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Melanocortin 4 receptor

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https://www.readbyqxmd.com/read/29924583/arg-phe-phe-d-amino-acid-stereochemistry-scan-in-the-macrocyclic-agouti-related-protein-antagonist-scaffold-c-pro-arg-phe-phe-xaa-ala-phe-dpro-results-in-unanticipated-melanocortin-1-receptor-agonist-profiles
#1
Mark D Ericson, Zoe M Koerperich, Katie T Freeman, Katlyn A Fleming, Carrie Haskell-Luevano
The melanocortin-3 and melanocortin-4 receptors (MC3R and MC4R), endogenous agonists derived from the proopiomelanocortin gene transcript, and naturally-occurring antagonists agouti and agouti-related protein (AGRP) have been linked to biological pathways associated with energy homeostasis. The active tripeptide sequence of AGRP, Arg111-Phe112-Phe113, is located on a hypothesized β-hairpin loop. Herein, stereochemical modifications of the Arg-Phe-Phe sequence were examined in the octapeptide AGRP-derived macrocyclic scaffold c[Pro-Arg-Phe-Phe-Xxx-Ala-Phe-DPro], where Xxx was Asn or diaminopropionic acid (Dap)...
June 20, 2018: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/29911995/melanocortin-4-receptors-switch-reward-to-aversion
#2
Alexandra G DiFeliceantonio, Paul J Kenny
The ability to recognize and avoid noxious stimuli is essential for survival. The factors that determine whether a given stimulus is considered positive or negative are complex and not fully understood. In this issue of the JCI, Klawonn and colleagues demonstrate that melanocortin 4 receptor (MC4R) signaling is critical for proper responses to negative stimuli. Mice lacking MC4R were shown to have a surprising preference for aversive stimuli compared with WT animals. Moreover, the authors provide evidence that avoidance behaviors are mediated by hypothalamic POMC neurons signaling to striatal dopamine D1 receptor-expressing medium spiny neurons...
June 18, 2018: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29911992/motivational-valence-is-determined-by-striatal-melanocortin-4-receptors
#3
Anna Mathia Klawonn, Michael Fritz, Anna Nilsson, Jordi Bonaventura, Kiseko Shionoya, Elahe Mirrasekhian, Urban Karlsson, Maarit Jaarola, Björn Granseth, Anders Blomqvist, Michael Michaelides, David Engblom
It is critical for survival to assign positive or negative valence to salient stimuli in a correct manner. Accordingly, harmful stimuli and internal states characterized by perturbed homeostasis are accompanied by discomfort, unease, and aversion. Aversive signaling causes extensive suffering during chronic diseases, including inflammatory conditions, cancer, and depression. Here, we investigated the role of melanocortin 4 receptors (MC4Rs) in aversive processing using genetically modified mice and a behavioral test in which mice avoid an environment that they have learned to associate with aversive stimuli...
June 18, 2018: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29910730/binding-thermodynamics-and-selectivity-of-a-non-peptide-antagonist-to-the-melanocortin-4-receptor
#4
Noureldin Saleh, Gunnar Kleinau, Nicolas Heyder, Timothy Clark, Peter W Hildebrand, Patrick Scheerer
The melanocortin-4 receptor (MC4R) is a potential drug target for treatment of obesity, anxiety, depression, and sexual dysfunction. Crystal structures for MC4R are not yet available, which has hindered successful structure-based drug design. Using microsecond-scale molecular-dynamics simulations, we have investigated selective binding of the non-peptide antagonist MCL0129 to a homology model of human MC4R (hMC4R). This approach revealed that, at the end of a multi-step binding process, MCL0129 spontaneously adopts a binding mode in which it blocks the agonistic-binding site...
2018: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/29893663/associations-between-obesity-candidate-gene-polymorphisms-fat-mass-and-obesity-associated-fto-melanocortin-4-receptor-mc4r-leptin-lep-and-leptin-receptor-lepr-and-dietary-intake-in-pregnant-women
#5
Maisa C Martins, Janet Trujillo, Ana Amélia Freitas-Vilela, Dayana R Farias, Eliane L Rosado, Cláudio J Struchiner, Gilberto Kac
Genetic variants associated with dietary intake may be important as factors underlying the development of obesity. We investigated the associations between the obesity candidate genes (fat mass and obesity-associated (FTO), melanocortin-4 receptor (MC4R), leptin (LEP) and leptin receptor) and total energy intake and percentage of energy from macronutrients and ultra-processed foods before and during pregnancy. A sample of 149 pregnant women was followed up in a prospective cohort in Rio de Janeiro, Brazil. A FFQ was administered at 5-13 and 30-36 weeks of gestation...
June 12, 2018: British Journal of Nutrition
https://www.readbyqxmd.com/read/29861388/patients-with-obesity-caused-by-melanocortin-4-receptor-mutations-can-be-treated-with-a-glucagon-like-peptide-1-receptor-agonist
#6
Eva W Iepsen, Jinyi Zhang, Henrik S Thomsen, Elizaveta L Hansen, Mette Hollensted, Sten Madsbad, Torben Hansen, Jens J Holst, Jens-Christian Holm, Signe S Torekov
Pathogenic mutations in the appetite-regulating melanocortin-4 receptor (MC4R) represent the most common cause of monogenic obesity with limited treatment options. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) cause weight loss by reducing appetite. We assessed the effect of the GLP-1 RA liraglutide 3.0 mg for 16 weeks in 14 obese individuals with pathogenic MC4R mutations (BMI 37.5 ± 6.8) and 28 matched control participants without MC4R mutation (BMI 36.8 ± 4.8). Liraglutide decreased body weight by 6...
May 29, 2018: Cell Metabolism
https://www.readbyqxmd.com/read/29860743/-the-effect-of-metformin-on-metabolic-parameters-and-hypothalamic-signaling-systems-in-rats-with-obesity-induced-by-a-high-carbohydrate-high-fat-diet
#7
K V Derkach, I B Sukhov, V M Bondareva, A O Shpakov
Metformin (MF), a first-line drug in the treatment of diabetes mellitus, has been used in the recent years to treat obesity. Its therapeutic effect is due not only to the influence on the peripheral tissues, but also on the hypothalamus, which controls food behavior and energy metabolism. The aim was to study the effect of MF therapy (200 mg/kg/day, 8 weeks) in rats with obesity caused by a high-carbohydrate/high-fat diet on the metabolic and hormonal parameters and functional state of the hypothalamic signaling systems...
2018: Advances in Gerontology, Uspekhi Gerontologii
https://www.readbyqxmd.com/read/29812984/melanotan-ii-causes-hypothermia-in-mice-by-activation-of-mast-cells-and-stimulation-of-histamine-1-receptors
#8
Shalini Jain, Anna Panyutin, Naili Liu, Cuiying Xiao, Ramón A Piñol, Priyanka Pundir, Clemence Girardet, Andrew A Butler, Xinzhong Dong, Oksana Gavrilova, Marc L Reitman
Intraperitoneal administration of the melanocortin agonist melanotan II (MTII) to mice causes a profound, transient hypometabolism/hypothermia. It is preserved in mice lacking any one of melanocortin receptors 1, 3, 4, or 5, suggesting a mechanism independent of the canonical melanocortin receptors. Here we show that MTII-induced hypothermia was abolished in KitW-sh/W-sh mice, which lack mast cells, demonstrating that mast cells are required. MRGPRB2 is a receptor that detects many cationic molecules and activates mast cells in an antigen-independent manner...
May 29, 2018: American Journal of Physiology. Endocrinology and Metabolism
https://www.readbyqxmd.com/read/29802399/obeticholic-acid-protects-against-hepatocyte-death-and-liver-fibrosis-in-a-murine-model-of-nonalcoholic-steatohepatitis
#9
Toshihiro Goto, Michiko Itoh, Takayoshi Suganami, Sayaka Kanai, Ibuki Shirakawa, Takeru Sakai, Masahiro Asakawa, Toshihiro Yoneyama, Toshihiro Kai, Yoshihiro Ogawa
Accumulating evidence has suggested that farnesoid X receptor (FXR) agonists, such as obeticholic acid (OCA) are therapeutically useful for non-alcoholic steatohepatitis (NASH). However, it is still unclear how FXR agonists protect against NASH and which cell type is the main target of FXR agonists. In this study, we examined the effects of OCA on the development of NASH using melanocortin 4 receptor-deficient (MC4R-KO) mice that progressively developed hepatic steatosis and NASH on Western diet (WD). Treatment with OCA effectively prevented chronic inflammation and liver fibrosis in WD-fed MC4R-KO mice with only marginal effect on body weight and hepatic steatosis...
May 25, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29794140/the-stimulatory-g-protein-g-s-%C3%AE-is-required-in-melanocortin-4-receptor-expressing-cells-for-normal-energy-balance-thermogenesis-and-glucose-metabolism
#10
Brandon Podyma, Hui Sun, Eric A Wilson, Bradley Carlson, Ethan Pritikin, Oksana Gavrilova, Lee S Weinstein, Min Chen
Central melanocortin 4 receptors (MC4Rs) stimulate energy expenditure and inhibit food intake. MC4Rs activate the G protein Gs α, but whether Gs α mediates all MC4R actions has not been established. Individuals with Albright hereditary osteodystrophy (AHO), who have heterozygous Gs α-inactivating mutations, only develop obesity when the Gs α mutation is present on the maternal allele because of tissue-specific genomic imprinting. Furthermore, evidence in mice implicates Gs α imprinting within the central nervous system (CNS) in this disorder...
May 24, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29783840/discovery-of-melanocortin-ligands-via-a-double-simultaneous-substitution-strategy-based-on-the-ac-his-dphe-arg-trp-nh-2-template
#11
Aleksandar Todorovic, Cody J Lensing, Jerry Ryan Holder, Joseph W Scott, Nicholas B Sorensen, Carrie Haskell-Luevano
The melanocortin system regulates an array of diverse physiological functions including pigmentation, feeding behavior, energy homeostasis, cardiovascular regulation, sexual function, and steroidogenesis. Endogenous melanocortin agonist ligands all possess the minimal messaging tetrapeptide sequence His-Phe-Arg-Trp. Based on this endogenous sequence, the Ac-His1-DPhe2-Arg3-Trp4-NH2 tetrapeptide has previously been shown to be a useful scaffold when utilizing traditional positional scanning approaches to modify activity at the various melanocortin receptors (MC1-5R)...
May 21, 2018: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/29771759/finding-treatable-genetic-obesity-strategies-for-success
#12
Kristin Dayton, Jennifer Miller
PURPOSE OF REVIEW: Genetic obesity is responsible for up to 7% of severe childhood obesity. Although current Pediatric Endocrine Society guidelines recommend assessment of children with early-onset morbid obesity and hyperphagia for underlying genetic disorders, a vast majority of patients are not being appropriately screened for genetic obesity syndromes. RECENT FINDINGS: With advances in genetic testing, more genetic causes of obesity are being identified. Treatments are likely to be individualized, depending on the cause of the obesity, and must be targeted at addressing the underlying cause...
May 15, 2018: Current Opinion in Pediatrics
https://www.readbyqxmd.com/read/29736023/mc4r-agonism-promotes-durable-weight-loss-in-patients-with-leptin-receptor-deficiency
#13
Karine Clément, Heike Biebermann, I Sadaf Farooqi, Lex Van der Ploeg, Barbara Wolters, Christine Poitou, Lia Puder, Fred Fiedorek, Keith Gottesdiener, Gunnar Kleinau, Nicolas Heyder, Patrick Scheerer, Ulrike Blume-Peytavi, Irina Jahnke, Shubh Sharma, Jacek Mokrosinski, Susanna Wiegand, Anne Müller, Katja Weiß, Knut Mai, Joachim Spranger, Annette Grüters, Oliver Blankenstein, Heiko Krude, Peter Kühnen
Genetic defects underlying the melanocortin-4 receptor (MC4R) signaling pathway lead to severe obesity. Three severely obese LEPR-deficient individuals were administered the MC4R agonist setmelanotide, resulting in substantial and durable reductions in hyperphagia and body weight over an observation period of 45-61 weeks. Compared to formerly developed and tested MC4R agonists, setmelanotide has the unique capability of activating nuclear factor of activated T cell (NFAT) signaling and restoring function of this signaling pathway for selected MC4R variants...
May 7, 2018: Nature Medicine
https://www.readbyqxmd.com/read/29726959/melanocortin-4-receptor-pathway-dysfunction-in-obesity-patient-stratification-aimed-at-mc4r-agonist-treatment
#14
Kristin L Ayers, Benjamin S Glicksberg, Alastair S Garfield, Simonne Longerich, Joseph A White, Pengwei Yang, Lei Du, Thomas W Chittenden, Jeffery R Gulcher, Sophie Roy, Fred Fiedorek, Keith Gottesdiener, Sarah Cohen, Kari E North, Eric E Schadt, Shuyu D Li, Rong Chen, Lex H T Van der Ploeg
Context: The hypothalamic melanocortin 4 receptor (MC4R)-pathway serves a critical role in regulating bodyweight. Loss of function (LoF) mutations in the MC4R pathway including mutations in the POMC (1), PCSK1, LEPR (2) or the MC4R genes (3) have been shown to be causative of early-onset severe obesity. Methods: Through a comprehensive epidemiological analysis of known and predicted LoF variants in the POMC, PCSK1 and LEPR genes, we sought to estimate the number of US individuals with bi-allelic MC4R pathway LoF variants...
May 2, 2018: Journal of Clinical Endocrinology and Metabolism
https://www.readbyqxmd.com/read/29714486/melanoma-imaging-using-18-f-labeled-%C3%AE-melanocyte-stimulating-hormone-derivatives-with-positron-emission-tomography
#15
Chengcheng Zhang, Zhengxing Zhang, Kuo-Shyan Lin, Joseph Lau, Jutta Zeisler, Nadine Colpo, David M Perrin, François Bénard
Melanocortin 1 receptor (MC1R) is specifically expressed in the majority of melanomas, a leading cause of death related to skin cancers. Accurate staging and early detection is crucial in managing melanoma. Based on the α-melanocyte-stimulating hormone (αMSH) sequence, MC1R-targeted peptides have been studied for melanoma imaging, predominately for use with single-photon emission computed tomography, with few attempts made for positron emission tomography (PET). 18 F is a commonly used PET isotope due to readily available cyclotron production, pure positron emission, and a favorable half-life (109...
June 4, 2018: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/29704154/pharmacological-effect-of-human-melanocortin-2-receptor-accessory-protein-2-variants-on-hypothalamic-melanocortin-receptors
#16
Jinye Liang, Lei Li, Xuanxuan Jin, Bingxin Xu, Linyu Pi, Shangyun Liu, Wei Zhu, Cong Zhang, Bing Luan, Lulu Gong, Chao Zhang
PURPOSE: Melanocortin-3 receptor (MC3R), melanocortin-4 receptor (MC4R), and a recently identified melanocortin-2 receptor accessory protein 2 (MRAP2), are highly expressed in hypothalamus and coordinately regulate energy homeostasis, but the single cellular transcriptome of melanocortin system remains unknown. Several infrequent MRAP2 variants are reported from severe obese human patients but the mechanisms on how they affect melanocortin signaling are unclear. METHODS: First, we performed in silico analysis of mouse hypothalamus RNA sequencing datasets at single-cell resolution from two independent studies...
July 2018: Endocrine
https://www.readbyqxmd.com/read/29679901/replacement-of-arg-with-nle-and-modified-d-phe-in-the-core-sequence-of-mshs-ac-his-d-phe-arg-trp-nh-2-leads-to-hmc1r-selectivity-and-pigmentation
#17
Saghar Mowlazadeh Haghighi, Yang Zhou, Jixun Dai, Jonathon R Sawyer, Victor J Hruby, Minying Cai
Melanoma skin cancer is the fastest growing cancer in the US [1]. A great need exists for improved formulations and mechanisms to prevent and protect human skin from cancers and other skin damage caused by sunlight exposure. Current efforts to prevent UV damage to human skin, which in many cases leads to melanoma and other skin cancers. The primordial melanocortin-1 receptor (MC1R) is involved in regulating skin pigmentation and hair color, which is a natural prevention from UV damage. The endogenous melanocortin agonists induce pigmentation and share a core pharmacophore sequence "His-Phe-Arg-Trp", and it was found that substitution of the Phe by D-Phe results in increasing melanocortin receptor potency...
May 10, 2018: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29679223/association-between-lepr-fto-mc4r-and-pparg-2-polymorphisms-with-obesity-traits-and-metabolic-phenotypes-in-school-aged-children
#18
Sílvia M Almeida, José M Furtado, Paulo Mascarenhas, Maria E Ferraz, José C Ferreira, Mariana P Monteiro, Manuel Vilanova, Fernando P Ferraz
PURPOSE: Evaluate the relationship of leptin receptor (LEPR) rs1137101, fat mass obesity-associated (FTO) receptors 9939609, melanocortin-4 receptors (MC4R) rs2229616 and rs17782313, and proliferator-activated receptor-gamma (PPARG) rs1801282 with clinical and metabolic phenotypes in prepubertal children. RESEARCH QUESTION: What is the effect of polymorphisms on clinical and metabolic phenotypes in prepubertal children? METHODS: A cross-sectional descriptive study was performed to evaluate anthropometric features, percentage body fat (%BF), biochemical parameters, and genotype in 773 prepubertal children...
June 2018: Endocrine
https://www.readbyqxmd.com/read/29669202/developing-a-biased-unmatched-bivalent-ligand-bumbl-design-strategy-to-target-the-gpcr-homodimer-allosteric-signaling-camp-over-%C3%AE-arrestin-2-recruitment-within-the-melanocortin-receptors
#19
Cody J Lensing, Katie T Freeman, Sathya M Schnell, Robert C Speth, Adam T Zarth, Carrie Haskell-Luevano
Understanding the functional relevance of G protein-coupled receptor (GPCR) homodimerization has been limited by the insufficient tools to assess asymmetric signaling occurring within dimers comprised of the same receptor type. We present unmatched bivalent ligands (UmBLs) to study the asymmetric function of melanocortin homodimers. UmBLs contain one agonist and one antagonist pharmacophore designed to target a melanocortin homodimer such that one receptor is occupied by an agonist and the other receptor by an antagonist pharmacophore...
May 9, 2018: Journal of Medicinal Chemistry
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
#20
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
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