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Melanocortin

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https://www.readbyqxmd.com/read/28081251/physical-activity-and-sedentary-behaviors-modify-the-association-between-melanocortin-4-receptor-gene-variant-and-obesity-in-chinese-children-and-adolescents
#1
Jie-Yun Song, Qi-Ying Song, Shuo Wang, Jun Ma, Hai-Jun Wang
Effects of MC4R variants in previous Chinese population studies were inconsistent. Gene-environment interactions might influence the effect of MC4R variants on obesity, which was still unclear. We performed the study to clarify the association of variants near MC4R gene with obesity-related phenotypes and gene-environment interactions in Chinese children and adolescents. Two common variants (rs12970134 and rs17782313) near MC4R were genotyped in 2179 children and adolescents aged 7-18 years in Beijing of China...
2017: PloS One
https://www.readbyqxmd.com/read/28073831/deletion-of-protein-kinase-c-lambda-in-pomc-neurons-predisposes-to-diet-induced-obesity
#2
Mauricio D Dorfman, Jordan E Krull, Jarrad M Scarlett, Stephan J Guyenet, Mini P Sajan, Vincent Damian, Hong T Nguyen, Michael Leitges, Gregory J Morton, Robert V Farese, Michael W Schwartz, Joshua P Thaler
Effectors of the phosphoinositide 3-kinase (PI3K) signal transduction pathway contribute to the hypothalamic regulation of energy and glucose homeostasis in divergent ways. Here we show that CNS action of the PI3K signaling intermediate atypical protein kinase C (aPKC) constrains food intake, weight gain, and glucose intolerance in both rats and mice. Pharmacologic inhibition of CNS aPKC activity acutely increases food intake and worsens glucose tolerance in chow-fed rodents and causes excess weight gain during high fat diet (HFD) feeding...
January 10, 2017: Diabetes
https://www.readbyqxmd.com/read/28073065/in-silico-approach-to-identify-non-synonymous-snps-in-human-obesity-related-gene-mc3r-melanocortin-3-receptor
#3
Rajan Kumar Singh, Kulandaivelu Mahalingam
The melanocortin-3-receptor (MC3R) is a novel gene candidate for human obesity, which involved in controlling the energy homeostasis and food intake behavior. The main aim behind this work is to investigate the potentially deleterious non-synonymous single nucleotide polymorphisms (nsSNPs) in obesity related gene MC3R by using six computational tools viz., PolyPhen, I-Mutant, PROVEAN, SIFT, PANTHER and PhD-SNP. In our study, we predicted eight nsSNPs i.e., rs74315393 (Ile146Asn), rs368205448 (Asp121Tyr), rs143321797 (Phe45Ser), rs17847261 (Cys274Ser), rs144166442 (Pro257His), rs370533946 (Leu224Pro), rs371354428 (Pro72Leu) and rs373708098 (Gly249Ser) found to be potentially deleterious...
December 29, 2016: Computational Biology and Chemistry
https://www.readbyqxmd.com/read/28063031/pharmacokinetics-and-pharmacodynamics-of-afamelanotide-and-its-clinical-use-in-treating-dermatologic-disorders
#4
REVIEW
Elisabeth I Minder, Jasmin Barman-Aksoezen, Xiaoye Schneider-Yin
Afamelanotide, the first α-melanocyte-stimulating hormone (MSH) analogue, synthesized in 1980, was broadly investigated in all aspects of pigmentation because its activity and stability were higher than the natural hormone. Afamelanotide binds to the melanocortin-1 receptor (MC1R), and MC1R signaling increases melanin synthesis, induces antioxidant activities, enhances DNA repair processes and modulates inflammation. The loss-of-function variants of the MC1R present in fair-skinned Caucasians are less effectively activated by the natural hormone...
January 6, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/28051332/activation-of-the-central-melanocortin-system-chronically-reduces-body-mass-without-the-necessity-of-long-term-caloric-restriction
#5
I Côté, Y Sakarya, N Kirichenko, D Morgan, C S Carter, N Tümer, P J Scarpace
Melanotan II (MTII) is a potent appetite suppressor that rapidly reduces body mass. Given the rapid loss of anorexic response upon chronic MTII treatment, most investigations have focused on the initial physiological adaptations. However, other evidence supports MTII as a long-term modulator of energy balance that remains to be established. Therefore, we examined the chronic effects of MTII on energy homeostasis. MTII (high or low dose) or artificial cerebrospinal fluid (aCSF) was infused into the lateral ventricle of the brain of 6-month-old F344BN rats (6-7/group) over 40 days...
October 19, 2016: Canadian Journal of Physiology and Pharmacology
https://www.readbyqxmd.com/read/28048872/we-fg-bra-10-radiodosimetry-of-a-novel-alpha-particle-therapy-targeted-to-uveal-melanoma-absorbed-dose-to-organs-in-mice
#6
Christopher J Tichacek, Narges K Tafreshi, Mikalai M Budzevich, Epifanio Ruiz, Thaddeus J Wadas, Mark L McLaughlin, Eduardo G Moros, David L Morse
PURPOSE: The melanocortin-1 receptor (MC1R) is expressed in 94% of uveal melanomas and is described as an ideal target for this untreatable disease. MC1RL is a high affinity MC1R specific peptidomimetic ligand that can serve as a scaffold for therapeutic conjugates such as alpha particle emitting isotopes. The purpose of this study was to assess normal tissue distribution and risk as a result of using the DOTA chelator conjugated to MC1RL to deliver (225) Ac: MC1RL-DOTA-(225) Ac. METHODS: 17 non-tumor bearing BALB/c mice were intravenously injected with the novel MC1RL-DOTA-(225) Ac radiopharmaceutical with an average initial administered activity of 2...
June 2016: Medical Physics
https://www.readbyqxmd.com/read/28045525/a-macrocyclic-agouti-related-protein-nle-4-dphe-7-%C3%AE-melanocyte-stimulating-hormone-chimeric-scaffold-produces-sub-nanomolar-melanocortin-receptor-ligands
#7
Mark D Ericson, Katie T Freeman, Sathya M Schnell, Carrie Haskell-Luevano
The melanocortin system consists of five receptor subtypes, endogenous agonists, and naturally occurring antagonists. These receptors and ligands have been implicated in numerous biological pathways including processes linked to obesity and food intake. Herein, a truncation structure-activity relationship study of chimeric agouti-related protein (AGRP)/[Nle4, DPhe7]α-Melanocyte Stimulating Hormone (NDP-MSH) ligands is reported. The tetrapeptide His-DPhe-Arg-Trp or tripeptide DPhe-Arg-Trp replaced the Arg-Phe-Phe sequence in the AGRP active loop derivative c[Pro-Arg-Phe-Phe-Xxx-Ala-Phe-DPro], where Xxx was the native Asn of AGRP or a diaminopropionic (Dap) acid residue previously shown to increase antagonist potency at the mMC4R...
January 3, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28030540/severe-atherosclerosis-and-hypercholesterolemia-in-mice-lacking-both-the-melanocortin-type-4-receptor-and-low-density-lipoprotein-receptor
#8
Vera Lede, Christin Franke, Andrej Meusel, Daniel Teupser, Albert Ricken, Joachim Thiery, Jürgen Schiller, Daniel Huster, Torsten Schöneberg, Angela Schulz
Dysfunction of the melanocortin system can result in severe obesity accompanied with dyslipidemia and symptoms of the metabolic syndrome but the effect on vascular atherogenesis is not known. To study the impact of obesity and dyslipidemia on the cardiovascular system, we generated mice double-deficient for the melanocortin type 4 receptor (Mc4rmut mice) and the LDL receptor (Ldlr-/- mice). Mc4rmut mice develop obesity due to hyperphagia. Double-mutant mice (Mc4rmut;Ldlr-/-) exhibited massive increases in body weight, plasma cholesterol and triacylglycerol levels and developed atherosclerosis...
2016: PloS One
https://www.readbyqxmd.com/read/28028605/neuropeptide-systems-and-new-treatments-for-nicotine-addiction
#9
REVIEW
Adriaan W Bruijnzeel
RATIONALE: The mildly euphoric and cognitive enhancing effects of nicotine play a role in the initiation of smoking, while dysphoria and anxiety associated with smoking cessation contribute to relapse. After the acute withdrawal phase, smoking cues, a few cigarettes (i.e., lapse), and stressors can cause relapse. Human and animal studies have shown that neuropeptides play a critical role in nicotine addiction. OBJECTIVES: The goal of this paper is to describe the role of neuropeptide systems in the initiation of nicotine intake, nicotine withdrawal, and the reinstatement of extinguished nicotine seeking...
December 28, 2016: Psychopharmacology
https://www.readbyqxmd.com/read/28024137/-secrets-of-the-red-headed
#10
REVIEW
Zygmunt Zdrojewicz, Małgorzata Kowalik, Adam Jagodziński
Only 1-2% of people is red-headed but in the Russian Udmurt Republic or United Kingdom they can be met more often. A specific variant of MC1R gene (R allele) is responsible for the red hair. The gene encodes a receptor for melanocortins. These substances stimulate melanocytes to product melanin- a dye of the skin which is transported to keratinocytes. It protects a cellular nucleus from ultraviolet radiation. Melanin has two types: eumelanin which is dark brown or even black and red/orange pheomelanin. The second one is mostly observed in red-headed which is caused by R allele...
December 22, 2016: Polski Merkuriusz Lekarski: Organ Polskiego Towarzystwa Lekarskiego
https://www.readbyqxmd.com/read/28019657/the-melanoma-linked-redhead-mc1r-influences-dopaminergic-neuron-survival
#11
Xiqun Chen, Hongxiang Chen, Waijiao Cai, Michael Maguire, Bailiu Ya, Fuxing Zuo, Robert Logan, Hui Li, Katey Robinson, Charles R Vanderburg, Yang Yu, Yinsheng Wang, David E Fisher, Michael A Schwarzschild
OBJECTIVE: Individuals with Parkinson's disease are more likely to develop melanoma, and melanoma patients are reciprocally at higher risk of developing Parkinson's disease. Melanoma is strongly tied to red hair/fair skin, a phenotype of loss-of-function polymorphisms in the MC1R (melanocortin 1 receptor) gene. Loss-of-function variants of MC1R have also been linked to increased risk of Parkinson's disease. The present study is to investigate the role of MC1R in dopaminergic neurons in vivo...
December 26, 2016: Annals of Neurology
https://www.readbyqxmd.com/read/28013339/genetics-of-obesity-can-an-old-dog-teach-us-new-tricks
#12
REVIEW
Giles S H Yeo
At one level, obesity is clearly a problem of simple physics, a result of eating too much and not expending enough energy. The more complex question, however, is why do some people eat more than others? Studies of human and mouse genetics over the past two decades have uncovered a number of pathways within the brain that play a key role in the control of food intake. A prime example is the leptin-melanocortin pathway, which we now know greatly contributes to mammalian appetitive behaviour. However, genetic disruption of this pathway remains rare and does not represent the major burden of the disease that is carried by those of us with 'common obesity'...
December 24, 2016: Diabetologia
https://www.readbyqxmd.com/read/28009464/effect-of-melanotan-ii-on-brain-fos-immunoreactivity-and-oxytocin-neuronal-activity-and-secretion-in-rats
#13
Luis Paiva, Nancy Sabatier, Gareth Leng, Mike Ludwig
Melanocortins stimulate the central oxytocin systems which are involved in regulating social behaviours. Alterations in central oxytocin have been linked to neurological disorders such as autism, and melanocortins have been proposed for therapeutic treatment. Here, we investigated how systemic administration of melanotan-II (MT-II), a melanocortin agonist, affects oxytocin neuronal activity and secretion in rats. Our results show that intravenous (i.v.), but not intranasal, administration of MT-II markedly induced Fos expression in magnocellular neurones of the supraoptic (SON) and paraventricular nuclei (PVN) of the hypothalamus, and this response was attenuated by prior intracerebroventricular (i...
December 23, 2016: Journal of Neuroendocrinology
https://www.readbyqxmd.com/read/28006784/long-term-energy-deficit-in-mice-causes-long-lasting-hypothalamic-alterations-after-recovery
#14
Mathieu Méquinion, Ophélia Le Thuc, Sara Zgheib, David Alexandre, Nicolas Chartrel, Carole Rovère, Pierre Hardouin, Odile Viltart, Christophe Chauveau
Although short-term effects on fasting or energy deficit on hypothalamic neuropeptide circuitries are now better understood, the effects of long-term energy deficit and refeeding remain to be elucidated. We showed that after a long-term energy deficit mice exhibited persistent hypoleptinemia following the refeeding period despite restoration of fat mass, ovarian activity and feeding behavior. We aimed to examine the hypothalamic adaptations after 10 weeks of energy deficit and after 10 further weeks of nutritional recovery...
December 23, 2016: Neuroendocrinology
https://www.readbyqxmd.com/read/28003536/deficient-melanocortin-4-receptor-causes-abnormal-reproductive-neuroendocrine-profile-in-female-mice
#15
Xiaolin Chen, Lili Huang, Hwee Y Tan, Hongzhuo Li, Ying Wan, Michael Cowley, Johannes D Veldhuis, Chen Chen
Deletion of the melanocortin-4-receptor (Mc4r) gene in mice causes hyperphagia, followed by hyperinsulinemia, obesity and progressive infertility. Evidence shows that the number of developed corpora lutea is reduced in obese MC4R-knockout (MC4R KO) female mice, but the mechanism is unclear. The effect of hyperphagia and obesity by MC4R KO on pulsatile luteinizing hormone (LH) secretion and ovulation remains unknown. In MC4R KO mice and wild-type littermates (WT LM) during the diestrus period throughout different ages, we examined and monitored their metabolic status, pulsatile LH profiles, follicular morphology and the number of corpora lutea...
March 2017: Reproduction: the Official Journal of the Society for the Study of Fertility
https://www.readbyqxmd.com/read/28002929/coat-colour-phenotype-of-qingyu-pig-is-associated-with-polymorphisms-of-melanocortin-receptor-1-gene
#16
Xiaoqian Wu, Zhendong Tan, Linyuan Shen, Qiong Yang, Xiao Cheng, Kun Liao, Lin Bai, Surong Shuai, Mingzhou Li, Xuewei Li, Shunhua Zhang, Li Zhu
Melanocortin receptor 1 (MC1R) and Agouti signaling protein (ASIP) are two widely reported pivotal genes that significantly affect the regulation of coat colour. Qingyu pig, a Chinese indigenous pig breed, exhibits two types of coat colour phenotypes, including pure black and white with black spotting respectively. The objectives of this study were to investigate whether the polymorphisms of these two genes are associated with coat colour and analyze the molecular mechanism of the coat colour separation in Qingyu pig...
December 17, 2016: Asian-Australasian Journal of Animal Sciences
https://www.readbyqxmd.com/read/28000361/cyclopropane-based-peptidomimetics-mimicking-wide-ranging-secondary-structures-of-peptides-conformational-analysis-and-their-use-in-rational-ligand-optimization
#17
Akira Mizuno, Tomoshi Kameda, Tomoki Kuwahara, Hideyuki Endoh, Yoshihiko Ito, Shizuo Yamada, Kimiko Hasegawa, Akihito Yamano, Mizuki Watanabe, Mitsuhiro Arisawa, Satoshi Shuto
Detailed conformational analyses of our previously reported cyclopropane-based peptidomimetics and conformational analysis-driven ligand optimization are described. Computational calculations and X-ray crystallography showed that the characteristic features of cyclopropane function effectively to constrain the molecular conformation in a three-dimensionally diverse manner. Subsequent principal component analysis revealed that the diversity covers the broad chemical space filled by peptide secondary structures in terms of both main-chain and side-chain conformations...
December 21, 2016: Chemistry: a European Journal
https://www.readbyqxmd.com/read/27998021/melanocortin-receptor-agonists-mcr1-5-protect-photoreceptors-from-high-glucose-damage-and-restore-antioxidant-enzymes-in-primary-retinal-cell-culture
#18
Rosa Maisto, Carlo Gesualdo, Maria Consiglia Trotta, Paolo Grieco, Francesco Testa, Francesca Simonelli, Jorge Miquel Barcia, Michele D'Amico, Clara Di Filippo, Settimio Rossi
Retinal photoreceptors are particularly vulnerable to local high-glucose concentrations. Oxidative stress is a risk factor for diabetic retinopathy development. Melanocortin receptors represent a family of G-protein-coupled receptors classified in five subtypes and are expressed in retina. Our previous data indicate that subtypes 1 and 5 receptor agonists exert a protective role on experimental diabetic retinopathy. This study focuses on their role in primary retinal cell cultures in high-glucose concentrations...
December 20, 2016: Journal of Cellular and Molecular Medicine
https://www.readbyqxmd.com/read/27997171/pyrimidine-based-inhibitors-of-dynamin-i-gtpase-activity-competitive-inhibition-at-the-pleckstrin-homology-domain
#19
Luke R Odell, Mohammed K Abdel-Hamid, Timothy A Hill, Ngoc Chau, Kelly A Young, Fiona M Deane, Jennette A Sakoff, Sofia Andersson, James A Daniel, Phillip J Robinson, Adam McCluskey
The large GTPase dynamin mediates membrane fission during clathrin-mediated endocytosis (CME). The aminopyrimidine compounds were reported to disrupt dynamin localization to the plasma membrane via the PH domain and implicate this mechanism in the inhibition of CME. We have used a computational approach of binding site identification, docking, and interaction energy calculations to design and synthesize a new library of aminopyrimidine analogues targeting site-2 of the pleckstrin homology (PH) domain. The optimized analogues showed low micromolar inhibition against both dynamin I (IC50 = 10...
December 20, 2016: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27991864/gs%C3%AE-deficiency-in-the-dorsomedial-hypothalamus-underlies-obesity-associated-with-gs%C3%AE-mutations
#20
Min Chen, Yogendra B Shrestha, Brandon Podyma, Zhenzhong Cui, Benedetta Naglieri, Hui Sun, Thuy Ho, Eric A Wilson, Yong-Qi Li, Oksana Gavrilova, Lee S Weinstein
Gsα, encoded by Gnas, mediates hormone and neurotransmitter receptor-stimulated cAMP generation. Heterozygous Gsα-inactivating mutations lead to obesity in Albright hereditary osteodystrophy (AHO) patients, but only when the mutations occur on the maternal allele. This parent-of-origin effect is due to Gsα imprinting in the CNS, although the relevant CNS regions are unknown. We have now shown that mice with a Gnas gene deletion disrupting Gsα expression on the maternal allele, but not the paternal allele, in the dorsomedial nucleus of the hypothalamus (DMH) developed obesity and reduced energy expenditure without hyperphagia...
December 19, 2016: Journal of Clinical Investigation
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