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MC4R

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https://www.readbyqxmd.com/read/28093215/melanocortin-4-receptor-constitutive-activity-inhibits-l-type-voltage-gated-calcium-channels-in-neurons
#1
F Agosti, S Cordisco Gonzalez, V Martinez Damonte, M J Tolosa, N Di Siervi, H B Schioth, C Davio, M Perello, J Raingo
The melanocortin 4 receptor (MC4R) is a G protein-coupled receptor (GPCR) that is expressed in several brain nuclei playing a crucial role in the regulation of energy balance controlling the homeostasis of the organism. It displays both agonist-evoked and constitutive activity, and moreover, it can couple to different G proteins. Most of the research on MC4R has been focused on agonist-induced activity, while the molecular and cellular basis of MC4R constitutive activity remains scarcely studied. We have previously shown that neuronal N-type voltage-gated calcium channels (CaV2...
January 13, 2017: Neuroscience
https://www.readbyqxmd.com/read/28090739/obesity-related-genetic-polymorphisms-and-adiposity-indices-in-a-young-italian-population
#2
Laura Bordoni, Francesca Marchegiani, Marco Piangerelli, Valerio Napolioni, Rosita Gabbianelli
Pediatric obesity develops when a complex biological predisposition collides with an obesogenic environment. To further elucidate the role of genetics in obesity onset, we performed a candidate-gene association study in a young and sportive Italian population by testing the association of functional polymorphisms in ACE (rs4646994), FTO (rs9939609), MC4R (rs17782313) and PPARG (rs1801282) genes with body mass index (BMI) and waist-to-height ratio (WHtR). We also tested the combinations of identified risk genotypes and epistatic interactions among them to determine the existence of cumulative effects in predicting the predisposition to gain weight...
January 16, 2017: IUBMB Life
https://www.readbyqxmd.com/read/28081251/physical-activity-and-sedentary-behaviors-modify-the-association-between-melanocortin-4-receptor-gene-variant-and-obesity-in-chinese-children-and-adolescents
#3
Jie-Yun Song, Qi-Ying Song, Shuo Wang, Jun Ma, Hai-Jun Wang
Effects of MC4R variants in previous Chinese population studies were inconsistent. Gene-environment interactions might influence the effect of MC4R variants on obesity, which was still unclear. We performed the study to clarify the association of variants near MC4R gene with obesity-related phenotypes and gene-environment interactions in Chinese children and adolescents. Two common variants (rs12970134 and rs17782313) near MC4R were genotyped in 2179 children and adolescents aged 7-18 years in Beijing of China...
2017: PloS One
https://www.readbyqxmd.com/read/28045525/a-macrocyclic-agouti-related-protein-nle-4-dphe-7-%C3%AE-melanocyte-stimulating-hormone-chimeric-scaffold-produces-subnanomolar-melanocortin-receptor-ligands
#4
Mark D Ericson, Katie T Freeman, Sathya M Schnell, Carrie Haskell-Luevano
The melanocortin system consists of five receptor subtypes, endogenous agonists, and naturally occurring antagonists. These receptors and ligands have been implicated in numerous biological pathways including processes linked to obesity and food intake. Herein, a truncation structure-activity relationship study of chimeric agouti-related protein (AGRP)/[Nle4,DPhe7]α-melanocyte stimulating hormone (NDP-MSH) ligands is reported. The tetrapeptide His-DPhe-Arg-Trp or tripeptide DPhe-Arg-Trp replaced the Arg-Phe-Phe sequence in the AGRP active loop derivative c[Pro-Arg-Phe-Phe-Xxx-Ala-Phe-DPro], where Xxx was the native Asn of AGRP or a diaminopropionic (Dap) acid residue previously shown to increase antagonist potency at the mMC4R...
January 17, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28035522/analysis-of-gene-candidate-snp-and-ancestral-origin-associated-to-obesity-and-postoperative-weight-loss-in-a-cohort-of-obese-patients-undergoing-rygb
#5
David Velázquez-Fernández, Gabriela Mercado-Celis, Jeny Flores-Morales, Diana Clavellina-Gaytán, Ramón Vidrio, Eduardo Vidrio, Maureen Mosti, Hugo Sánchez-Aguilar, Donaji Rodriguez, Pablo León, Miguel F Herrera
INTRODUCTION: Obesity is the result of a complex interaction between multiple genetic traits and psychological, behavioral, nutritional and environmental factors. OBJECTIVES: The aims of the study were (a) to comparatively evaluate the presence of 20 candidate gene single nucleotide polymorphisms (SNPs) in morbidly obese patients, (2) their association to comorbid conditions and (3) their impact on weight loss after a Roux-en-Y gastric bypass (RYGB). PATIENTS AND METHODS: Two hundred forty-nine patients were eligible for this study...
December 29, 2016: Obesity Surgery
https://www.readbyqxmd.com/read/28025578/bmi-loci-and-longitudinal-bmi-from-adolescence-to-young-adulthood-in-an-ethnically-diverse-cohort
#6
M Graff, K E North, A S Richardson, K L Young, A L Mazul, H M Highland, K L Mohlke, L A Lange, E M Lange, K M Harris, P Gordon-Larsen
OBJECTIVE: The association of obesity susceptibility variants with change in body mass index (BMI) across the life course is not well understood. SUBJECTS: In ancestry stratified models of 5962 European American (EA), 2080 African American (AA), and 1582 Hispanic American (HA) individuals from the National Longitudinal Study of Adolescent to Adult Health (Add Health), we examined associations between 34 obesity SNPs with per year change in BMI, measured by the slope from a growth-curve analysis of two or more BMI measurements between adolescence and young adulthood...
December 27, 2016: International Journal of Obesity: Journal of the International Association for the Study of Obesity
https://www.readbyqxmd.com/read/28003536/deficient-melanocortin-4-receptor-causes-abnormal-reproductive-neuroendocrine-profile-in-female-mice
#7
Xiaolin Chen, Lili Huang, Hwee Y Tan, Hongzhuo Li, Ying Wan, Michael Cowley, Johannes D Veldhuis, Chen Chen
Deletion of the melanocortin-4-receptor (Mc4r) gene in mice causes hyperphagia, followed by hyperinsulinemia, obesity and progressive infertility. Evidence shows that the number of developed corpora lutea is reduced in obese MC4R-knockout (MC4R KO) female mice, but the mechanism is unclear. The effect of hyperphagia and obesity by MC4R KO on pulsatile luteinizing hormone (LH) secretion and ovulation remains unknown. In MC4R KO mice and wild-type littermates (WT LM) during the diestrus period throughout different ages, we examined and monitored their metabolic status, pulsatile LH profiles, follicular morphology and the number of corpora lutea...
March 2017: Reproduction: the Official Journal of the Society for the Study of Fertility
https://www.readbyqxmd.com/read/27991864/gs%C3%AE-deficiency-in-the-dorsomedial-hypothalamus-underlies-obesity-associated-with-gs%C3%AE-mutations
#8
Min Chen, Yogendra B Shrestha, Brandon Podyma, Zhenzhong Cui, Benedetta Naglieri, Hui Sun, Thuy Ho, Eric A Wilson, Yong-Qi Li, Oksana Gavrilova, Lee S Weinstein
Gsα, encoded by Gnas, mediates hormone and neurotransmitter receptor-stimulated cAMP generation. Heterozygous Gsα-inactivating mutations lead to obesity in Albright hereditary osteodystrophy (AHO) patients, but only when the mutations occur on the maternal allele. This parent-of-origin effect is due to Gsα imprinting in the CNS, although the relevant CNS regions are unknown. We have now shown that mice with a Gnas gene deletion disrupting Gsα expression on the maternal allele, but not the paternal allele, in the dorsomedial nucleus of the hypothalamus (DMH) developed obesity and reduced energy expenditure without hyperphagia...
December 19, 2016: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/27936173/insights-into-basal-signaling-regulation-oligomerization-and-structural-organization-of-the-human-g-protein-coupled-receptor-83
#9
Anne Müller, Julia Catherine Berkmann, Patrick Scheerer, Heike Biebermann, Gunnar Kleinau
The murine G-protein coupled receptor 83 (mGPR83) is expressed in the hypothalamus and was previously suggested to be involved in the regulation of metabolism. The neuropeptide PEN has been recently identified as a potent GPR83 ligand. Moreover, GPR83 constitutes functionally relevant hetero-oligomers with other G-protein coupled receptors (GPCR) such as the ghrelin receptor (GHSR) or GPR171. Previous deletion studies also revealed that the long N-terminal extracellular receptor domain (eNDo) of mGPR83 may act as an intra-molecular ligand, which participates in the regulation of basal signaling activity, which is a key feature of GPCR function...
2016: PloS One
https://www.readbyqxmd.com/read/27926527/meqtl-analysis-of-childhood-obesity-links-epigenetics-with-a-risk-snp-rs17782313-near-mc4r-from-meta-analysis
#10
Yuping Tang, Bo Jin, Lingling Zhou, Weifeng Lu
Earlier GWAS has identified that rs17782313 near MC4R was associated with obesity. However, subsequent studies showed conflicting results, especially among childhood. Besides, the mechanisms underlying the association between rs17782313 and childhood obesity remain largely unexplored, and genetic and epigenetic may interact and together affect the development of childhood obesity. We conducted a comprehensive meta-analysis to assess the association between rs17782313 and childhood obesity. MeQTL and eQTL analysis was applied to explore the effect of rs17782313 on DNA methylation and MC4R expression...
December 1, 2016: Oncotarget
https://www.readbyqxmd.com/read/27920511/relationships-between-fto-rs9939609-mc4r-rs17782313-and-ppar%C3%AE-rs1801282-polymorphisms-and-the-occurrence-of-selected-metabolic-and-hormonal-disorders-in-middle-aged-and-elderly-men-a-preliminary-study
#11
Iwona Rotter, Karolina Skonieczna-Żydecka, Danuta Kosik-Bogacka, Grażyna Adler, Aleksandra Rył, Maria Laszczyńska
PURPOSE: Metabolic disorders, including MetS, obesity, and lipid disorders, may be related to genetic factors. Metabolic disorders are associated with decreased TS levels in aging men. The aim of this study was to evaluate the relationship between FTO rs9939609, MC4R rs17782313, and PPARγ rs1801282 polymorphisms and the presence of MetS and its components, the concurrent lipid disorders, as well as sex hormone concentrations. SUBJECTS AND METHODS: This study involved 272 men of Caucasian descent aged 50-75 years...
2016: Clinical Interventions in Aging
https://www.readbyqxmd.com/read/27911598/type-3-deiodinase-role-on-central-thyroid-hormone-action-affects-the-leptin-melanocortin-system-and-circadian-activity
#12
Zhaofei Wu, M Elena Martinez, Donald L St Germain, Arturo Hernandez
The role of thyroid hormones (TH) in the central regulation of energy balance is increasingly appreciated. Mice lacking the type 3 deiodinase (DIO3), which inactivates TH, have decreased circulating TH levels relative to control mice due to defects in the hypothalamic-pituitary-thyroid axis. However, we have shown that the TH status of the adult Dio3(-/-) brain is opposite that of the serum, exhibiting enhanced levels of TH action. Since the brain, specially the hypothalamus, harbors important circuitries that regulate metabolism, we aimed to examine the energy balance phenotype of Dio3(-/-) mice and determine whether it is associated with hypothalamic abnormalities...
December 2, 2016: Endocrinology
https://www.readbyqxmd.com/read/27890744/gene-expression-of-pro-opiomelanocortin-and-melanocortin-receptors-is-regulated-in-the-hypothalamus-and-mesocorticolimbic-system-following-nicotine-administration
#13
Damla E Tapinc, Rabia Ilgin, Egemen Kaya, Oguz Gozen, Muzeyyen Ugur, Ersin O Koylu, Lutfiye Kanit, Aysegul Keser, Burcu Balkan
Pro-opiomelanocortin (POMC)-derived peptides and their receptors have been shown to play important roles in natural and drug-induced reward and reinforcement. Reward process may involve the regulation of POMC gene expression and the gene expression of POMC-derived peptide receptors. The present study investigated the alterations observed in the transcript levels of POMC, melanocortin 3 (MC3R), melanocortin 4 (MC4R) and mu-opioid receptors (MOR) in the hypothalamus and mesocorticolimbic system during nicotine exposure...
January 10, 2017: Neuroscience Letters
https://www.readbyqxmd.com/read/27886210/physical-activity-energy-expenditure-and-defense-of-body-weight-in-melanocortin-4-receptor-deficient-male-rats
#14
Tariq I Almundarij, Mark E Smyers, Addison Spriggs, Lydia A Heemstra, Lisa Beltz, Eric Dyne, Caitlyn Ridenour, Colleen M Novak
Melanocortin 4 receptor (MC4R) variants contribute to human obesity, and rats lacking functional MC4R (Mc4r(K314X/K314X)) are obese. We investigated the hypothesis that low energy expenditure (EE) and physical activity contribute to this obese phenotype in male rats, and determined whether lack of functional MC4R conferred protection from weight loss during 50% calorie restriction. Though Mc4r(K314X/K314X) rats showed low brown adipose Ucp1 expression and were less physically active than rats heterozygous for the mutation (Mc4r(+/K314X)) or wild-type (Mc4r(+/+)) rats, we found no evidence of lowered EE in Mc4r(K314X/K314X) rats once body weight was taken into account using covariance...
November 25, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27869800/a-rapidly-acting-glutamatergic-arc%C3%A2-pvh-satiety-circuit-postsynaptically-regulated-by-%C3%AE-msh
#15
Henning Fenselau, John N Campbell, Anne M J Verstegen, Joseph C Madara, Jie Xu, Bhavik P Shah, Jon M Resch, Zongfang Yang, Yael Mandelblat-Cerf, Yoav Livneh, Bradford B Lowell
Arcuate nucleus (ARC) neurons sense the fed or fasted state and regulate hunger. Agouti-related protein (AgRP) neurons in the ARC (ARC(AgRP) neurons) are stimulated by fasting and, once activated, they rapidly (within minutes) drive hunger. Pro-opiomelanocortin (ARC(POMC)) neurons are viewed as the counterpoint to ARC(AgRP) neurons. They are regulated in an opposite fashion and decrease hunger. However, unlike ARC(AgRP) neurons, ARC(POMC) neurons are extremely slow in affecting hunger (many hours). Thus, a temporally analogous, rapid ARC satiety pathway does not exist or is presently unidentified...
January 2017: Nature Neuroscience
https://www.readbyqxmd.com/read/27849360/robust-reductions-of-excess-weight-and-hyperphagia-by-beloranib-in-rat-models-of-genetic-and-hypothalamic-obesity
#16
Clinton T Elfers, Christian L Roth
Hypothalamic lesions or deficient melanocortin (MC) signaling via MC4 receptor (MC4r) mutations often lead to hyperphagia and severe treatment resistant obesity. We tested the methionine amino peptidase 2-inhibitor beloranib (ZGN-440) in two male rat models of obesity, one modeling hypothalamic obesity (HO) with combined medial hypothalamic lesions (CMHL), and the other modeling a monogenic form of obesity with MC4r mutations (MC4rKO). In CMHL rats (age 3 months), post-surgery excess weight gain was significantly inhibited (ZGN-440 0...
November 16, 2016: Endocrinology
https://www.readbyqxmd.com/read/27833052/dietary-calcium-supplementation-in-adult-rats-reverts-brown-adipose-tissue-dysfunction-programmed-by-postnatal-early-overfeeding
#17
Ellen Paula Santos Conceição, Egberto Gaspar Moura, Elaine Oliveira, Deysla Sabino Guarda, Mariana Sarto Figueiredo, Fernanda Torres Quitete, Camila Calvino, Rosiane Aparecida Miranda, Paulo Cezar Freitas Mathias, Alex Christian Manhães, Patricia Cristina Lisboa
Brown adipose tissue (BAT) dysfunction is associated with obesity and its comorbidities, such as hypertension, and the improvement of BAT function seems important for obesity management. Here we investigated the effects of dietary calcium supplementation on BAT autonomic nerve activity, sympathoadrenal function and cardiovascular parameters in adult obese rats that were raised in small litters (SL group). Three days after birth, SL litters were adjusted to three pups to induce early overfeeding. The control group remained with 10 pups/litter until weaning (NL group)...
January 2017: Journal of Nutritional Biochemistry
https://www.readbyqxmd.com/read/27829468/fat-mass-obesity-associated-fto-rs9939609-and-melanocortin-4-receptor-mc4r-rs17782313-snp-are-positively-associated-with-obesity-and-blood-pressure-in-mexican-school-aged-children
#18
Pablo García-Solís, Marissa Reyes-Bastidas, Karla Flores, Olga P García, Jorge L Rosado, Lorena Méndez-Villa, Carlota Garcia-G, David García-Gutiérrez, Aarón Kuri-García, Hebert L Hernández-Montiel, Ofelia Soriano-Leon, Maria Elena Villagrán-Herrera, Juan C Solis-Sainz
Childhood overweight and obesity are worldwide public health problems and risk factors for chronic diseases. The presence of SNP in several genes has been associated with the presence of obesity. A total of 580 children (8-13 years old) from Queretaro, Mexico, participated in this cross-sectional study, which evaluated the associations of rs9939609 (fat mass obesity-associated (FTO)), rs17782313 (melanocortin 4 receptor (MC4R)) and rs6548238 (transmembrane protein 18 (TMEM18)) SNP with obesity and metabolic risk factors...
November 10, 2016: British Journal of Nutrition
https://www.readbyqxmd.com/read/27829153/stimulation-of-the-hippocampal-pomc-mc4r-circuit-alleviates-synaptic-plasticity-impairment-in-an-alzheimer-s-disease-model
#19
Yang Shen, Min Tian, Yuqiong Zheng, Fei Gong, Amy K Y Fu, Nancy Y Ip
Hippocampal synaptic plasticity is modulated by neuropeptides, the disruption of which might contribute to cognitive deficits observed in Alzheimer's disease (AD). Although pro-opiomelanocortin (POMC)-derived neuropeptides and melanocortin 4 receptor (MC4R) are implicated in hippocampus-dependent synaptic plasticity, how the POMC/MC4R system functions in the hippocampus and its role in synaptic dysfunction in AD are largely unknown. Here, we mapped a functional POMC circuit in the mouse hippocampus, wherein POMC neurons in the cornu ammonis 3 (CA3) activate MC4R in the CA1...
November 8, 2016: Cell Reports
https://www.readbyqxmd.com/read/27791019/central-role-for-melanocortin-4-receptors-in-offspring-hypertension-arising-from-maternal-obesity
#20
Anne-Maj S Samuelsson, Amandine Mullier, Nuria Maicas, Nynke R Oosterhuis, Sung Eun Bae, Tatiana V Novoselova, Li F Chan, Joaquim M Pombo, Paul D Taylor, Jaap A Joles, Clive W Coen, Nina Balthasar, Lucilla Poston
Melanocortin-4 receptor (Mc4r)-expressing neurons in the autonomic nervous system, particularly in the paraventricular nucleus of the hypothalamus (PVH), play an essential role in blood pressure (BP) control. Mc4r-deficient (Mc4rKO) mice are severely obese but lack obesity-related hypertension; they also show a reduced pressor response to salt loading. We have previously reported that lean juvenile offspring born to diet-induced obese rats (OffOb) exhibit sympathetic-mediated hypertension, and we proposed a role for postnatally raised leptin in its etiology...
October 25, 2016: Proceedings of the National Academy of Sciences of the United States of America
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