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melanocortin receptor agonist

Benjamin P Tooke, Hui Yu, Jessica M Adams, Graham L Jones, Talisha Sutton-Kennedy, Lakshmi Mundada, Nathan R Qi, Malcolm J Low, Kavaljit H Chhabra
OBJECTIVE: Life-threatening hypoglycemia is a major limiting factor in the management of diabetes. While it is known that counterregulatory responses to hypoglycemia are impaired in diabetes, molecular mechanisms underlying the reduced responses remain unclear. Given the established roles of the hypothalamic proopiomelanocortin (POMC)/melanocortin 4 receptor (MC4R) circuit in regulating sympathetic nervous system (SNS) activity and the SNS in stimulating counterregulatory responses to hypoglycemia, we hypothesized that hypothalamic POMC as well as MC4R, a receptor for POMC derived melanocyte stimulating hormones, is required for normal hypoglycemia counterregulation...
November 20, 2018: Molecular Metabolism
Maria Consiglia Trotta, Rosa Maisto, Nicola Alessio, Anca Hermenean, Michele D'Amico, Clara Di Filippo
The study explored the anti-hypertrophic effect of the melanocortin MC5R stimulation in H9c2 cardiac myocytes exposed to high glucose. This has been done by using α-MSH and selective MC5R agonists and assessing the expression of GLUT4 and GLUT1 transporters, miR-133 and urotensin receptor levels as a marker of cardiac hypertrophy. The study shows for the first time an up-regulation of MC5R expression levels in H9c2 cardiomyocytes exposed to high glucose medium (33 mM D-glucose) for 48 h, compared to cells grown in normal glucose medium (5...
2018: Frontiers in Physiology
Hai-Jie Zhang, Hua-Jie Xie, Wei Wang, Zhi-Qiang Wang, Ya-Xiong Tao
The melanocortin-3 receptor (MC3R) is a member of the G protein-coupled receptor superfamily that plays a critical role in controlling energy balance and metabolism. Although pharmacological characterization of MC3R has been reported previously in several other species, there is no report on the MC3R from giant panda (Ailuropoda melanoleuca). This ancient species is known as a 'living fossil' and is among the most endangered animals in the world. Giant panda survive on a specialized diet of bamboo despite possessing a typical carnivorous digestive system...
October 31, 2018: General and Comparative Endocrinology
Lovisa Bergwall, Hanna Wallentin, Johannes Elvin, Peidi Liu, Roberto Boi, Carina Sihlbom, Kyle Hayes, Dale Wright, Börje Haraldsson, Jenny Nyström, Lisa Buvall
The melanocortin-1 receptor (MC1R) in podocytes has been suggested as the mediator of the ACTH renoprotective effect in patients with nephrotic syndrome with the mechanism of action beeing stabilization of the podocyte actin cytoskeleton. To understand how melanocortin receptors are regulated in nephrotic syndrome and how they are involved in restoration of filtration barrier function, melanocortin receptor expression was evaluated in patients and a rat model of nephrotic syndrome in combination with cell culture analysis...
October 24, 2018: Scientific Reports
Giuseppe Bruschetta, Jung Dae Kim, Sabrina Diano, Li F Chan
OBJECTIVE: Melanocortin 2 receptor accessory protein 2 (MRAP2) has a critical role in energy homeostasis. Although MRAP2 has been shown to regulates a number of GPCRs involved in metabolism, the key neurons responsible for the phenotype of gross obesity in MRAP2 deficient animals are unclear. Furthermore, to date, all the murine MRAP2 models involve the prenatal deletion of MRAP2. METHODS: To target Melanocortin 4 receptor (MC4R)-expressing neurons in the hypothalamic paraventricular nucleus (PVN), we performed stereotaxic surgery using AAV to selectively overexpress MRAP2 postnatally in adult Mc4r-cre mice...
December 2018: Molecular Metabolism
K Eerola, S Virtanen, L Vähätalo, L Ailanen, M Cai, V Hruby, M Savontaus, E Savontaus
γ-Melanocyte stimulating hormone (γ-MSH) is an endogenous agonist of the melanocortin 3-receptor (MC3R). Genetic disruption of MC3Rs increases adiposity and blunts responses to fasting, suggesting that increased MC3R signaling could be physiologically beneficial in the long term. Interestingly, several studies have concluded that activation of MC3Rs is orexigenic in the short term. Therefore, we aimed to examine the short- and long-term effects of γ-MSH in the hypothalamic arcuate nucleus (ARC) on energy homeostasis and hypothesized that the effect of MC3R agonism is dependent on the state of energy balance and nutrition...
October 1, 2018: Journal of Endocrinology
Shengchen Liao, Jingjing Dong, Weina Xu, Bingwen Xi, Yaxiong Tao, Bo Liu, Jun Xie
The melanocortin-5 receptor (MC5R) plays an important role in the regulation of exocrine secretion in mammals. Its function in fish is not well established. In this study, we reported the molecular cloning, tissue expression, and pharmacological characterization of Megalobrama amblycephala MC5R (MamMC5R), as well as the effect of catching stress on its expression. The full-length cDNA of Mammc5r gene was 1237 bp, consisted of a 990-bp open reading frame encoding 329 amino acids. Sequence analyses revealed that the nucleotide and amino acid sequences of Mammc5r were highly homologous (> 90%) with MC5Rs of zebrafish, common carp, and goldfish...
October 4, 2018: Fish Physiology and Biochemistry
S Almeida Scalvino, A Chapelle, N Hajem, E Lati, P Gasser, J-C Choulot, L Michel, M Hocquaux, E Loing, J Attia, J Wdzieczak-Bakala
OBJECTIVE: Hair greying (i.e., canities) is a component of chronological ageing and occurs regardless of gender or ethnicity. Canities is directly linked to the loss of melanin and increase in oxidative stress in the hair follicle and shaft. To promote hair pigmentation and reduce the hair greying process, an agonist of α-melanocyte-stimulating hormone (α-MSH), a biomimetic peptide (palmitoyl tetrapeptide-20; PTP20) was developed. The aim of this study was to describe the effects of the designed peptide on hair greying...
October 2018: International Journal of Cosmetic Science
Ye Ran Yoon, Tae-Gul Lee, Mi-Hyun Choi, Seung Woo Shin, Young-Gyu Ko, Im Joo Rhyu, Dong-Hoon Kim, Je Kyung Seong, Ja-Hyun Baik
The melanocortin-4 receptor (MC4R) belongs to the G protein-coupled receptor (GPCR) family and plays an essential role in the control of energy homeostasis. Here, we identified a novel MC4R-interacting protein, glucose-regulated protein 78 (GRP78), from a pulldown assay using hypothalamic protein extracts and the third intracellular loop of MC4R. We found that MC4R interacted with GRP78 in both the cytosol and at the cell surface and that this interaction increased when MC4R was internalized in the presence of the agonist melanotan-II (MTII)...
September 12, 2018: Experimental & Molecular Medicine
Xiao-Chen Yuan, Ya-Xiong Tao
It is time-consuming and costly to bring new drugs to market, making it necessary and urgent to exploit existing drugs for new uses. Recently, fenoprofen was demonstrated as an allosteric modulator at melanocortin receptors (MCRs), although the exact mode of action has not been clarified. MCRs regulate multiple functions, including pigmentation, adrenal steroidogenesis, inflammation, energy homeostasis, and exocrine gland secretion. In this study, we showed that fenoprofen failed to displace the orthosteric agonist Nle4 -d-Phe7 -α-melanocyte stimulating hormone from binding to MC3-5R while possessing positive allosteric modulator activities at these receptors...
October 11, 2018: ACS Chemical Neuroscience
Ti-Lin Yi, Li-Kun Yang, Guo-Liang Ruan, Dai-Qin Yang, Ya-Xiong Tao
Melanocortin-4 receptor (MC4R) plays critical roles in the regulation of various physiological processes, such as energy homeostasis, reproduction and sexual function, cardiovascular function, and other functions in mammals. Although the functions of the MC4R in fish have not been extensively studied, the importance of MC4R in regulation of piscine energy expenditure and sexual functions is emerging. Swamp eel (Monopterus albus) is an economically and evolutionarily important fish widely distributed in tropics and subtropics...
December 15, 2018: Gene
Bethany A Falls, Yan Zhang
Human melanocortin-4 receptor (hMC4R) mutations have been implicated as the cause for about 6-8% of all severe obesity cases. Drug-like molecules that are able to rescue the functional activity of mutated receptors are highly desirable to combat genetic obesity among this population of patients. One such molecule is the selective MC4R agonist RM-493 (setmelanotide). While this molecule has been shown to activate mutated receptors with 20-fold higher potency over the endogenous agonist, little is known about its binding mode and how it effectively interacts with hMC4R despite the presence of mutations...
August 13, 2018: ACS Chemical Neuroscience
Ann A Coulter, Candida J Rebello, Frank L Greenway
For many years, obesity was believed to be a condition of overeating that could be resolved through counseling and short-term drug treatment. Obesity was not recognized as a chronic disease until 1985 by the scientific community, and 2013 by the medical community. Pharmacotherapy for obesity has advanced remarkably since the first class of drugs, amphetamines, were approved for short-term use. Most amphetamines were removed from the obesity market due to adverse events and potential for addiction, and it became apparent that obesity pharmacotherapies were needed that could safely be administered over the long term...
July 2018: Drugs
Kim Eerola, Siru Virtanen, Laura Vähätalo, Liisa Ailanen, Minying Cai, Victor Hruby, Mikko Savontaus, Eriika Savontaus
γ-melanocyte stimulating hormone (γ-MSH) is an endogenous agonist of the melanocortin 3-receptor (MC3R). Genetic disruption of MC3Rs increases adiposity and blunts responses to fasting, suggesting that increased MC3R signaling could be physiologically beneficial in the long-term. Interestingly, several studies have concluded that activation of MC3Rs is orexigenic in the short term. Therefore, we aimed to examine the short- and long-term effects of γ-MSH in the hypothalamic arcuate nucleus (ARC) on energy homeostasis and hypothesized that the effect of MC3R-agonism is dependent on the state of energy balance and nutrition...
July 13, 2018: Journal of Endocrinology
Anthony P Coll
Safe and effective pharmacological treatments for severe obesity remain scarce. In this issue of Cell Metabolism, Iepsen et al. (2018) show that obese patients with pathogenic melanocortin 4 receptor mutations, the most common form of monogenic obesity, lose weight with glucagon-like peptide 1 (GLP-1) receptor agonist therapy.
July 3, 2018: Cell Metabolism
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)...
July 20, 2018: ACS Chemical Neuroscience
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
Sid Topiol
The determination of the potential value of receptor trafficking at melanocortin receptors has been hampered by the absence of known biased ligands. Heterobivalent MC4R ligands linking agonist to antagonist small peptidic moieties were designed and found to act as Gαs enhancers while minimally activating β-arrestin recruitment. The strategy invoked offers intriguing promise as a surprising approach that is possibly broadly applicable to the challenge of designing biased ligands at other GPCRs.
June 4, 2018: Journal of Medicinal Chemistry
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...
July 3, 2018: Cell Metabolism
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
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