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Clement C Zai, Arun K Tiwari, Gwyneth C Zai, Miriam S Maes, James L Kennedy
PURPOSE OF REVIEW: This review highlights recent advances in the investigation of genetic factors for antipsychotic response and side effects. RECENT FINDINGS: Antipsychotics prescribed to treat psychotic symptoms are variable in efficacy and propensity for causing side effects. The major side effects include tardive dyskinesia, antipsychotic-induced weight gain (AIWG), and clozapine-induced agranulocytosis (CIA). Several promising associations of polymorphisms in genes including HSPG2, CNR1, and DPP6 with tardive dyskinesia have been reported...
March 9, 2018: Current Opinion in Psychiatry
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
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
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
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
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...
February 15, 2018: Neuropharmacology
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
Majid Nikpay, Adam W Turner, Ruth McPherson
BACKGROUND: The objective of this study is to investigate the extent and nature of pleiotropy between coronary artery disease (CAD) and body mass index (BMI). METHODS: We examined the contribution of genome-wide single-nucleotide polymorphisms (minor allele frequency ≥0.01) to co-occurrence of CAD and BMI in a sample of genetically unrelated 8041 subjects (genetic resemblance ≤0.025) of European ancestry using mixed-linear-models. We further partitioned the estimated pleiotropy according to biological features to gain insight into the nature of pleiotropy between CAD and BMI...
February 2018: Circ Genom Precis Med
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
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
Siwei Cai, Qianhui Yang, Mengzhu Hou, Qian Han, Hanyu Zhang, Jiantao Wang, Chen Qi, Qiyu Bo, Yusha Ru, Wei Yang, Zhongxiu Gu, Ruihua Wei, Yunshan Cao, Xiaorong Li, Yan Zhang
BACKGROUND/AIMS: Blood-retinal barrier (BRB) breakdown and vascular leakage is the leading cause of blindness of diabetic retinopathy (DR). Hyperglycemia-induced oxidative stress and inflammation are primary pathogenic factors of this severe DR complication. An effective interventional modality against the pathogenic factors during early DR is needed to curb BRB breakdown and vascular leakage. This study sought to examine the protective effects of α-Melanocyte-stimulating hormone (α-MSH) on early diabetic retina against vascular hyperpermeability, electrophysiological dysfunction, and morphological deterioration in a rat model of diabetes and probe the mechanisms underlying the α-MSH's anti-hyperpermeability in both rodent retinas and simian retinal vascular endothelial cells (RF6A)...
January 25, 2018: Cellular Physiology and Biochemistry
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
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
Alexandre A da Silva, John Nathan Freeman, John E Hall, Jussara M do Carmo
Although central melanocortin 4 receptor (MC4R) blockade abolishes the CNS-mediated anorexogenic, antidiabetic and cardiovascular actions of leptin, chronic MC4R stimulation fails to completely mimic leptin's effects. Because neuropeptide Y (NPY) and MC4R exert opposite effects on cardiovascular and metabolic functions, we tested its role 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/d...
December 20, 2017: American Journal of Physiology. Regulatory, Integrative and Comparative Physiology
Charlotte Schröder, Fabian Czerwensky, Stefan Leucht, Werner Steimer
INTRODUCTION: Weight gain is a limiting and frequent adverse effect of second-generation antipsychotic therapy. Identifying genetic risk factors would significantly improve pharmacotherapy. METHODS: We focused on rs7185735 and rs9939609, 2 common single nucleotide polymorphisms of the fat mass and obesity-associated (FTO) gene reported to be associated with obesity. Three-hundred fifty Caucasian inpatients were included in a naturalistic study. RESULTS: After 4 weeks of treatment, we did not observe any significant association of polymorphisms with weight change in the whole study population (p>0...
January 15, 2018: Pharmacopsychiatry
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...
January 9, 2018: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
Marica Franzago, Federica Fraticelli, Daniela Marchetti, Claudio Celentano, Marco Liberati, Liborio Stuppia, Ester Vitacolonna
AIM: Gestational diabetes mellitus (GDM) is the most frequent metabolic disorder in pregnancy and it can be considered a silent risk associated to T2DM and CVD later in life. The aim of this study was to investigate the association of clinical parameters with nine single nucleotide polymorphisms (SNPs) involved with nutrients and metabolism in women with or without GDM in order to identify potential routine clinical markers for early prevention. METHODS: Nine gene variants associated with nutrients and metabolism, namely PPARG2 rs1801282 (C>G); PPARGC1A rs8192678 (C>T); TCF7L2 rs7903146 (C>T); LDLR rs2228671 (C>T); MTHFR rs1801133 (C>T); APOA5 rs662799 (T>C); GCKR rs1260326 (C>T); FTO rs9939609 (T>A); MC4R rs17782313 (T>C) were genotyped in 104 GDM cases and 124 controls using High Resolution Melting (HRM) analysis...
January 8, 2018: Diabetes Research and Clinical Practice
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
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 humans 1-3 . Recently, ADCY3 (adenylyl cyclase 3) gene mutations have been implicated in obesity 4,5 . 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 ...
January 8, 2018: Nature Genetics
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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