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Melanocortin 4 receptor

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https://www.readbyqxmd.com/read/29031731/evaluation-of-a-melanocortin-4-receptor-mc4r-agonist-setmelanotide-in-mc4r-deficiency
#1
Tinh-Hai Collet, Béatrice Dubern, Jacek Mokrosinski, Hillori Connors, Julia M Keogh, Edson Mendes de Oliveira, Elana Henning, Christine Poitou-Bernert, Jean-Michel Oppert, Patrick Tounian, Florence Marchelli, Rohia Alili, Johanne Le Beyec, Dominique Pépin, Jean-Marc Lacorte, Andrew Gottesdiener, Rebecca Bounds, Shubh Sharma, Cathy Folster, Bart Henderson, Stephen O'Rahilly, Elizabeth Stoner, Keith Gottesdiener, Brandon L Panaro, Roger D Cone, Karine Clément, I Sadaf Farooqi, Lex H T Van der Ploeg
OBJECTIVE: Pro-opiomelanocortin (POMC)-derived peptides act on neurons expressing the Melanocortin 4 receptor (MC4R) to reduce body weight. Setmelanotide is a highly potent MC4R agonist that leads to weight loss in diet-induced obese animals and in obese individuals with complete POMC deficiency. While POMC deficiency is very rare, 1-5% of severely obese individuals harbor heterozygous mutations in MC4R. We sought to assess the efficacy of Setmelanotide in human MC4R deficiency. METHODS: We studied the effects of Setmelanotide on mutant MC4Rs in cells and the weight loss response to Setmelanotide administration in rodent studies and a human clinical trial...
October 2017: Molecular Metabolism
https://www.readbyqxmd.com/read/29031713/peripheral-cannabinoid-1-receptor-blockade-restores-hypothalamic-leptin-signaling
#2
Joseph Tam, Gergő Szanda, Adi Drori, Ziyi Liu, Resat Cinar, Yoshihiro Kashiwaya, Marc L Reitman, George Kunos
OBJECTIVE: In visceral obesity, an overactive endocannabinoid/CB1 receptor (CB1R) system promotes increased caloric intake and decreases energy expenditure, which are mitigated by global or peripheral CB1R blockade. In mice with diet-induced obesity (DIO), inhibition of food intake by the peripherally restricted CB1R antagonist JD5037 could be attributed to endogenous leptin due to the rapid reversal of hyperleptinemia that maintains leptin resistance, but the signaling pathway engaged by leptin has remained to be determined...
October 2017: Molecular Metabolism
https://www.readbyqxmd.com/read/29031712/mitochondrial-uncoupling-in-the-melanocortin-system-differentially-regulates-npy-and-pomc-neurons-to-promote-weight-loss
#3
Natalie Jane Michael, Stephanie Elise Simonds, Marco van den Top, Michael Alexander Cowley, David Spanswick
OBJECTIVE: The mitochondrial uncoupling agent 2,4-dinitrophenol (DNP), historically used as a treatment for obesity, is known to cross the blood-brain-barrier, but its effects on central neural circuits controlling body weight are largely unknown. As hypothalamic melanocortin neuropeptide Y/agouti-related protein (NPY/AgRP) and pro-opiomelanocortin (POMC) neurons represent key central regulators of food intake and energy expenditure we investigated the effects of DNP on these neurons, food intake and energy expenditure...
October 2017: Molecular Metabolism
https://www.readbyqxmd.com/read/29030576/genetic-induction-of-hypometabolism-by-ablation-of-mc4r-does-not-suppress-als-like-phenotypes-in-the-g93a-mutant-sod1-mouse-model
#4
Shachee Doshi, Preetika Gupta, Robert G Kalb
Dysfunction and death of motor neurons leads to progressive paralysis in amyotrophic lateral sclerosis (ALS). Recent studies have reported organism-level metabolic dysfunction as a prominent but poorly understood feature of the disease. ALS patients are hypermetabolic with increased resting energy expenditure, but if and how hypermetabolism contributes to disease pathology is unknown. We asked if decreasing metabolism in the mutant superoxide dismutase 1 (SOD1) mouse model of ALS (G93A SOD1) would alter motor function and survival...
October 13, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29020973/the-%C3%AE-melanocyte-stimulating-hormone-peroxisome-proliferator-activated-receptor-%C3%AE-pathway-down-regulates-proliferation-in-melanoma-cell-lines
#5
Enrica Flori, Eleonora Rosati, Giorgia Cardinali, Daniela Kovacs, Barbara Bellei, Mauro Picardo, Vittoria Maresca
BACKGROUND: The α-Melanocyte Stimulating Hormone (αMSH)/Melanocortin-1 receptor (MC1R) interaction promotes melanogenesis through the cAMP/PKA pathway. The direct induction of this pathway by Forskolin (FSK) is also known to enhance melanocyte proliferation. αMSH acts as a mitogenic agent in melanocytes and its effect on proliferation of melanoma cells is less known. We previously identified the αMSH/Peroxisome Proliferator Activated Receptor (PPARγ) pathway as a new pathway on the B16-F10 mouse melanoma cell line...
October 11, 2017: Journal of Experimental & Clinical Cancer Research: CR
https://www.readbyqxmd.com/read/28974783/environmental-perturbation-of-the-circadian-clock-during-pregnancy-leads-to-transgenerational-mood-disorder-like-behaviors-in-mice
#6
Peng Zhang, Guang Li, Hui Li, XiaoQiu Tan, Hai-Ying Mary Cheng
It remains unknown whether chronic circadian disturbance (CCD) during pregnancy can lead to mood disorders in the offspring. Here we show that pregnant mice in the F0 generation that were exposed to CCD stress displayed depression-like behaviors, and produced offspring in the F1 and F2 generations that also exhibited mood-associated behavioral phenotypes despite the lack of direct stressful experiences during their postnatal or adult period. Prenatal CCD stress was correlated with the elevation of plasma corticosterone levels in F1 mice...
October 3, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28972753/click-chemistry-mediated-synthesis-of-selective-melanocortin-receptor-4-agonists
#7
Daniel Palmer, Juliana Pereira Lopes Gonçalves, Louise Valentin Hansen, Boqian Wu, Helle Hald, Sanne Schoffelen, Frederik Diness, Sebastian Thordal Le Quement, Thomas E Nielsen, Morten Meldal
The Melanocortin Receptor-4 (MC4R) subtype of the melanocortin receptor family is a target for therapeutics to ameliorate metabolic dysfunction. Endogenous MC4R agonists possess a critical pharmacophore (HFRW) and cyclization of peptide agonists often enhances potency. Thus, 17 cyclized peptides were synthesized by solid phase click chemistry to develop novel, potent, selective MC4R agonists. Using cAMP measurements and a transcriptional reporter assay, we observed that several constrained agonists generated by a cycloadditon reaction displayed high selectivity (223-467 fold) towards MC4R over MC3R and MC5R receptor subtypes without compromising agonist potency...
October 3, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28968061/comparative-in-vivo-investigation-of-intrathecal-and-intracerebroventricular-administration-with-melanocortin-ligands-mtii-and-agrp-into-mice
#8
Danielle N Adank, Mary M Lunzer, Cody J Lensing, Stacey L Wilber, Amy M Gancarz, Carrie Haskell-Luevano
Central administration of melanocortin ligands has been used as a critical technique to study energy homeostasis. While intracerebroventricular (ICV) injection is the most commonly used method during these investigations, intrathecal (IT) injection can be equally efficacious for the central delivery of ligands. Importantly, intrathecal administration can optimize exploration of melanocortin receptors in the spinal cord. Herein, we investigate comparative IT and ICV administration of two melanocortin ligands, the synthetic MTII (Ac-Nle-c[Asp-His-DPhe-Arg-Trp-Lys]-NH2) MC4R agonist and agouti-related peptide [AGRP(87-132)] MC4R inverse agonist/antagonist, on the same batch of age-matched mice in TSE metabolic cages undergoing a nocturnal satiated paradigm...
October 19, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28959025/mrap2-regulates-ghrelin-receptor-signaling-and-hunger-sensing
#9
Dollada Srisai, Terry C Yin, Abigail A Lee, Alix A J Rouault, Nicole A Pearson, Justin L Grobe, Julien A Sebag
Ghrelin is the only known circulating orexigenic hormone. It is primarily secreted by the stomach and acts at its receptor, the growth hormone secretagogue receptor 1a (GHSR1a), in the hypothalamus to signal hunger and promote food intake. The melanocortin receptor accessory protein 2 (MRAP2) was previously shown to regulate energy homeostasis through the modulation of the activity of the melanocortin-4 receptor and prokineticin receptors. In this study we identify MRAP2 as a partner of ghrelin-GHSR1a signaling...
September 28, 2017: Nature Communications
https://www.readbyqxmd.com/read/28953924/the-first-transcriptome-of-italian-wall-lizard-a-new-tool-to-infer-about-the-island-syndrome
#10
Martina Trapanese, Maria Buglione, Valeria Maselli, Simona Petrelli, Serena Aceto, Domenico Fulgione
Some insular lizards show a high degree of differentiation from their conspecific mainland populations, like Licosa island lizards, which are described as affected by Reversed Island Syndrome (RIS). In previous works, we demonstrated that some traits of RIS, as melanization, depend on a differential expression of gene encoding melanocortin receptors. To better understand the basis of syndrome, and providing raw data for future investigations, we generate the first de novo transcriptome of the Italian wall lizard...
2017: PloS One
https://www.readbyqxmd.com/read/28936166/nucleus-accumbens-mc4-r-stimulation-reduces-food-and-ethanol-intake-in-adult-rats-regardless-of-binge-like-ethanol-exposure-during-adolescence
#11
Francisca Carvajal, José M Lerma-Cabrera, Manuel Alcaraz-Iborra, Montserrat Navarro, Todd E Thiele, Inmaculada Cubero
The melanocortin (MC) system regulates feeding and ethanol consumption. Recent evidence shows that melanocortin 4 receptor (MC4-R) stimulation within the nucleus accumbens (NAc) elicits anorectic responses and reduces ethanol consumption and ethanol palatability in adult rats. Ethanol exposure during adolescence causes long-lasting changes in neural pathways critically involved in neurobehavioral responses to ethanol. In this regard, binge-like ethanol exposure during adolescence reduces basal alpha-melanocyte-stimulating hormone (α-MSH) and alters the levels of agouti-related peptide (AgRP) in hypothalamic and limbic areas...
2017: Frontiers in Behavioral Neuroscience
https://www.readbyqxmd.com/read/28930194/developmental-programming-of-obesity-and-liver-metabolism-by-maternal-perinatal-nutrition-involves-the-melanocortin-system
#12
Paul Cordero, Jiawei Li, Vi Nguyen, Joaquim Pombo, Nuria Maicas, Marco Novelli, Paul D Taylor, Anne-Maj Samuelsson, Manlio Vinciguerra, Jude A Oben
Maternal obesity predisposes offspring to metabolic dysfunction and Non-Alcoholic Fatty Liver Disease (NAFLD). Melanocortin-4 receptor (Mc4r)-deficient mouse models exhibit obesity during adulthood. Here, we aim to determine the influence of the Mc4r gene on the liver of mice subjected to perinatal diet-induced obesity. Female mice heterozygous for Mc4r fed an obesogenic or a control diet for 5 weeks were mated with heterozygous males, with the same diet continued throughout pregnancy and lactation, generating four offspring groups: control wild type (C_wt), control knockout (C_KO), obese wild type (Ob_wt), and obese knockout (Ob_KO)...
September 20, 2017: Nutrients
https://www.readbyqxmd.com/read/28924523/the-interplay-of-genetics-and-environmental-factors-in-the-development-of-obesity
#13
REVIEW
Abu Baker Sheikh, Adeel Nasrullah, Shujaul Haq, Aisha Akhtar, Haider Ghazanfar, Amara Nasir, Rao M Afzal, Marvi M Bukhari, Ahtsham Yousaf Chaudhary, Syed W Naqvi
Obesity is a major health issue in the developed nations, and it has been increasingly clear that both genetics and environment play an important role in determining if an individual will be obese or not. We reviewed the latest researches which were carried out to identify the obesity susceptible genes and to identify the metabolic pathways having a central role in energy balance. Obesity is a heritable disorder, and some of the many obesity susceptible genes are fat mass and obesity (FTO), leptin, and Melanocortin-4 receptor (MC4R)...
July 6, 2017: Curēus
https://www.readbyqxmd.com/read/28904020/gtrap3-18-regulates-food-intake-and-body-weight-by-interacting-with-pro-opiomelanocortin
#14
Koji Aoyama, Wattanaporn Bhadhprasit, Masahiko Watabe, Fan Wang, Nobuko Matsumura, Toshio Nakaki
Pro-opiomelanocortin (POMC)-expressing neurons provide α-melanocyte-stimulating hormone (α-MSH), which stimulates melanocortin 4 receptor to induce hypophagia by AMPK inhibition in the hypothalamus. α-MSH is produced by POMC cleavage in secretory granules and released. However, it is not known yet whether any posttranscriptional regulatory mechanism of POMC signaling exists upstream of the secretory granules in neurons. Here we show that glutamate transporter-associated protein 3-18 (GTRAP3-18), an anchor protein that retains interacting proteins in the endoplasmic reticulum, is a critical regulator of food intake and body weight by interacting with POMC...
September 13, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/28878020/lipid-stress-inhibits-endocytosis-of-melanocortin-4-receptor-from-modified-clathrin-enriched-sites-and-impairs-receptor-desensitization
#15
Kimberly A Cooney, Brent M Molden, Nicholas S Kowalczyk, Susan Russell, Giulia Baldini
Melanocortin-4 receptor (MC4R) is a G protein coupled receptor expressed in the brain hypothalamus where it regulates energy homeostasis. MC4R agonists function to lower food intake and weight. In this respect, while obesity promotes hyperlipidemia and hypothalamic injury, MC4R agonists are nevertheless more effective to reduce food intake within hours of administration in overweight, rather than lean, mice. MC4R undergoes constitutive internalization and recycling to the plasma membrane, with agonist binding inducing receptor retention along the intracellular route and, under prolonged exposure, desensitization...
September 6, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28852042/the-mc4r-genotype-is-associated-with-postpartum-weight-reduction-and-glycemic-changes-among-women-with-prior-gestational-diabetes-longitudinal-analysis
#16
Aline Martins de Carvalho, Ping Shao, Huikun Liu, Han-Ling Cheng, Yan Zheng, Junhong Leng, Weiqin Li, Tao Huang, Tiange Wang, Leishen Wang, Shuang Zhang, Gang Hu, Lu Qi
The genetic variants near the Melanocortin-4 receptor gene (MC4R), a key protein regulating energy balance and adiposity, have been related to obesity and glucose metabolism. We aimed to assess whether the MC4R genotype affected longitudinal changes in body weight and glucose metabolism biomarkers among women with prior gestational diabetes mellitus (GDM). The MC4R genotype, postpartum weight reduction, and glycemic changes between after delivery and pregnancy were assessed in a cohort of 1208 Chinese women who had experienced GDM...
August 29, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28851749/the-thermogenic-effect-of-nesfatin-1-requires-recruitment-of-the-melanocortin-system
#17
Riccardo Dore, Luka Levata, Sogol Gachkar, Olaf Jöhren, Jens Mittag, Hendrik Lehnert, Carla Schulz
Nesfatin-1 is a bioactive polypeptide expressed both in the brain and peripheral tissues and involved in the control of energy balance by reducing food intake. Central administration of nesfatin-1 significantly increases energy expenditure, as demonstrated by a higher dry heat loss; yet, the mechanisms underlying the thermogenic effect of central nesfatin-1 remain unknown. Therefore, in this study, we sought to investigate whether the increase in energy expenditure induced by nesfatin-1 is mediated by the central melanocortin pathway, which was previously reported to mediate central nesfatin-1´s effects on feeding and numerous other physiological functions...
November 2017: Journal of Endocrinology
https://www.readbyqxmd.com/read/28829041/loss-of-the-melanocortin-4-receptor-in-mice-causes-dilated-cardiomyopathy
#18
Michael J Litt, G Donald Okoye, Daniel Lark, Isin Cakir, Christy Moore, Mary C Barber, James Atkinson, Josh Fessel, Javid Moslehi, Roger D Cone
Haploinsufficiency of the melanocortin-4 receptor, the most common monogenetic obesity syndrome in humans, is associated with a reduction in autonomic tone, bradycardia, and incidence of obesity-associated hypertension. Thus, it has been assumed that melanocortin obesity syndrome may be protective with respect to obesity-associated cardiovascular disease. We show here that absence of the melanocortin-4 receptor (MC4R) in mice causes dilated cardiomyopathy, characterized by reduced contractility and increased left ventricular diameter...
August 22, 2017: ELife
https://www.readbyqxmd.com/read/28828082/impact-of-the-polymorphism-near-mc4r-rs17782313-on-obesity-and-metabolic-related-traits-in-women-participating-in-an-aerobic-training-program
#19
Agata Leońska-Duniec, Zbigniew Jastrzębski, Aleksandra Zarębska, Wojciech Smółka, Paweł Cięszczyk
The C/T polymorphism (rs17782313) mapped 188 kb downstream of the melanocortin-4 receptor gene (MC4R) shows a strong relationship with an increased body mass index (BMI) and the risk of type 2 diabetes. However, the information on polymorphism's potential modifying effect on obesity- and metabolic-related traits achieved through training is still unknown. Therefore, we decided to check if selected body measurements observed in physically active participants would be modulated by the genotype. The genotype distribution was examined in a group of 201 Polish women measured for chosen traits before and after the completion of a 12 week moderate-intensive aerobic training program...
September 2017: Journal of Human Kinetics
https://www.readbyqxmd.com/read/28813605/structure-activity-relationship-studies-on-a-macrocyclic-agouti-related-protein-agrp-scaffold-reveal-agouti-signaling-protein-asp-residue-substitutions-maintain-melanocortin-4-receptor-antagonist-potency-and-result-in-inverse-agonist-pharmacology-at-the-melanocortin
#20
Mark D Ericson, Katie T Freeman, Sathya M Schnell, Katlyn A Fleming, Carrie Haskell-Luevano
The melanocortin system consists of five reported receptors, agonists from the proopiomelanocortin gene transcript, and two antagonists, agouti-signaling protein (ASP) and agouti-related protein (AGRP). For both ASP and AGRP, the hypothesized Arg-Phe-Phe pharmacophores are on exposed β-hairpin loops. In this study, the Asn and Ala positions of a reported AGRP macrocyclic scaffold (c[Pro-Arg-Phe-Phe-Asn-Ala-Phe-DPro]) were explored with 14-compound and 8-compound libraries, respectively, to generate more potent, selective melanocortin receptor antagonists...
October 12, 2017: Journal of Medicinal Chemistry
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