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Melanocortin activity

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https://www.readbyqxmd.com/read/29742429/diet-induced-growth-is-regulated-via-acquired-leptin-resistance-and-engages-a-pomc-somatostatin-growth-hormone-circuit
#1
Heiko Löhr, Simon Hess, Mafalda M A Pereira, Philip Reinoß, Sandra Leibold, Christel Schenkel, Claudia M Wunderlich, Peter Kloppenburg, Jens C Brüning, Matthias Hammerschmidt
Anorexigenic pro-opiomelanocortin (Pomc)/alpha-melanocyte stimulating hormone (αMSH) neurons of the hypothalamic melanocortin system function as key regulators of energy homeostasis, also controlling somatic growth across different species. However, the mechanisms of melanocortin-dependent growth control still remain ill-defined. Here, we reveal a thus-far-unrecognized structural and functional connection between Pomc neurons and the somatotropic hypothalamo-pituitary axis. Excessive feeding of larval zebrafish causes leptin resistance and reduced levels of the hypothalamic satiety mediator pomca...
May 8, 2018: Cell Reports
https://www.readbyqxmd.com/read/29736023/mc4r-agonism-promotes-durable-weight-loss-in-patients-with-leptin-receptor-deficiency
#2
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/29714486/melanoma-imaging-using-18-f-labeled-%C3%AE-melanocyte-stimulating-hormone-derivatives-with-positron-emission-tomography
#3
Chengcheng Zhang, Zhengxing Zhang, Kuo-Shyan Lin, Joseph Lau, Jutta Zeisler, Nadine Colpo, David M Perrin, Francois Benard
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 (SPECT), 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...
May 1, 2018: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/29689050/activation-of-temperature-sensitive-trpv1-like-receptors-in-arc-pomc-neurons-reduces-food-intake
#4
Jae Hoon Jeong, Dong Kun Lee, Shun-Mei Liu, Streamson C Chua, Gary J Schwartz, Young-Hwan Jo
Proopiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus (ARC) respond to numerous hormonal and neural signals, resulting in changes in food intake. Here, we demonstrate that ARC POMC neurons express capsaicin-sensitive transient receptor potential vanilloid 1 receptor (TRPV1)-like receptors. To show expression of TRPV1-like receptors in ARC POMC neurons, we use single-cell reverse transcription-polymerase chain reaction (RT-PCR), immunohistochemistry, electrophysiology, TRPV1 knock-out (KO), and TRPV1-Cre knock-in mice...
April 2018: PLoS Biology
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
#5
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...
April 20, 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-arrestin2-recruitment-within-the-melanocortin-receptors
#6
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...
April 18, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29660981/development-of-macrocyclic-peptidomimetics-containing-constrained-%C3%AE-%C3%AE-dialkylated-amino-acids-with-potent-and-selective-activity-at-human-melanocortin-receptors
#7
Francesco Merlino, Yang Zhou, Minying Cai, Alfonso Carotenuto, Ali Munaim Yousif, Diego Brancaccio, Salvatore Di Maro, Silvia Zappavigna, Antonio Limatola, Ettore Novellino, Paolo Grieco, Victor J Hruby
We report the development of macrocyclic melanocortin derivatives of MT-II and SHU-9119, achieved by modifying the cycle dimension, and incorporating constrained amino acids in ring-closing. This study culminated in the discovery of novel agonists/antagonists with an unprecedented activity profile, by adding pieces to the puzzle of the melanocortin receptor selec-tivity. Finally, the resulting 19- and 20-membered rings represent a suitable frame for the design of further therapeutic ligands as selective modulators of the melanocortin system...
April 16, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29660453/tgf-%C3%AE-1-down-regulation-in-the-mediobasal-hypothalamus-attenuates-hypothalamic-inflammation-and-protects-against-diet-induced-obesity
#8
Natália F Mendes, Joana M Gaspar, José C Lima-Júnior, Jose Donato, Lício A Velloso, Eliana P Araújo
BACKGROUND: The consumption of large amounts of dietary fats induces hypothalamic inflammation and impairs the function of the melanocortin system, leading to a defective regulation of caloric intake and whole-body energy expenditure. In mice fed a high-fat diet (HFD), TGF-β1 expression was increased and NF-κB signaling was activated in proopiomelanocortin neurons, which plays an important role in the obesity-associated hypothalamic inflammation scenario. However, whether excessive hypothalamic TGF-β1 impairs energy homeostasis remains unclear...
April 13, 2018: Metabolism: Clinical and Experimental
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
#9
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/29642438/sesamol-inhibited-melanogenesis-by-regulating-melanin-related-signal-transduction-in-b16f10-cells
#10
Po-Yuan Wu, Ya-Jhen You, Yi-Jung Liu, Chien-Wei Hou, Chin-Sheng Wu, Kuo-Ching Wen, Chien-Yih Lin, Hsiu-Mei Chiang
Melanin is synthesized through a series of interactions catalyzed by melanogenic enzymes such as tyrosinase, dopachrome tautomerase (tyrosinase-related protein-2; TRP-2), and tyrosinase-related protein-1 (TRP-1). Tyrosinase plays a key role in catalysing the initial and limiting steps of melanogenesis. The melanin that results from melanogenesis has the protective effect of absorbing ultraviolet radiation. However, overproduction of melanin, in addition to altering the appearance of skin, may lead to skin disorders such as melasma, solar lentigo, and postinflammatory hyperpigmentation...
April 7, 2018: International Journal of Molecular Sciences
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
#11
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/29622793/camp-independent-non-pigmentary-actions-of-variant-melanocortin-1-receptor-akt-mediated-activation-of-protective-responses-to-oxidative-dna-damage
#12
María Castejón-Griñán, Cecilia Herraiz, Conchi Olivares, Celia Jiménez-Cervantes, Jose Carlos García-Borrón
The melanocortin 1 receptor gene (MC1R), a well-established melanoma susceptibility gene, regulates the amount and type of melanin pigments formed within epidermal melanocytes. MC1R variants associated with increased melanoma risk promote the production of photosensitizing pheomelanins as opposed to photoprotective eumelanins. Wild-type (WT) MC1R activates DNA repair and antioxidant defenses in a cAMP-dependent fashion. Since melanoma-associated MC1R variants are hypomorphic in cAMP signaling, these non-pigmentary actions are thought to be defective in MC1R-variant human melanoma cells and epidermal melanocytes, consistent with a higher mutation load in MC1R-variant melanomas...
April 6, 2018: Oncogene
https://www.readbyqxmd.com/read/29605997/development-of-novel-melanocortin-receptor-agonists-based-on-the-cyclic-peptide-framework-of-sunflower-trypsin-inhibitor-1
#13
Thomas Durek, Philipp M Cromm, Andrew M White, Christina I Schroeder, Quentin Kaas, Joachim Weidmann, Abdullah Ahmad Fuaad, Olivier Cheneval, Peta J Harvey, Norelle L Daly, Yang Zhou, Anita Dellsén, Torben Österlund, Niklas Larsson, Laurent Knerr, Udo Bauer, Horst Kessler, Minying Cai, Victor J Hruby, Alleyn T Plowright, David J Craik
Ultra-stable cyclic peptide frameworks offer great potential for drug design due to their improved bioavailability compared to their linear analogues. Using the sunflower trypsin inhibitor-1 (SFTI-1) peptide scaffold in combination with systematic N-methylation of the grafted pharmacophore led to the identification of novel subtype selective melanocortin receptor (MCR) agonists. Multiple bicyclic peptides were synthesized and tested towards their activity at MC1R and MC3-5R. Double N-methylated compound 18 showed a pKi of 8...
March 31, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29599718/re-evaluation-of-adrenocorticotropic-hormone-and-melanocyte-stimulating-hormone-activation-of-gpr139-in-vitro
#14
Diane Nepomuceno, Chester Kuei, Curt Dvorak, Timothy Lovenberg, Changlu Liu, Pascal Bonaventure
It is now well established that GPR139, a G-protein coupled receptor exclusively expressed in the brain and pituitary, is activated by the essential amino acids L-tryptophan (L-Trp) and L-phenylalanine (L-Phe) via Gαq -coupling. The in vitro affinity and potency values of L-Trp and L-Phe are within the physiological concentration ranges of L-Trp and L-Phe. A recent paper suggests that adrenocorticotropic hormone (ACTH), α and β melanocyte stimulating hormones (α-MSH and β-MSH) and derivatives α-MSH1-9 /α-MSH1-10 can also activate GPR139 in vitro ...
2018: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/29578343/human-%C3%AE-defensin-1-and-%C3%AE-defensin-3-mouse-ortholog-mbd14-function-as-full-endogenous-agonists-at-select-melanocortin-receptors
#15
Mark D Ericson, Anamika Singh, Srinivasa R Tala, Erica M Haslach, Marvin Louie Servanez Dirain, Jay W Schaub, Viktor Flores, Natalie Eick, Cody J Lensing, Katie T Freeman, Branden A Smeester, Danielle N Adank, Stacey L Wilber, Robert Speth, Carrie Haskell-Luevano
β-Defensin 3 (BD3) was identified as a ligand for the melanocortin receptors (MCRs) in 2007, although the pharmacology activity of BD3 has not been clearly elucidated. Herein, it is demonstrated that human and mouse BD3 are full micromolar agonists at the MCRs. Furthermore, mouse and human β-defensin 1 (BD1) are also MCR micromolar agonists. This work identifies BD1 as an endogenous MCR ligand and clarifies the controversial role of BD3 as a micromolar agonist.
March 26, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29574148/%C3%AE-melanocyte-stimulating-hormone-promotes-bone-resorption-resulting-from-increased-osteoblastic-and-osteoclastic-activities-in-goldfish
#16
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/29566460/inherently-lean-rats-have-enhanced-activity-and-skeletal-muscle-response-to-central-melanocortin-receptors
#17
Chaitanya K Gavini, Steven L Britton, Lauren G Koch, Colleen M Novak
OBJECTIVE: Activity thermogenesis and energy expenditure (EE) are elevated in intrinsically lean rats (high-capacity runners [HCR]) and are also stimulated by melanocortin receptor activation in the ventromedial hypothalamus (VMH). This study determined whether HCR are more responsive to central modulation of activity EE compared with low-capacity runners (LCR). METHODS: HCR and LCR rats received intra-VMH microinjections of melanotan II (MTII), a mixed melanocortin receptor agonist...
March 22, 2018: 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
#18
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/29524525/evaluating-the-interactions-between-red-stingray-dasyatis-akajei-melanocortin-receptors-and-elephant-shark-callorhinchus-milii-mrap1-and-mrap2-following-stimulation-with-either-stingray-acth-1-24-or-stingray-des-acetyl-%C3%AE-msh-a-pharmacological-study-in-chinese
#19
Robert M Dores, Michelle Scuba-Gray, Bridgette McNally, Perry Davis, Akiyoshi Takahashi
Previous studies on bony vertebrate MC2R orthologs (i.e., ray finned fishes, amphibians, reptiles, birds, and mammals) have shown that these MC2R orthologs have an obligatory requirement for interaction with bony vertebrate MRAP1 orthologs to a) allow for the trafficking of the MC2R ortholog to the plasma membrane; and b) to allow activation by ACTH, but not by any MSH-sized ligand. In addition, previous studies have found that co-expression of teleost and mammalian MC4R orthologs with corresponding MRAP2 has positive effects on sensitivity to stimulation by αMSH or ACTH...
March 7, 2018: General and Comparative Endocrinology
https://www.readbyqxmd.com/read/29471473/bidirectional-gpr119-agonism-requires-peptide-yy-and-glucose-for-activity-in-mouse-and-human-colon-mucosa
#20
Iain R Tough, Sarah Forbes, Herbert Herzog, Robert M Jones, Thue W Schwartz, Helen M Cox
The lipid sensor G protein-coupled receptor 119 (GPR119) is highly expressed by enteroendocrine L-cells and pancreatic β-cells that release the hormones, peptide YY (PYY) and glucagonlike peptide 1, and insulin, respectively. Endogenous oleoylethanolamide (OEA) and the dietary metabolite, 2-monoacylglycerol (2-OG), can each activate GPR119. Here, we compared mucosal responses with selective, synthetic GPR119 agonists (AR440006 and AR231453) and the lipids, OEA, 2-OG, and N-oleoyldopamine (OLDA), monitoring epithelial ion transport as a readout for L-cell activity in native mouse and human gastrointestinal (GI) mucosae...
April 1, 2018: Endocrinology
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