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Melanocortin 4 receptor

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https://www.readbyqxmd.com/read/29642894/activation-of-melanocortin-receptor-4-with-ro27-3225-attenuates-neuroinflammation-through-ampk-jnk-p38-mapk-pathway-after-intracerebral-hemorrhage-in-mice
#1
Shengpan Chen, Lianhua Zhao, Prativa Sherchan, Yan Ding, Jing Yu, Derek Nowrangi, Jiping Tang, Ying Xia, John H Zhang
BACKGROUND: Neuroinflammation plays an important role in the pathogenesis of intracerebral hemorrhage (ICH)-induced secondary brain injury. Activation of melanocortin receptor 4 (MC4R) has been shown to elicit anti-inflammatory effects in many diseases. The objective of this study was to explore the role of MC4R activation on neuroinflammation in a mouse ICH model and to investigate the contribution of adenosine monophosphate-activated protein kinase (AMPK)/c-Jun N-terminal kinase (JNK)/p38 mitogen-activated protein kinase (p38 MAPK) pathway in MC4R-mediated protection...
April 11, 2018: Journal of Neuroinflammation
https://www.readbyqxmd.com/read/29625570/the-inhibition-of-human-lung-fibroblast-proliferation-and-differentiation-by-gs-coupled-receptors-is-not-predicted-by-the-magnitude-of-camp-response
#2
Maxine J Roberts, Rebecca E Broome, Toby C Kent, Steven J Charlton, Elizabeth M Rosethorne
BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive fibrotic lung disease for which there is no cure. Current therapeutics are only able to slow disease progression, therefore there is a need to explore alternative, novel treatment options. There is increasing evidence that the 3', 5' cyclic adenosine monophosphate (cAMP) pathway is an important modulator in the development of fibrosis, with increasing levels of cAMP able to inhibit cellular processes associated with IPF...
April 7, 2018: Respiratory Research
https://www.readbyqxmd.com/read/29598821/association-between-the-dna-methylations-of-pomc-mc4r-and-hnf4a-and-metabolic-profiles-in-the-blood-of-children-aged-7-9-years
#3
Eun Jin Kwon, Young-Ah You, Bohyun Park, Eun Hee Ha, Hae Soon Kim, Hyesook Park, Young Ju Kim
BACKGROUND: Proopiomelanocortin (POMC), melanocortin 4 receptor (MC4R), and hepatocyte nuclear factor 4 alpha (HNF4A) are closely associated with weight gain and metabolic traits. In a previous study, we demonstrated associations between the methylations of POMC, MC4R, and HNF4A and metabolic profiles at birth. However, little is known about these associations in obese children. To evaluate the clinical utility of epigenetic biomarkers, we investigated to determine whether an association exists between the methylations of POMC, MC4R, and HNF4A and metabolic profiles in blood of normal weight and overweight and obese children...
March 29, 2018: BMC Pediatrics
https://www.readbyqxmd.com/read/29574148/%C3%AE-melanocyte-stimulating-hormone-promotes-bone-resorption-resulting-from-increased-osteoblastic-and-osteoclastic-activities-in-goldfish
#4
Hidenori Ishizu, Toshio Sekiguchi, Takahiro Ikari, Kei-Ichiro Kitamura, Yoichiro Kitani, Masato Endo, Makoto Urata, Yasuko Kinoshita, Atsuhiko Hattori, Ajai K Srivastav, Hiroyuki Mishima, Kanta Mizusawa, Akiyoshi Takahashi, Nobuo Suzuki
We examined the effects of α -melanocyte-stimulating hormone (α -MSH) on bone metabolism using regenerating goldfish scales. Normally developed scales on the bodies of goldfish were removed to allow the regeneration of scales under anesthesia. Thereafter, the influence of α -MSH on the regeneration of goldfish scales was investigated in vivo. In brief, α -MSH was injected at a low dose (0.1 μg/g body weight) or a high dose (1μg/g body weight) into goldfish every other day. Ten days after removing the scales, we collected regenerating scales and analyzed osteoblastic and osteoclastic activities as respective marker enzyme (alkaline phosphatase for osteoblasts, tartrate-resistant acid phosphatase for osteoclasts) activity in the regenerating scales as well as plasma calcium levels...
March 21, 2018: General and Comparative Endocrinology
https://www.readbyqxmd.com/read/29568105/early-childhood-bmi-trajectories-in-monogenic-obesity-due-to-leptin-leptin-receptor-and-melanocortin-4-receptor-deficiency
#5
Katja Kohlsdorf, Adriana Nunziata, Jan-Bernd Funcke, Stephanie Brandt, Julia von Schnurbein, Heike Vollbach, Belinda Lennerz, Maria Fritsch, Susanne Greber-Platzer, Elke Fröhlich-Reiterer, Manuel Luedeke, Guntram Borck, Klaus-Michael Debatin, Pamela Fischer-Posovszky, Martin Wabitsch
OBJECTIVE: To evaluate whether early childhood body mass index (BMI) is an appropriate indicator for monogenic obesity. METHODS: A cohort of n = 21 children living in Germany or Austria with monogenic obesity due to congenital leptin deficiency (group LEP, n = 6), leptin receptor deficiency (group LEPR, n = 6) and primarily heterozygous MC4 receptor deficiency (group MC4R, n = 9) was analyzed. A control group (CTRL) was defined that consisted of n = 22 obese adolescents with no mutation in the above mentioned genes...
February 27, 2018: International Journal of Obesity: Journal of the International Association for the Study of Obesity
https://www.readbyqxmd.com/read/29545738/subdiaphragmatic-vagotomy-with-pyloroplasty-ameliorates-the-obesity-caused-by-genetic-deletion-of-the-melanocortin-4-receptor-in-the-mouse
#6
Ghazaul Dezfuli, Richard A Gillis, Jaclyn E Tatge, Kimbell R Duncan, Kenneth L Dretchen, Patrick G Jackson, Joseph G Verbalis, Niaz Sahibzada
Background/Objectives: We tested the hypothesis that abolishing vagal nerve activity will reverse the obesity phenotype of melanocortin 4 receptor knockout mice ( Mc4r -/- ). Subjects/Methods: In two separate studies, we examined the efficacy of bilateral subdiaphragmatic vagotomy (SDV) with pyloroplasty in the prevention and treatment of obesity in Mc4r -/- mice. Results: In the first study, SDV prevented >20% increase in body weight (BW) associated with this genotype. This was correlated with a transient reduction in overall food intake (FI) in the preventative arm of the study...
2018: Frontiers in Neuroscience
https://www.readbyqxmd.com/read/29501261/neuronal-cilia-another-player-in-the-melanocortin-system
#7
Luis Varela, Tamas L Horvath
Melanocortin receptors play crucial roles in multiple physiological processes. Melanocortin receptor 4 (MC4R) is expressed in key brain regions, and MC4R gene mutations can cause severe obesity. However, the cellular biology of MC4R is less well understood owing to the lack of reliable methods to visualize its location. Recently, Siljee and colleagues localized MC4R to the cilia of the neurons within the hypothalamus and showed that cilial expression of MC4R is crucial for the control of metabolic phenotype...
February 28, 2018: Trends in Molecular Medicine
https://www.readbyqxmd.com/read/29478721/mc4r-agonists-structural-overview-on-antiobesity-therapeutics
#8
REVIEW
Juliana Pereira Lopes Gonçalves, Daniel Palmer, Morten Meldal
The melanocortin-4 receptor (MC4R) regulates adipose tissue formation and energy homeostasis, and is believed to be a monogenic target for novel antiobesity therapeutics. Several research efforts targeting this receptor have identified potent and selective agonists. While viable agonists have been characterized in vitro, undesirable side effects frequently appeared during clinical trials. The most promising candidates have diverse structures, including linear peptides, cyclic peptides, and small molecules. Herein, we present a compilation of potent MC4R agonists and discuss the pivotal structural differences within those molecules that resulted in good selectivity for MC4R over other melanocortins...
February 22, 2018: Trends in Pharmacological Sciences
https://www.readbyqxmd.com/read/29466028/analysis-of-the-impact-of-common-polymorphisms-of-the-fto-and-mc4r-genes-with-the-risk-of-severe-obesity-in-saudi-arabian-population
#9
Cyril Cyrus, Mona H Ismail, Shahanas Chathoth, Chittibabu Vatte, Majd Hasen, Amein Al Ali
BACKGROUND: Obesity has reached epidemic proportions worldwide resulting in a serious public health problem. In Saudi Arabia, 28.7% of the population is obese due largely to the adoption of western dietary patterns over the last decade. The Fat-mass and obesity associated (FTO) and melanocortin-4 receptor (MC4R) genes are ubiquitously expressed in the brain and pancreatic islets, and are the main link between the central nervous system and energy homeostasis based on food intake and energy expenditure...
February 21, 2018: Genetic Testing and Molecular Biomarkers
https://www.readbyqxmd.com/read/29454840/melanocortin-4-receptor-stimulation-improves-social-deficits-in-mice-through-oxytocin-pathway
#10
Andrea Mastinu, Marika Premoli, Giuseppina Maccarinelli, Mariagrazia Grilli, Maurizio Memo, Sara Anna Bonini
Several studies on humans and mice support oxytocin's role in improving social behaviour, but its use in pharmacotherapy presents some important limiting factors. To date, it is emerging a pharmacological potential for melanocortin 4 receptor (MC4R) agonism in social deficits treatment. Recently, we demonstrated that the deletion of the NFKB1 gene, which encodes the p50 NF-κB subunit, causes impairment in social behaviours, with reductions in social interactions in mice. In this work, we tested the acute effects of THIQ, a selective melanocortin 4 receptor (MC4R) agonist...
May 1, 2018: Neuropharmacology
https://www.readbyqxmd.com/read/29454748/fatty-acid-binding-protein-4-fabp4-overexpression-in-intratumoral-hepatic-stellate-cells-within-hepatocellular-carcinoma-with-metabolic-risk-factors
#11
Norimichi Chiyonobu, Shu Shimada, Yoshimitsu Akiyama, Kaoru Mogushi, Michiko Itoh, Keiichi Akahoshi, Satoshi Matsumura, Kosuke Ogawa, Hiroaki Ono, Yusuke Mitsunori, Daisuke Ban, Atsushi Kudo, Shigeki Arii, Takayoshi Suganami, Shoji Yamaoka, Yoshihiro Ogawa, Minoru Tanabe, Shinji Tanaka
Metabolic syndrome is a newly identified risk factor for hepatocellular carcinoma (HCC); however, tumor-specific biomarkers still remain unclear. We performed cross-species analysis to compare gene signatures of HCC from human patients and melanocortin 4 receptor-knockout (MC4R-KO) mice, which develop HCC with obesity, insulin resistance, and dyslipidemia. Unsupervised hierarchical clustering and principle component analysis of 746 differentially expressed orthologous genes classified HCC of 152 human patients and MC4R-KO mice into two distinct subgroups, one of which included mouse HCC and was etiologically associated with metabolic risk factors...
February 15, 2018: American Journal of Pathology
https://www.readbyqxmd.com/read/29407371/g-protein-coupled-receptors-mc4r-and-drd1-can-serve-as-surrogate-odorant-receptors-in-mouse-olfactory-sensory-neurons
#12
Markella Katidou, Xavier Grosmaitre, Jiangwei Lin, Peter Mombaerts
In the mouse, most mature olfactory sensory neurons (OSNs) express one allele of one gene from the repertoire of ~1100 odorant receptor (OR) genes, which encode G-protein coupled receptors (GPCRs). Axons of OSNs that express a given OR coalesce into homogeneous glomeruli, which reside at conserved positions in the olfactory bulb. ORs are intimately involved in ensuring the expression of one OR per OSN and the coalescence of OSN axons into glomeruli. But the mechanisms whereby ORs accomplish these diverse functions remain poorly understood...
January 30, 2018: Molecular and Cellular Neurosciences
https://www.readbyqxmd.com/read/29402900/canagliflozin-an-sglt2-inhibitor-attenuates-the-development-of-hepatocellular-carcinoma-in-a-mouse-model-of-human-nash
#13
Kumiko Shiba, Kyoichiro Tsuchiya, Chikara Komiya, Yasutaka Miyachi, Kentaro Mori, Noriko Shimazu, Shinobu Yamaguchi, Naomi Ogasawara, Makoto Katoh, Michiko Itoh, Takayoshi Suganami, Yoshihiro Ogawa
Sodium glucose cotransporter 2 (SGLT2) inhibitors, an antidiabetic drug, promotes urinary excretion of glucose by blocking its reabsorption in the renal proximal tubules. It is unclear whether SGLT2 inhibition could attenuate nonalcoholic steatohepatitis (NASH) and NASH-associated hepatocellular carcinoma. We examined the preventive effects of an SGLT2 inhibitor canagliflozin (CANA) in Western diet (WD)-fed melanocortin 4 receptor-deficient (MC4R-KO) mice, a mouse model of human NASH. An eight-week CANA treatment attenuated hepatic steatosis in WD-fed MC4R-KO mice, with increased epididymal fat mass without inflammatory changes...
February 5, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29363944/structure-activity-relationship-studies-of-a-macrocyclic-agrp-mimetic-scaffold-c-pro-arg-phe-phe-asn-ala-phe-dpro-yield-potent-and-selective-melanocortin-4-receptor-antagonists-and-melanocortin-5-receptor-inverse-agonists-that-increase-food-intake-in-mice
#14
Katlyn A Fleming, Mark D Ericson, Katie T Freeman, Danielle N Adank, Mary M Lunzer, Stacey L Wilber, Carrie Haskell-Luevano
The melanocortin system has five receptors and antagonists of the central melanocortin receptors (MC3R, MC4R) are postulated to be viable therapeutics for disorders of negative energy balance such as anorexia, cachexia, and failure to thrive. Agouti-related protein (AGRP) is an antagonist of the MC3R and an antagonist/inverse agonist of the MC4R. Biophysical NMR based structural studies have demonstrated that the active sequence of this hormone, Arg-Phe-Phe, is located on an exposed β-hairpin loop. It has previously been demonstrated that the macrocyclic octapeptide scaffold c[Pro1-Arg2-Phe3-Phe4-Asn5-Ala6-Phe7-DPro8] is 16-fold less potent than AGRP at the mMC4R...
January 24, 2018: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/29360464/molecular-characterization-of-feline-melanocortin-4-receptor-and-melanocortin-2-receptor-accessory-protein-2
#15
Makoto Habara, Nobuko Mori, Yuki Okada, Koh Kawasumi, Nobuhiro Nakao, Yoshikazu Tanaka, Toshiro Arai, Ichiro Yamamoto
Melanocortin 4 receptor (MC4R), which is a member of the G protein-coupled receptor (GPCR) family, mediates regulation of energy homeostasis upon the binding of α-melanocyte-stimulating hormone (α-MSH) in the central nervous system (CNS). Melanocortin 2 receptor accessory protein 2 (MRAP2) modulates the function of MC4R. We performed cDNA cloning of cat MC4R and MRAP2 and characterized their amino acid sequences, mRNA expression patterns in cat tissues, protein-protein interactions, and functions. We found high sequence homology (>88%) with other mammalian MC4R and MRAP2 encoding 332 and 206 amino acid residues, respectively...
January 19, 2018: General and Comparative Endocrinology
https://www.readbyqxmd.com/read/29351428/control-of-appetite-blood-glucose-and-blood-pressure-during-melanocortin-4-receptor-activation-in-normoglycemic-and-diabetic-npy-deficient-mice
#16
Alexandre A da Silva, J Nathan Freeman, John E Hall, Jussara M do Carmo
Although central melanocortin 4 receptor (MC4R) blockade abolishes the central nervous system (CNS)-mediated anorexogenic, antidiabetic, and cardiovascular actions of leptin, chronic MC4R stimulation fails to completely mimic the effects of leptin. Because neuropeptide Y (NPY) and MC4R exert opposite effects on cardiovascular and metabolic functions, we tested the role of NPY in offsetting the long-term actions of MC4R activation. Wild-type (WT) and NPY-deficient (NPY-/- ) mice were implanted with telemetry probes for measuring mean arterial pressure (MAP) and heart rate (HR) 24 h/day...
April 1, 2018: American Journal of Physiology. Regulatory, Integrative and Comparative Physiology
https://www.readbyqxmd.com/read/29329999/understanding-melanocortin-4-receptor-control-of-neuronal-circuits-toward-novel-therapeutics-for-obesity-syndrome
#17
REVIEW
Sang Hyeon Ju, Gyu-Bon Cho, Jong-Woo Sohn
It is well known that melanocortin-4 receptors (MC4Rs) and central melanocortin pathways regulate food intake, energy expenditure, and glucose homeostasis. Importantly, MC4R deficiency is the most common monogenic cause of human obesity. Interestingly, MC4Rs expressed by distinct central nuclei are responsible for the different physiological function of MC4R stimulation. In addition, MC4Rs activate multiple intracellular and/or synaptic signaling molecules for the regulation of neuronal circuits. Therefore, MC4Rs and the downstream signal molecules are plausible targets for development of novel therapeutics against obesity and obesity-related metabolic disorders...
March 2018: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/29315078/associations-between-the-components-of-metabolic-syndrome-and-the-polymorphisms-in-the-peroxisome-proliferator-activated-receptor-gamma-ppar-%C3%AE-the-fat-mass-and-obesity-associated-fto-and-the-melanocortin-4-receptor-mc4r-genes
#18
Małgorzata Szkup, Aleksander Jerzy Owczarek, Daria Schneider-Matyka, Jacek Brodowski, Beata Łój, Elżbieta Grochans
INTRODUCTION: Metabolic syndrome (MetS) is regarded as a set of abnormalities, increasing the risk of serious functioning disorders. It can develop as a result of genetic predisposition. AIM: The aim of this study was to establish associations between MetS-related abnormalities and the PPAR-γ rs1801282, FTO rs9939609, and MC4R rs17782313 polymorphisms. MATERIAL AND METHODS: The study involved 425 women aged 45-60 years. The participants were surveyed and subjected to anthropometric, biochemical and genetic analysis...
January 9, 2018: Aging
https://www.readbyqxmd.com/read/29311635/subcellular-localization-of-mc4r-with-adcy3-at-neuronal-primary-cilia-underlies-a-common-pathway-for-genetic-predisposition-to-obesity
#19
Jacqueline E Siljee, Yi Wang, Adelaide A Bernard, Baran A Ersoy, Sumei Zhang, Aaron Marley, Mark Von Zastrow, Jeremy F Reiter, Christian Vaisse
Most monogenic cases of obesity in humans have been linked to mutations in genes encoding members of the leptin-melanocortin pathway. Specifically, mutations in MC4R, the melanocortin-4 receptor gene, account for 3-5% of all severe obesity cases in humans1-3 . Recently, ADCY3 (adenylyl cyclase 3) gene mutations have been implicated in obesity4,5 . ADCY3 localizes to the primary cilia of neurons 6 , organelles that function as hubs for select signaling pathways. Mutations that disrupt the functions of primary cilia cause ciliopathies, rare recessive pleiotropic diseases in which obesity is a cardinal manifestation 7 ...
February 2018: Nature Genetics
https://www.readbyqxmd.com/read/29296625/molecular-therapy-of-melanocortin-4-receptor-obesity-by-an-autoregulatory-bdnf-vector
#20
Jason J Siu, Nicholas J Queen, Xianglan Liu, Wei Huang, Travis McMurphy, Lei Cao
Mutations in the melanocortin-4-receptor ( MC4R ) comprise the most common monogenic form of severe early-onset obesity, and conventional treatments are either ineffective long-term or contraindicated. Immediately downstream of MC4R-in the pathway for regulating energy balance-is brain-derived neurotrophic factor (BDNF). Our previous studies show that adeno-associated virus (AAV)-mediated hypothalamic BDNF gene transfer alleviates obesity and diabetes in both diet-induced and genetic models. To facilitate clinical translation, we developed a built-in autoregulatory system to control therapeutic gene expression mimicking the body's natural feedback systems...
December 15, 2017: Molecular Therapy. Methods & Clinical Development
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