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Melanocortin system

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https://www.readbyqxmd.com/read/29440124/sorcs1-and-sorcs3-control-energy-balance-and-orexigenic-peptide-production
#1
Aygul Subkhangulova, Anna R Malik, Guido Hermey, Oliver Popp, Gunnar Dittmar, Thomas Rathjen, Matthew N Poy, Alexander Stumpf, Prateep Sanker Beed, Dietmar Schmitz, Tilman Breiderhoff, Thomas E Willnow
SORCS1 and SORCS3 are two related sorting receptors expressed in neurons of the arcuate nucleus of the hypothalamus. Using mouse models with individual or dual receptor deficiencies, we document a previously unknown function of these receptors in central control of metabolism. Specifically, SORCS1 and SORCS3 act as intracellular trafficking receptors for tropomyosin-related kinase B to attenuate signaling by brain-derived neurotrophic factor, a potent regulator of energy homeostasis. Loss of the joint action of SORCS1 and SORCS3 in mutant mice results in excessive production of the orexigenic neuropeptide agouti-related peptide and in a state of chronic energy excess characterized by enhanced food intake, decreased locomotor activity, diminished usage of lipids as metabolic fuel, and increased adiposity, albeit at overall reduced body weight...
February 12, 2018: EMBO Reports
https://www.readbyqxmd.com/read/29378226/membrane-initiated-estrogen-signaling-via-gq-coupled-gpcr-in-the-central-nervous-system
#2
Gwyndolin Vail, Troy A Roepke
The last few decades have revealed increasing complexity and depth to our knowledge of receptor-mediated estrogen signaling. Nuclear estrogen receptors (ERs) ERα and ERβ remain the fundamental dogma, but developing research targeting membrane-bound ERs urges for a more expanded view on ER signaling. ERα and ERβ are also involved in membrane-delineated signaling alongside membrane-specific G protein-coupled estrogen receptor 1 (GPER1), ER-X, and the Gq-coupled membrane ER (Gq-mER). Membrane ERs are responsible for eliciting rapid responses to estrogen signaling, and their importance has been increasingly indicated in central nervous system (CNS) regulation of such functions as reproduction, energy homeostasis, and stress...
January 26, 2018: Steroids
https://www.readbyqxmd.com/read/29363944/structure-activity-relationship-studies-of-a-macrocyclic-agrp-mimetic-scaffold-c-pro-arg-phe-phe-asn-ala-phe-dpro-yield-potent-and-selective-melanocortin-4-receptor-antagonists-and-melanocortin-5-receptor-inverse-agonists-that-increase-food-intake-in-mice
#3
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
https://www.readbyqxmd.com/read/29360464/molecular-characterization-of-feline-melanocortin-4-receptor-and-melanocortin-2-receptor-accessory-protein-2
#4
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
https://www.readbyqxmd.com/read/29317531/melanocortin-overexpression-limits-diet-induced-inflammation-and-atherosclerosis-in-ldlr-mice
#5
Salla Nuutinen, Liisa Ailanen, Eriika Savontaus, Petteri Rinne
Atherosclerosis is a chronic inflammatory disease of the arteries. The disease is initiated by endothelial dysfunction that allows the transport of leukocytes and low-density lipoprotein into the vessel wall forming atherosclerotic plaques. The melanocortin system is an endogenous peptide system that regulates, for example, energy homeostasis and cardiovascular function. Melanocortin treatment with endogenous or synthetic melanocortin peptides reduces body weight, protects the endothelium and alleviates vascular inflammation, but the long-term effects of melanocortin system activation on atheroprogression remain largely unknown...
January 9, 2018: Journal of Endocrinology
https://www.readbyqxmd.com/read/29316344/widespread-dynamic-and-pleiotropic-expression-of-the-melanocortin-1-receptor-mc1r-system-is-conserved-across-chick-mouse-and-human-embryonic-development
#6
Anna C Thomas, Pauline Heux, Chloe Santos, Wisenave Arulvasan, Nita Solanky, Magalie E Carey, Dianne Gerrelli, Veronica A Kinsler, Heather C Etchevers
BACKGROUND: MC1R, a G-protein coupled receptor with high affinity for alpha-melanocyte stimulating hormone (αMSH), modulates pigment production in melanocytes from many species and is associated with human melanoma risk. MC1R mutations affecting human skin and hair color also have pleiotropic effects on the immune response and analgesia. Variants affecting human pigmentation in utero alter the congenital phenotype of both oculocutaneous albinism and congenital melanocytic naevi, and have a possible effect on birthweight...
January 8, 2018: Birth Defects Research
https://www.readbyqxmd.com/read/29297124/metabolic-parameters-and-functional-state-of-hypothalamic-signaling-systems-in-ay-a-mice-with-genetic-predisposition-to-obesity-and-the-effect-of-metformin
#7
K V Derkach, I O Zakharova, I V Romanova, I I Zorina, A L Mikhrina, A O Shpakov
The metabolic parameters and functional state of hypothalamic systems in mice with the Yellow mutation in the Agouti locus and with obesity of the melanocortin type and the effect of metformin (MF) treatment (9 days, 200 mg/kg/day) were studied. The MF treatment led to decreased body weight and to normalization of glucose tolerance in mice. In the hypothalamus, MF restored the decreased activity of Akt kinase, the main component of leptin pathway, and normalized the increased expression of subtype 1B serotonin receptor...
November 2017: Doklady. Biochemistry and Biophysics
https://www.readbyqxmd.com/read/29296625/molecular-therapy-of-melanocortin-4-receptor-obesity-by-an-autoregulatory-bdnf-vector
#8
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
https://www.readbyqxmd.com/read/29290621/a-gut-brain-axis-regulating-glucose-metabolism-mediated-by-bile-acids-and-competitive-fibroblast-growth-factor-actions-at-the-hypothalamus
#9
Shunmei Liu, Genevieve Marcelin, Clemence Blouet, Jae Hoon Jeong, Young-Hwan Jo, Gary J Schwartz, Streamson Chua
OBJECTIVE: Bile acids have been implicated as important regulators of glucose metabolism via activation of FXR and GPBAR1. We have previously shown that FGF19 can modulate glucose handling by suppressing the activity of hypothalamic AGRP/NPY neurons. As bile acids stimulate the release of FGF19/FGF15 into the circulation, we pursued the potential of bile acids to improve glucose tolerance via a gut-brain axis involving FXR and FGF15/FGF19 within enterocytes and FGF receptors on hypothalamic AGRP/NPY neurons...
December 9, 2017: Molecular Metabolism
https://www.readbyqxmd.com/read/29275211/up-regulation-of-pomc-and-cart-mrnas-by-intermittent-hypoxia-via-gata-transcription-factors-in-human-neuronal-cells
#10
Ryogo Shobatake, Ken Takasawa, Hiroyo Ota, Asako Itaya-Hironaka, Akiyo Yamauchi, Sumiyo Sakuramoto-Tsuchida, Tomoko Uchiyama, Mai Makino, Kazuma Sugie, Shin Takasawa, Satoshi Ueno
Sleep apnea syndrome (SAS) is characterized by intermittent hypoxia (IH) during sleep. SAS and obesity are strongly related to each other. Here, we investigated the effect of IH on the expression of major appetite regulatory genes in human neuronal cells. We exposed NB-1, SH-SY5Y, and SK-N-SH human neuronal cells to IH (64 cycles of 5 min hypoxia and 10 min normoxia), normoxia, or sustained hypoxia for 24 h and measured the mRNA levels of proopiomelanocortin (POMC), cocaine- and amphetamine-regulated transcript (CART), galanin, galanin-like peptide, ghrelin, pyroglutamylated RFamide peptide, agouti-related peptide, neuropeptide Y, and melanocortin 4 receptor by real-time RT-PCR...
December 21, 2017: International Journal of Biochemistry & Cell Biology
https://www.readbyqxmd.com/read/29206201/selection-on-the-major-color-gene-melanocortin-1-receptor-shaped-the-evolution-of-the-melanocortin-system-genes
#11
Linda Dib, Luis M San-Jose, Anne-Lyse Ducrest, Nicolas Salamin, Alexandre Roulin
Modular genetic systems and networks have complex evolutionary histories shaped by selection acting on single genes as well as on their integrated function within the network. However, uncovering molecular coevolution requires the detection of coevolving sites in sequences. Detailed knowledge of the functions of each gene in the system is also necessary to identify the selective agents driving coevolution. Using recently developed computational tools, we investigated the effect of positive selection on the coevolution of ten major genes in the melanocortin system, responsible for multiple physiological functions and human diseases...
December 5, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29198512/understanding-the-role-of-serotonin-in-female-hypoactive-sexual-desire-disorder-and-treatment-options
#12
REVIEW
Harry A Croft
BACKGROUND: The neurobiology of sexual response is driven in part by dopamine and serotonin-the former modulating excitatory pathways and the latter regulating inhibitory pathways. Neurobiological underpinnings of hypoactive sexual desire disorder (HSDD) are seemingly related to overactive serotonin activity that results in underactive dopamine activity. As such, pharmacologic agents that decrease serotonin, increase dopamine, or some combination thereof, have therapeutic potential for HSDD...
December 2017: Journal of Sexual Medicine
https://www.readbyqxmd.com/read/29177811/genetic-and-syndromic-causes-of-obesity-and-its-management
#13
REVIEW
Ildiko H Koves, Christian Roth
The aim of this article is to provide an in depth review of the rare genetic and syndromic forms of childhood obesity. The authors demonstrate the complexity and inter-relationships of the leptin-melanocortin signaling pathway and its central nervous system and systemic effects. Authors highlight the clinical distinctive features of genetic/syndromic causes for childhood obesity, in particular, relative shorter height to their genetic potential, developmental challenges and in some instances, ophthalmological and retina changes...
November 27, 2017: Indian Journal of Pediatrics
https://www.readbyqxmd.com/read/29131966/activation-of-the-central-melanocortin-system-in-rats-persistently-reduces-body-and-fat-mass-independently-of-caloric-reduction
#14
Isabelle Côté, Sara M Green, Drake Morgan, Christy Carter, Nihal Tümer, Philip James Scarpace
Recent evidence indicate that Melanotan II (MTII) reduces body mass independently of caloric reduction. Because MTII induces a transient hypophagia, caloric reduction is still considered a primary mechanism for MTII-mediated body mass loss. To examine the contribution of caloric reduction to long-term body mass loss in response to Melanotan II (MTII), we centrally infused MTII or vehicle in ad libitum fed (MTII and Control) animals in comparison to a group of animals that were pair-fed (PF) to the MTII group...
November 13, 2017: Canadian Journal of Physiology and Pharmacology
https://www.readbyqxmd.com/read/29124692/ultraviolet-radiations-skin-defense-damage-mechanism
#15
Dheeraj Mohania, Shikha Chandel, Parveen Kumar, Vivek Verma, Kumar Digvijay, Deepika Tripathi, Khushboo Choudhury, Sandeep Kumar Mitten, Dilip Shah
UV-radiations are the invisible part of light spectra having a wavelength between visible rays and X-rays. Based on wavelength, UV rays are subdivided into UV-A (320-400 nm), UV-B (280-320 nm) and UV-C (200-280 nm). Ultraviolet rays can have both harmful and beneficial effects. UV-C has the property of ionization thus acting as a strong mutagen, which can cause immune-mediated disease and cancer in adverse cases. Numbers of genetic factors have been identified in human involved in inducing skin cancer from UV-radiations...
2017: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/29113896/neuroinflammation-produced-by-heavy-alcohol-intake-is-due-to-loops-of-interactions-between-toll-like-4-and-tnf-receptors-peroxisome-proliferator-activated-receptors-and-the-central-melanocortin-system-a-novel-hypothesis-and-new-therapeutic-avenues
#16
Osvaldo Flores-Bastías, Eduardo Karahanian
Excessive alcohol intake induces an inflammatory response in the brain, via TNFα, TLR4 and NF-κB signaling pathways. It has been proposed that neuroinflammation would play a very important role in the development of alcohol addiction. In addition to stimulating the synthesis of inflammatory mediators such as IL-6, IL-1β and TNFα, NF-κB is capable of reducing the anti-inflammatory activity of PPARα and PPARγ. Reciprocally, PPARα, PPARγ and melanocortin 4 receptor (MC4R) can decrease the proinflammatory activity of NF-κB, establishing an interplay of inactivations between such nuclear factors and receptors...
November 4, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/29099963/activity-of-the-hypothalamic-melanocortin-system-decreases-in-middle-aged-and-increases-in-old-rats
#17
Nóra Füredi, Alexandra Mikó, Balázs Gaszner, Diána Feller, Ildikó Rostás, Judit Tenk, Margit Solymár, Márta Balaskó, Erika Pétervári
Appearance of middle-aged obesity and aging anorexia both in humans and rodents suggests a role for regulatory alterations. Hypothalamic melanocortin agonist, alpha-melanocyte-stimulating hormone (alpha-MSH) produced in the arcuate nucleus (ARC) reduces body weight via inducing hypermetabolism and anorexia mainly through melanocortin 4 receptors (MC4R) in the paraventricular nucleus (PVN). Orexigenic ARC-derived agouti-related protein (AgRP) is an inverse agonist on MC4R in the PVN. Previously we demonstrated that characteristic age-related shifts in the catabolic effects of alpha-MSH may contribute both to middle-aged obesity and aging anorexia...
November 1, 2017: Journals of Gerontology. Series A, Biological Sciences and Medical Sciences
https://www.readbyqxmd.com/read/29097517/neuropeptides-in-obesity-and-metabolic-disease
#18
REVIEW
Agatha A van der Klaauw
BACKGROUND: The global rise in the prevalence of obesity and associated comorbidities such as type 2 diabetes, cardiovascular disease, and cancer represents a major public health concern. CONTENT: Studies in rodents with the use of global and targeted gene disruption, and mapping of neurocircuitry by using optogenetics and designer receptors exclusively activated by designer drugs (DREADDs) have greatly advanced our understanding of the neural control of body weight...
January 2018: Clinical Chemistry
https://www.readbyqxmd.com/read/29056149/the-role-of-the-melanocortin-system-in-drug-and-alcohol-abuse
#19
Montserrat Navarro
The melanocortin (MC) system is composed of different peptides centrally produced by proopiomelanocortin neurons in the arcuate nucleus of the hypothalamus (N.Arc) and the medulla. These peptides act through five subtypes of melanocortin receptors (MCRs) that belong to the family of seven-transmembrane G-protein-coupled receptors that are coupled through Gαs signaling pathways. MC3R and MC4R are the predominant MCR subtypes in the brain, and they are widely expressed in brain regions thought to modulate drug self-administration, including the nucleus accumbens, the hypothalamus, and the ventral tegmental area...
2017: International Review of Neurobiology
https://www.readbyqxmd.com/read/29031726/reduced-renal-sympathetic-nerve-activity-contributes-to-elevated-glycosuria-and-improved-glucose-tolerance-in-hypothalamus-specific-pomc-knockout-mice
#20
Kavaljit H Chhabra, Donald A Morgan, Benjamin P Tooke, Jessica M Adams, Kamal Rahmouni, Malcolm J Low
OBJECTIVE: Hypothalamic arcuate nucleus-specific pro-opiomelanocortin deficient (ArcPomc(-/-)) mice exhibit improved glucose tolerance despite massive obesity and insulin resistance. We demonstrated previously that their improved glucose tolerance is due to elevated glycosuria. However, the underlying mechanisms that link glucose reabsorption in the kidney with ArcPomc remain unclear. Given the function of the hypothalamic melanocortin system in controlling sympathetic outflow, we hypothesized that reduced renal sympathetic nerve activity (RSNA) in ArcPomc(-/-) mice could explain their elevated glycosuria and consequent enhanced glucose tolerance...
October 2017: Molecular Metabolism
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