with homozygous females, all the pups died in the perinatal period. Attempts to rescue the perinatal lethality of pups from homozygous breeder pairs by supplementing the mother's drinking water with glucocorticoids were unsuccessful. Furthermore, failure to stimulate adrenal development and corticosterone production/release with daily exogenous adreno-corticotropin-stimulating hormone (ACTH) injections indicates an adrenal dependence on POMC peptides for normal development and function. While the original Pomc(-/-) mice, bred on a mixed white-bellied agouti (A(w)/ A(w)) 129 genetic background, had patchy alternations in their coat color, they clearly were not a uniform yellow like the lethal yellow (A(y)/a) mice. Our Pomc(-/-) mice bred onto the C57BL/6 (a/a) genetic background had a black coat color indistinguishable from that of the wild-type C57BL/6 mice, further suggesting that the POMC peptide melanocyte-stimulating hormone (alpha-MSH) is not essential for the production of eumelanin (black/brown) pigmentation.
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PMID:Lack of proopiomelanocortin peptides results in obesity and defective adrenal function but normal melanocyte pigmentation in the murine C57BL/6 genetic background. 1285 17

Proopiomelanocortin (POMC) is expressed in the arcuate nucleus of the hypothalamus (ARC) and the commissural nucleus of the solitary tract (cNTS). Post-translational processing of POMC produces two melanocortin receptor ligands, alpha- and gamma-melanocyte-stimulating hormone (MSH). Two melanocortin receptors (MC3R, MC4R) are expressed in brain regions receiving projections of POMC fibers, most of which also receive projections from a population of ARC neurons that co-express neuropeptide Y (NPY) and the MC3R/MC4R antagonist agouti-related peptide (AgRP). MC4R haploinsufficient humans and MC4R knockout (MC4RKO) mice exhibit increased adiposity and linear growth. MC4RKO mice exhibit hyperleptinemia and hyperinsulinemia and sometimes, but not always, develop type 2 diabetes (T2D). Individually housed MC4RKO mice fed low-fat diets are not hyperphagic when food intake is corrected for lean mass, whereas hyperphagia is observed after the introduction of diets with increased fat content. POMC knockout (POMCKO) mice are similar in that the severity of hyperphagia increases with the introduction of high-fat diets. By contrast, targeted deletion of the MC3R in the mouse results in increased adiposity despite the absence of hyperphagia. MC3RKO mice also exhibit reduced linear growth and lean mass; while MC3RKO mice are hyperleptinemic and hyperinsulinemic, the development of T2D has not been reported. The MC4R, but not the MC3R, is required for the stimulation of energy expenditure in response to melanocortin agonists and voluntary hyperphagia. Evidence for altered physical activity has also been reported for both knockout models. Analysis of MC4RKO mice indicates that this receptor is involved in rapidly coordinating energy consumption with energy expenditure through diet-induced thermogenesis and activity.
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PMID:Knockout studies defining different roles for melanocortin receptors in energy homeostasis. 1285 22

The characterization of the melanocortin 1 receptor (MC1R) expressed on human melanocytes and the findings that certain mutations in the POMC gene or the MC1R gene result in red hair phenotype underscore the significance of melanocortins and MC1R in regulating human pigmentation. We demonstrated that human melanocytes respond to alpha-melanocortin (alpha-MSH) or ACTH with increased proliferation and melanogenesis, and to agouti signaling protein by abrogation of these effects. alpha-MSH and ACTH were equipotent and more potent than beta-MSH, and gamma-MSH was the least potent in activating the MC1R and stimulating melanogenesis and proliferation of human melanocytes. We characterized the MC1R genotype in a panel of human melanocyte cultures and identified three cultures that were homozygous for Arg160Trp, heterozygous for Arg151Cys and Asp294His, and heterozygous for Arg160Trp and Asp294His substitutions, respectively. Those cultures failed to respond to alpha-MSH with increase in cAMP levels, tyrosinase activity, or proliferation and had an exaggerated response to the cytotoxic effect of ultraviolet (UV) radiation. These loss-of-function mutations have been associated with red hair phenotype and increased risk for skin cancer. Melanocytes homozygous for Val29Met substitution in MC1R responded normally to alpha-MSH and UVB, suggesting that this variant is a polymorphism. We observed that alpha-MSH promotes human melanocyte survival by inhibiting the UV-induced apoptosis independently of melanin synthesis. This effect was absent in human melanocytes with loss of function MC1R mutations. We predict that the survival effect of alpha-MSH is caused by reduction of UV-induced DNA damage and contributes to the prevention of melanoma.
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PMID:Significance of the melanocortin 1 receptor in regulating human melanocyte pigmentation, proliferation, and survival. 1285 36

Food intake and energy expenditure are regulated by neuropeptides in the hypothalamus. While cocaine- and amphetamine-regulated transcript (CART) peptide and melanocortins such as alpha-melanocyte-stimulating hormone (alpha-MSH) are anorexigenic and increase energy expenditure, the endogenous melanocortin receptor antagonist agouti gene-related protein (AGRP), melanin-concentrating hormone (MCH) and neuropeptide Y (NPY) are orexigenic, anabolic peptides. Alterations in the regulatory balance may promote excessive weight gain. The action of these peptides on paraventricular hypothalamic neurons was studied in brain slices of overweight, adult rats previously subjected to early postnatal overfeeding in small litters of only three pups per mother, compared to 12 pups per dam in control litters. CART, melanocortins and NPY significantly excited paraventricular neurons of controls, whereas neurons of small-litter rats were mainly inhibited. Inhibition was dominant following administration of AGRP, MCH and NPY. The altered responses of paraventricular neurons in adult small-litter rats might reflect a general mechanism of neurochemical plasticity and 'malprogramming' of hypothalamic neuropeptidergic systems acquired during the postnatal critical differentiation period, thus leading to permanently altered function of these regulatory systems of body weight.
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PMID:Altered responses to orexigenic (AGRP, MCH) and anorexigenic (alpha-MSH, CART) neuropeptides of paraventricular hypothalamic neurons in early postnatally overfed rats. 1291 57


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