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https://www.readbyqxmd.com/read/28699792/novel-approaches-to-the-design-of-bioavailable-melanotropins
#1
Yang Zhou, Minying Cai
The melanocortin system is a primordial and critical system for survival, involved in a wide variety of physiological functions. It includes melanocortin receptors (MCRs) and melanotropin ligands (MCLs). MCRs are important drug targets that can regulate several key physiological processes. Extensive efforts have been made to develop peptide and peptidomimetics targeting melanocortin receptors including MC1R, MC3R, MC4R and MC5R. Most research is focused on developing potent and selective melanotropins. However, developing bioavailable melanotropins remains challenging...
July 12, 2017: Expert Opinion on Drug Discovery
https://www.readbyqxmd.com/read/28636007/analysis-of-association-of-gene-variants-with-obesity-traits-in-new-zealand-european-children-at-6-years-of-age
#2
Mohanraj Krishnan, John M D Thompson, Edwin A Mitchell, Rinki Murphy, Lesley M E McCowan, Andrew N Shelling, G On Behalf Of The Children Of Scope Study Group
Childhood obesity is a public health problem, which is associated with a long-term increased risk of cardiovascular disease and premature mortality. Several gene variants have previously been identified that have provided novel insights into biological factors that contribute to the development of obesity. As obesity tracks through childhood into adulthood, identification of the genetic factors for obesity in early life is important. The objective of this study was to identify putative associations between genetic variants and obesity traits in children at 6 years of age...
June 21, 2017: Molecular BioSystems
https://www.readbyqxmd.com/read/28617454/corrigendum-mc4r-dependent-suppression-of-appetite-by-bone-derived-lipocalin-2
#3
Ioanna Mosialou, Steven Shikhel, Jian-Min Liu, Antonio Maurizi, Na Luo, Zhenyan He, Yiru Huang, Haihong Zong, Richard A Friedman, Jonathan Barasch, Patricia Lanzano, Liyong Deng, Rudolph L Leibel, Mishaela Rubin, Thomas Nickolas, Wendy Chung, Lori M Zeltser, Kevin W Williams, Jeffrey E Pessin, Stavroula Kousteni
This corrects the article DOI: 10.1038/nature21697.
June 14, 2017: Nature
https://www.readbyqxmd.com/read/28593922/copy-number-variations-in-classical-obesity-candidate-genes-are-not-frequently-associated-with-severe-early-onset-obesity-in-children
#4
Jan Windholz, Peter Kovacs, Marina Schlicke, Christin Franke, Anubha Mahajan, Andrew P Morris, Johannes R Lemke, Jürgen Klammt, Wieland Kiess, Torsten Schöneberg, Roland Pfäffle, Antje Körner
BACKGROUND: Obesity is genetically heterogeneous and highly heritable, although polymorphisms explain the phenotype in only a small proportion of obese children. We investigated the presence of copy number variations (CNVs) in "classical" genes known to be associated with (monogenic) early-onset obesity in children. METHODS: In 194 obese Caucasian children selected for early-onset and severe obesity from our obesity cohort we screened for deletions and/or duplications by multiplex ligation-dependent probe amplification reaction (MLPA)...
May 1, 2017: Journal of Pediatric Endocrinology & Metabolism: JPEM
https://www.readbyqxmd.com/read/28590933/the-caudal-pedunculopontine-tegmental-nucleus-may-be-involved-in-the-regulation-of-skeletal-muscle-activity-by-melanocortinsympathetic-pathway-a-virally-mediated-trans-synaptic-tracing-study-in-spinally-transected-transgenic-mice
#5
Zhi-Gang He, Bao-Wen Liu, Zhi-Xiao Li, Xue-Bi Tian, San-Guang Liu, Anne Manyande, Ding-Yu Zhang, Hong-Bing Xiang
Understanding neuroanatomical sympathetic circuitry and neuronal connections from the caudal pedunculopontine tegmental nucleus to skeletal muscle is important to the study of possible mechanisms of pedunculopontine tegmental nucleus (PPTg) and cuneiform nucleus (CnF) that are involved in the regulation of skeletal muscle activity of the sympathetic pathway. The aim of this study was to use virus PRV-614 to trace the melanocortin-sympathetic neural pathways from PPTg and CnF to a hindlimb muscle (gastrocnemius) in spinally transected MC4R-GFP transgenic mice...
May 18, 2017: Oncotarget
https://www.readbyqxmd.com/read/28589422/modulatory-function-of-nmda-glutamate-receptor-on-mc3-mc4-receptors-agonist-induced-hypophagia-in-neonatal-meat-type-chicken
#6
Fariba Ahmadi, Morteza Zendehdel, Vahab Babapour, Negar Panahi, Shahin Hassanpour, Mina Khodadadi
Melanocortin 3 and 4 receptors (MC3R and MC4R) are known as the main receptors for melanocortin-induced hypophagia in mammalian and poultry. Also, central glutamatergic system has mediatory role on function of the melanocortin system in some brain areas. So, the aim of the current study was to determine the role of MC3/MC4 receptors agonist on food intake and its interaction with glutamatergic in 3-h food-deprived (FD3) neonatal broilers. In experiment 1, chickens were intracerebroventricular (ICV) injected with control solution, MTII (MC3/MC4 receptors agonist; 2...
June 6, 2017: Veterinary Research Communications
https://www.readbyqxmd.com/read/28579220/the-polymorphism-rs17782313-near-mc4r-gene-is-related-with-anthropometric-changes-in-women-submitted-to-bariatric-surgery-over-60-months
#7
Cristina Maria Mendes Resende, Danielle Fernandes Durso, Karina Braga Gomes Borges, Rafaela Messias Pereira, Gisele Kuhlmann Duarte Rodrigues, Kathryna Fontana Rodrigues, José Luiz Padilha Silva, Erica Castilho Rodrigues, Gloria Regina Franco, Jacqueline Isaura Alvarez-Leite
OBJECTIVE: Evaluate whether the polymorphism rs17782313 near MC4R gene influences long-term outcomes after bariatric surgery. METHODS: The rs16782313 polymorphism was genotyped in 217 individuals undergoing bariatric surgery and analyzed in detail in 141 women. Data for comorbidities, BMI, excess weight loss (EWL), and body composition were obtained before and during 60 months after surgery. RESULTS: The risk allele was found in 65 (47%) of the 141 women...
May 22, 2017: Clinical Nutrition: Official Journal of the European Society of Parenteral and Enteral Nutrition
https://www.readbyqxmd.com/read/28579117/key-amino-acid-residue-in-melanocortin-1-receptor-melanocyte-%C3%AE-msh-receptor-for-ligand-selectivity
#8
Yingkui Yang, Min Chen, George Ventro, Carroll M Harmon
The melanocortin-1 receptor (MC1R) is a subtype of the melanocortin receptor family and NDP-α-MSH is a non-selective agonist for MC1R. The core sequence of NDP-α-MSH, His-Phe-Arg-Trp, is important for ligand binding and biological activities at the melanocortin receptor subtypes (MCRs). A recent study indicates that Trp(9) in NDP-α-MSH plays an important role in ligand selectivity. Deletion of Trp(9) in NDP-α-MSH (des-Trp(9)-NDP-α-MSH) resulted in loss of agonist activity at MC4R, although remains agonist activity at MC1R...
June 1, 2017: Molecular and Cellular Endocrinology
https://www.readbyqxmd.com/read/28576837/hypothalamic-inflammation-in-human-obesity-is-mediated-by-environmental-and-genetic-factors
#9
Carina Kreutzer, Sönke Peters, Dominik M Schulte, Daniela Fangmann, Kathrin Türk, Stephan Wolff, Thilo van Eimeren, Markus Ahrens, Jan Beckmann, Clemens Schafmayer, Thomas Becker, Tina Kerby, Axel Rohr, Christian Riedel, Femke-Anouska Heinsen, Frauke Degenhardt, Andre Franke, Philip Rosenstiel, Nana Zubek, Christian Henning, Sandra Freitag-Wolf, Astrid Dempfle, Aristea Psilopanagioti, Helen Petrou-Papadaki, Lennart Lenk, Olav Jansen, Stefan Schreiber, Matthias Laudes
Obesity is associated with hypothalamic inflammation (HI) in animal models. In the present study we examined the mediobasal hypothalamus (MBH) of 57 obese human subjects and 54 age- and sex- matched non-obese controls by MRI and analyzed the T2-hyperintensity as a measure of HI. Obese subjects exhibited T2-hyperintensity in the left but not the right MBH which was strongly associated with systemic low-grade inflammation. MRI-spectroscopy revealed the number of neurons in the left hypothalamic region to be similar in obese versus control subjects suggesting functional but not structural impairment due to the inflammatory process...
June 2, 2017: Diabetes
https://www.readbyqxmd.com/read/28575455/adolescent-alcohol-exposure-induced-changes-in-alpha-melanocyte-stimulating-hormone-and-neuropeptide-y-pathways-via-histone-acetylation-in-the-brain-during-adulthood
#10
Dadasaheb M Kokare, Evan J Kyzar, Huaibo Zhang, Amul J Sakharkar, Subhash C Pandey
Background: Adolescent intermittent ethanol (AIE) exposure causes long-lasting alterations in brain epigenetic mechanisms. Melanocortin and neuropeptide Y (NPY) signaling interact and are affected by ethanol exposure in the brain. Here, the persistent effects of AIE on alpha-melanocyte stimulating hormone (α-MSH), melanocortin 4 receptor (MC4R) and NPY expression and their regulation by histone acetylation mechanisms were investigated in adulthood. Methods: Male rats were exposed to AIE (2 g/kg, i...
May 31, 2017: International Journal of Neuropsychopharmacology
https://www.readbyqxmd.com/read/28552734/melanocortin-4-receptor-regulation-of-pain
#11
REVIEW
Zhi-Xiao Li, Bao-Wen Liu, Zhi-Gang He, Hong-Bing Xiang
An increasingly high occurrence of chronic pain in patients highlights the importance of fundamental research. The melanocortin-4 receptor (MC4R) regulation of pain has attracted much attention in recent years due to its high expression in the mammalian brain regions related to nociception and pain. This review is devoted to anatomic distribution of MC4R in the brain and interaction between MC4R and other pathways for pain modulation. The experimental evidence available at present had expanded our understanding of melanocortin-4 receptor regulation of pain...
May 26, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28537674/correlations-of-mc4r-and-msh2-expression-with-obesity-in-colon-cancer-patients
#12
Y-Z Liu, K-Q Wang, D-H Ji, L-C Zhang, M Bi, B-Y Shi
OBJECTIVE: To investigate the correlations of MC4R and MSH2 with adult obesity, a total of 46 patients with early-stage colon cancer were treated in our hospital between February 2008 and February 2009 and were enrolled. PATIENTS AND METHODS: Venous blood was regularly drawn from subjects of the observation group and 48 healthy subjects for 6 years. Expression levels of MC4R and MSH2 genes were tested using quantitative polymerase chain reaction analyses, and the ensuing proteins were determined using enzyme-linked immunosorbent assays and Western blotting and immunohistochemical analyses...
May 2017: European Review for Medical and Pharmacological Sciences
https://www.readbyqxmd.com/read/28520814/rs12970134-near-mc4r-is-associated-with-appetite-and-beverage-intake-in-overweight-and-obese-children-a-family-based-association-study-in-chinese-population
#13
Shuo Wang, Jieyun Song, Yide Yang, Nitesh V Chawla, Jun Ma, Haijun Wang
BACKGROUND: Recent studies indicated that eating behaviors are under genetic influence, and the melanocortin 4 receptor (MC4R) gene polymorphisms can affect the total energy intake and the consumption of fat, protein and carbohydrates. Our study aims at investigating the association of the MC4R polymorphism with appetite and food intake among Chinese children. METHODS: A family-based association study was conducted among 151 Chinese trios whose offsprings were overweight/obese children aged 9-15 years...
2017: PloS One
https://www.readbyqxmd.com/read/28512117/the-interaction-of-mc3r-and-mc4r-with-mrap2-acth-%C3%AE-msh-and-agrp-in-chickens
#14
Jiannan Zhang, Xin Li, Yawei Zhou, Lin Cui, Jing Li, Chenlei Wu, Yiping Wan, Juan Li, Yajun Wang
The interaction of melanocortin-4 (MC4R) and melanocortin-3 (MC3R) receptors with proopiomelanocortin (POMC)-derived peptides (e.g. α-MSH), agouti-related protein (AgRP), and melanocortin-2 receptor accessory protein 2 (MRAP2) is suggested to play critical roles in energy balance of vertebrates. However, evidence on their interaction in birds remains scarce. Our study aims to reveal their interaction in chickens and the results showed that: 1) chicken (c-)MC3R and cMC4R expressed in CHO cells can be activated by α-MSH and ACTH1-39 equipotently, monitored by a pGL3-CRE-luciferase reporter system; 2) cMC3R and cMC4R, when co-expressed with cMRAP2 (or cMRAP, a cMRAP2 homolog), show increased sensitivity to ACTH treatment and thus likely act as ACTH-preferring receptors, and the interaction between cMC3R/cMC4R and cMRAP2 was demonstrated by co-immunoprecipitation assay; 3) both cMC3R and cMC4R display constitutive activity when expressed in CHO cells, as monitored by Dual-luciferase reporter assay, and cMRAP2 (and cMRAP) can modulate their constitutive activity; 4) AgRP inhibits the constitutive activity of cMC3R/cMC4R, and it also antagonizes ACTH/α-MSH action on cMC4R/cMC3R, indicating that AgRP functions as the inverse agonist and antagonist for both receptors...
May 16, 2017: Journal of Endocrinology
https://www.readbyqxmd.com/read/28507313/chronic-intrahypothalamic-rather-than-subcutaneous-liraglutide-treatment-reduces-body-weight-gain-and-stimulates-the-melanocortin-receptor-system
#15
K Kaineder, T Birngruber, G Rauter, B Obermüller, J Eichler, J Münzker, W Al-Zoughbi, S I Mautner, S S Torekov, B Hartmann, P Kotzbeck, T R Pieber
BACKGROUND: The GLP-1 receptor agonist liraglutide is marketed for obesity treatment where it induces body weight reduction possibly via the hypothalamus, which regulates energy homeostasis. In animal studies, acute liraglutide treatment triggers satiety, weight loss and activates thermogenesis in adipose tissue. However, the precise mechanisms how liraglutide affects in particular chronic weight loss are still under investigation. OBJECTIVES: We aimed to evaluate whether chronic hypothalamic or chronic subcutaneous administration of liraglutide induces sustained weight loss through altered adipose tissue function and to what extent hypothalamic neuronal appetite regulators are involved in the liraglutide-induced weight loss in healthy lean rats on a normal diet...
April 25, 2017: International Journal of Obesity: Journal of the International Association for the Study of Obesity
https://www.readbyqxmd.com/read/28500249/maternal-high-fat-diet-induces-metabolic-stress-response-disorders-in-offspring-hypothalamus
#16
Long The Nguyen, Sonia Saad, Yi Tan, Carol Pollock, Hui Chen
Maternal obesity has been shown to increase the risk of obesity and related disorders in the offspring, which has been partially attributed to changes of appetite regulators in the offspring hypothalamus. On the other hand, endoplasmic reticulum (ER) stress and autophagy have been implicated in hypothalamic neuropeptide dysregulation, thus may also play important roles in such transgenerational effect.  In this study, we show that offspring born to HFD-fed dams showed significantly increased body weight and glucose intolerance, adiposity and plasma triglyceride level at weaning...
May 12, 2017: Journal of Molecular Endocrinology
https://www.readbyqxmd.com/read/28499988/melanocortin-neurons-multiple-routes-to-regulation-of-metabolism
#17
REVIEW
Wen-Jie Shen, Ting Yao, Xingxing Kong, Kevin W Williams, Tiemin Liu
The burden of disability, premature death, escalating health care costs and lost economic productivity due to obesity and its associated complications including hypertension, stroke, cardiovascular disease and type 2 diabetes is staggering [1,2]. A better understanding of metabolic homeostatic pathways will provide us with insights into the biological mechanisms of obesity and how to fundamentally address this epidemic [3-6]. In mammals, energy balance is maintained via a homeostatic system involving both peripheral and central melanocortin systems; changes in body weight reflect an unbalance of the energetic state [7-9]...
May 9, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28472148/genetic-analysis-of-single-minded-1-gene-in-early-onset-severely-obese-children-and-adolescents
#18
Daniela Stanikova, Marek Buzga, Patrik Krumpolec, Martina Skopkova, Martina Surova, Barbara Ukropcova, Lubica Ticha, Miroslava Petrasova, Dominika Gabcova, Miroslava Huckova, Lucie Piskorova, Jan Bozensky, Marian Mokan, Jozef Ukropec, Ivona Zavacka, Iwar Klimes, Juraj Stanik, Daniela Gasperikova
BACKGROUND: Inactivating mutations of the hypothalamic transcription factor singleminded1 (SIM1) have been shown as a cause of early-onset severe obesity. However, to date, the contribution of SIM1 mutations to the obesity phenotype has only been studied in a few populations. In this study, we screened the functional regions of SIM1 in severely obese children of Slovak and Moravian descent to determine if genetic variants within SIM1 may influence the development of obesity in these populations...
2017: PloS One
https://www.readbyqxmd.com/read/28453292/discovery-of-mixed-pharmacology-melanocortin-3-agonists-and-melanocortin-4-receptor-tetrapeptide-antagonist-compounds-tacos-based-on-the-sequence-ac-xaa-1-arg-pi-dphe-xaa-4-nh2
#19
Skye R Doering, Katie T Freeman, Sathya M Schnell, Erica M Haslach, Marvin Dirain, Ginamarie Debevec, Phaedra Geer, Radleigh G Santos, Marc A Giulianotti, Clemencia Pinilla, Jon R Appel, Robert C Speth, Richard A Houghten, Carrie Haskell-Luevano
The centrally expressed melanocortin-3 and -4 receptors (MC3R/MC4R) have been studied as possible targets for weight management therapies, with a preponderance of studies focusing on the MC4R. Herein, a novel tetrapeptide scaffold [Ac-Xaa(1)-Arg-(pI)DPhe-Xaa(4)-NH2] is reported. The scaffold was derived from results obtained from a MC3R mixture-based positional scanning campaign. From these results, a set of 48 tetrapeptides were designed and pharmacologically characterized at the mouse melanocortin-1, -3, -4, and -5 receptors...
May 25, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28434791/neuronal-cells-derived-from-human-induced-pluripotent-stem-cells-as-a-functional-tool-of-melanocortin-system
#20
Nobuko Yamada-Goto, Yukari Ochi, Goro Katsuura, Yui Yamashita, Ken Ebihara, Michio Noguchi, Junji Fujikura, Daisuke Taura, Masakatsu Sone, Kiminori Hosoda, Paul E Gottschall, Kazuwa Nakao
BACKGROUND: The preparation of human neurons derived from human induced pluripotent stem (iPS) cells can serve as a potential tool for evaluating the physiological and pathophysiological properties of human neurons and for drug development. METHODS: In the present study, the functional activity in neuronal cells differentiated from human iPS cells was observed. RESULTS: The differentiated cells expressed mRNAs for classical neuronal markers (microtubule-associated protein 2, β-tubulin III, calbindin 1, synaptophysin and postsynaptic density protein 95) and for subunits of various excitatory and inhibitory transmitters (NR1, NR2A, NR2B, GABAA α1)...
April 7, 2017: Neuropeptides
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