scholarly journals Regulation of Brain Primary Cilia Length by MCH Signaling: Evidence from Pharmacological, Genetic, Optogenetic and Chemogenic Manipulations

2021 ◽  
Author(s):  
Wedad Alhassen ◽  
Yuki Kobayashi ◽  
Jessica Su ◽  
Brianna Robbins ◽  
Henry Ngyuen ◽  
...  
Keyword(s):  
Energy Homeostasis ◽  
Primary Cilia ◽  
Designer Drugs ◽  
Genetic Manipulations ◽  
Pathological Conditions ◽  
Melanin Concentrating Hormone ◽  
Agonist And Antagonist ◽  
And Migration ◽  
External Stimuli

AbstractThe melanin concentrating hormone (MCH) system is involved in numerous functions including energy homeostasis, food intake, sleep, stress, mood, aggression, reward, maternal behavior, social behavior, and cognition. MCH acts on a G protein-coupled receptor MCHR1, which expresses ubiquitously in the brain and localizes to neuronal primary cilia. Cilia act as cells’ antennas and play crucial roles in cell signaling to detect and transduce external stimuli to regulate cell differentiation and migration. Cilia are highly dynamic in terms of their length and morphology; however, it is not known if cilia length is causally regulated by MCH system activation in-vivo. In the current work, we examined the effects of the activation and inactivation of MCH system on cilia lengths by using different methodologies, including pharmacological (MCHR1 agonist and antagonist GW803430), germline and conditional genetic deletion of MCHR1 and MCH, optogenetic, and chemogenetic (Designer Receptors Exclusively Activated by Designer Drugs (DREADD)) approaches. We found that stimulation of MCH system either directly through MCHR1 activation, or indirectly through optogenetic and chemogenetic- mediated excitation of MCH neurons, causes cilia shortening. Contrarily, inactivation of MCH signaling through pharmacological MCHR1 blockade or through genetic manipulations - germline deletion of MCHR1 and conditional ablation of MCH neurons - induces cilia lengthening. Our study is the first to uncover the causal effects of the MCH system in the regulation of the length of brain neuronal primary cilia. These findings place MCH system at a unique position in the ciliary signaling in physiological and pathological conditions, and implicate cilia MCHR1 as a potential therapeutic target for the treatment of pathological conditions characterized by impaired cilia function.

scholarly journals Regulation of Brain Primary Cilia Length By MCH Signaling: Evidence From Pharmacological, Genetic, Optogenetic And Chemogenic Manipulations

2021 ◽  
Author(s):  
Wedad Alhassen ◽  
Yuki Kobayashi ◽  
Jessica Su ◽  
Brianna Robbins ◽  
Henry Nguyen ◽  
...  
Keyword(s):  
Energy Homeostasis ◽  
Primary Cilia ◽  
Designer Drugs ◽  
Genetic Manipulations ◽  
Pathological Conditions ◽  
Melanin Concentrating Hormone ◽  
Agonist And Antagonist ◽  
And Migration ◽  
External Stimuli

Abstract The melanin-concentrating hormone (MCH) system is involved in numerous functions, including energy homeostasis, food intake, sleep, stress, mood, aggression, reward, maternal behavior, social behavior, and cognition. MCH acts on a G protein-coupled receptor MCHR1, which expresses ubiquitously in the brain and localizes to neuronal primary cilia. Cilia act as cells' antennas and play crucial roles in cell signaling to detect and transduce external stimuli to regulate cell differentiation and migration. Cilia are highly dynamic in terms of their length and morphology; however, it is not known if cilia length is causally regulated by MCH system activation in-vivo. In the current work, we examined the effects of activation and inactivation of MCH system on cilia lengths by using different methodologies, including pharmacological (MCHR1 agonist and antagonist GW803430), germline and conditional genetic deletion of MCHR1 and MCH, optogenetic, and chemogenetic (Designer Receptors Exclusively Activated by Designer Drugs (DREADD)) approaches. We found that stimulation of MCH system either directly through MCHR1 activation, or indirectly through optogenetic and chemogenetic-mediated excitation of MCH neurons, causes cilia shortening. In contrast, inactivation of MCH signaling through pharmacological MCHR1 blockade or through genetic manipulations - germline deletion of MCHR1 and conditional ablation of MCH neurons - induces cilia lengthening. Our study is the first to uncover the causal effects of the MCH system in the regulation of the length of brain neuronal primary cilia. These findings place MCH system at a unique position in the ciliary signaling in physiological and pathological conditions, and implicate cilia MCHR1 as a potential therapeutic target for the treatment of pathological conditions characterized by impaired cilia function.

scholarly journals Determination of the Interaction and Pharmacological Modulation of MCHR1 Signaling by C Terminus of MRAP2 Protein

2021 ◽  
Author(s):  
Meng Wang ◽  
Yue Zhai ◽  
Xiaowei Lei ◽  
Jing Xu ◽  
Bopei Jiang ◽  
...  
Keyword(s):  
Energy Homeostasis ◽  
Transmembrane Protein ◽  
Melanocortin Receptor ◽  
Pharmacological Modulation ◽  
C Terminus ◽  
Melanin Concentrating Hormone ◽  
The Central Nervous System

Abstract Background: Melanin concentrating hormone (MCH), an orexigenic neuropeptide, is primarily secreted by the hypothalamus and acts at its receptor, the melanin-concentrating hormone receptor 1 (MCHR1), to regulate energy homeostasis and body weight. The Melanocortin Receptor Accessory Protein 2 (MRAP2), a small single transmembrane protein broadly expressed in multiple tissues, has been defined as a vital endocrine pivot of five melanocortin receptors (MC1R-MC5R) and several other GPCRs in the regulation of central neuronal appetite and peripheral energy homeostasis. However, the regulatory and relationship between MCHR1 and MRAP2 is unknown.Results: In this study, we show that MRAP2 interacts with MCHR1 and suppresses MCHR1 signaling in vitro. We also identified the C-terminal domains of MRAP2 protein required for pharmacological modulation of intracellular Ca2+ cascades and membrane transport.Conclusions: These findings elucidated the broad regulatory profile of MRAP2 protein in the central nervous system and may provide implications for the modulation of central MCHR1 function in vivo.

scholarly journals Dietary, Metabolic, and Potentially Environmental Modulation of the Lysine Acetylation Machinery

2010 ◽  
Vol 2010 ◽  
pp. 1-14 ◽  
Author(s):  
Go-Woon Kim ◽  
Goran Gocevski ◽  
Chao-Jung Wu ◽  
Xiang-Jiao Yang
Keyword(s):  
Expression Patterns ◽  
Chromatin Dynamics ◽  
Cellular Processes ◽  
The Past ◽  
Pathological Conditions ◽  
Good State ◽  
Therapeutic Development ◽  
Dietary Components ◽  
External Stimuli

Healthy lifestyles and environment produce a good state of health. A number of scientific studies support the notion that external stimuli regulate an individual's epigenomic profile. Epigenetic changes play a key role in defining gene expression patterns under both normal and pathological conditions. As a major posttranslational modification, lysine (K) acetylation has received much attention, owing largely to its significant effects on chromatin dynamics and other cellular processes across species. Lysine acetyltransferases and deacetylases, two opposing families of enzymes governing K-acetylation, have been intimately linked to cancer and other diseases. These enzymes have been pursued by vigorous efforts for therapeutic development in the past 15 years or so. Interestingly, certain dietary components have been found to modulate acetylation levelsin vivo. Here we review dietary, metabolic, and environmental modulators of the K-acetylation machinery and discuss how they may be of potential value in the context of disease prevention.

scholarly journals Fractalkine Preferentially Mediates Arrest and Migration of CD16+ Monocytes

2003 ◽  
Vol 197 (12) ◽  
pp. 1701-1707 ◽  
Author(s):  
Petronela Ancuta ◽  
Ravi Rao ◽  
Ashlee Moses ◽  
Andrew Mehle ◽  
Sunil K. Shaw ◽  
...  
Keyword(s):  
Chemokine Receptors ◽  
Molecular Mechanisms ◽  
Tissue Injury ◽  
Monocyte Subset ◽  
Blood Monocytes ◽  
Monocyte Chemoattractant Protein 1 ◽  
Pathological Conditions ◽  
Normal Individuals ◽  
And Migration

CD16+ monocytes represent 5–10% of peripheral blood monocytes in normal individuals and are dramatically expanded in several pathological conditions including sepsis, human immunodeficiency virus 1 infection, and cancer. CD16+ monocytes produce high levels of proinflammatory cytokines and may represent dendritic cell precursors in vivo. The mechanisms that mediate the recruitment of CD16+ monocytes into tissues remain unknown. Here we investigate molecular mechanisms of CD16+ monocyte trafficking and show that migration of CD16+ and CD16− monocytes is mediated by distinct combinations of adhesion molecules and chemokine receptors. In contrast to CD16− monocytes, CD16+ monocytes expressed high CX3CR1 and CXCR4 but low CCR2 and CD62L levels and underwent efficient transendo-thelial migration in response to fractalkine (FKN; FKN/CX3CL1) and stromal-derived factor 1α (CXCL12) but not monocyte chemoattractant protein 1 (CCL2). CD16+ monocytes arrested on cell surface–expressed FKN under flow with higher frequency compared with CD16− monocytes. These results demonstrate that FKN preferentially mediates arrest and migration of CD16+ monocytes and suggest that recruitment of this proinflammatory monocyte subset to vessel walls via the CX3CR1-FKN pathway may contribute to vascular and tissue injury during pathological conditions.

scholarly journals Small organelle, big responsibility: the role of centrosomes in development and disease

2014 ◽  
Vol 369 (1650) ◽  
pp. 20130468 ◽  
Author(s):  
Pavithra L. Chavali ◽  
Monika Pütz ◽  
Fanni Gergely
Keyword(s):  
Developmental Disorders ◽  
Primary Cilia ◽  
Spatial Organization ◽  
Growth Failure ◽  
Cell Types ◽  
Model Systems ◽  
And Migration ◽  
Division Cell

The centrosome, a key microtubule organizing centre, is composed of centrioles, embedded in a protein-rich matrix. Centrosomes control the internal spatial organization of somatic cells, and as such contribute to cell division, cell polarity and migration. Upon exiting the cell cycle, most cell types in the human body convert their centrioles into basal bodies, which drive the assembly of primary cilia, involved in sensing and signal transduction at the cell surface. Centrosomal genes are targeted by mutations in numerous human developmental disorders, ranging from diseases exclusively affecting brain development, through global growth failure syndromes to diverse pathologies associated with ciliary malfunction. Despite our much-improved understanding of centrosome function in cellular processes, we know remarkably little of its role in the organismal context, especially in mammals. In this review, we examine how centrosome dysfunction impacts on complex physiological processes and speculate on the challenges we face when applying knowledge generated from in vitro and in vivo model systems to human development.

scholarly journals MCH-R1 Antagonist GPS18169, a Pseudopeptide, Is a Peripheral Anti-Obesity Agent in Mice

Molecules ◽  
2021 ◽  
Vol 26 (5) ◽  
pp. 1291
Author(s):  
Jean A. Boutin ◽  
Magali Jullian ◽  
Lukasz Frankiewicz ◽  
Mathieu Galibert ◽  
Philippe Gloanec ◽  
...  
Keyword(s):  
Energy Homeostasis ◽  
Parent Compound ◽  
Insulin Level ◽  
Antagonistic Effect ◽  
Melanin Concentrating Hormone ◽  
The Brain ◽  
Nanomolar Range ◽  
Obesity Syndrome ◽  
Final Work

Melanin-concentrating hormone (MCH) is a 19 amino acid long peptide found in the brain of animals, including fishes, batrachians, and mammals. MCH is implicated in appetite and/or energy homeostasis. Antagonists at its receptor (MCH-R1) could be major tools (or ultimately drugs) to understand the mechanism of MCH action and to fight the obesity syndrome that is a worldwide societal health problem. Ever since the deorphanisation of the MCH receptor, we cloned, expressed, and characterized the receptor MCH-R1 and started a vast medicinal chemistry program aiming at the discovery of such usable compounds. In the present final work, we describe GPS18169, a pseudopeptide antagonist at the MCH-R1 receptor with an affinity in the nanomolar range and a Ki for its antagonistic effect in the 20 picomolar range. Its metabolic stability is rather ameliorated compared to its initial parent compound, the antagonist S38151. We tested it in an in vivo experiment using high diet mice. GPS18169 was found to be active in limiting the accumulation of adipose tissues and, correlatively, we observed a normalization of the insulin level in the treated animals, while no change in food or water consumption was observed.

scholarly journals Determination of the Interaction and Pharmacological Modulation of MCHR1 Signaling by C Terminus of MRAP2 Protein

2021 ◽  
Author(s):  
Meng Wang ◽  
Yue Zhai ◽  
Xiaowei Lei ◽  
Jing Xu ◽  
Bopei Jiang ◽  
...  
Keyword(s):  
Energy Homeostasis ◽  
Transmembrane Protein ◽  
Melanocortin Receptor ◽  
Pharmacological Modulation ◽  
C Terminus ◽  
Melanin Concentrating Hormone ◽  
The Central Nervous System

Abstract Background: Melanin concentrating hormone (MCH), an orexigenic neuropeptide, is primarily secreted by the hypothalamus and acts at its receptor, the melanin-concentrating hormone receptor 1 (MCHR1), to regulate energy homeostasis and body weight. The Melanocortin Receptor Accessory Protein 2 (MRAP2), a small single transmembrane protein broadly expressed in multiple tissues, has been defined as a vital endocrine pivot of five melanocortin receptors (MC1R-MC5R) and several other GPCRs in the regulation of central neuronal appetite and peripheral energy homeostasis. However, the regulatory and relationship between MCHR1 and MRAP2 is unknown.Results: In this study, we show that MRAP2 interacts with MCHR1 and suppresses MCHR1 signaling in vitro. We also identified the C-terminal domains of MRAP2 protein required for pharmacological modulation of intracellular Ca2+ cascades and membrane transport. Conclusions: These findings elucidated the broad regulatory profile of MRAP2 protein in the central nervous system and may provide implications for the modulation of central MCHR1 function in vivo.

Properties of primary cilia in melanin-concentrating hormone receptor 1-bearing hippocampal neurons in vivo and in vitro

2021 ◽  
Vol 142 ◽  
pp. 104902
Author(s):  
Yuki Kobayashi ◽  
Tomoya Okada ◽  
Daisuke Miki ◽  
Yuko Sekino ◽  
Noriko Koganezawa ◽  
...  
Keyword(s):  
Hormone Receptor ◽  
Hippocampal Neurons ◽  
Primary Cilia ◽  
Melanin Concentrating Hormone

scholarly journals Identification of Urop11, a novel leptin-modulated gene that is upregulated in the hypothalamus of mice with virus-induced obesity

2007 ◽  
Vol 38 (1) ◽  
pp. 3-17 ◽  
Author(s):  
O Verlaeten ◽  
C Casery ◽  
S Cavagna ◽  
D Naville ◽  
P Giraudon ◽  
...  
Keyword(s):  
Energy Homeostasis ◽  
Viral Infections ◽  
Lymphocyte Activation ◽  
Subtractive Library ◽  
Brain Infection ◽  
Pathological Conditions ◽  
Metabolic Systems ◽  
New Gene

Obesity results from disturbances of tightly regulated interactions between the nervous, endocrine, and metabolic systems that can be caused by external factors, such as viral infections. A mouse model of obesity induced by brain infection with a morbillivirus, canine distemper virus, allowed us to identify obesity-related genes. Using a subtractive library for the hypothalamus, the main brain structure regulating energy homeostasis, we identified a new gene on mouse chromosome 19 which we named upregulated obese product (Urop) 11 and, which has no homology with any known mRNA. A step-by-step molecular approach allowed us to isolate the full-length mRNA, predict the protein sequence, and identify consensus sites. Urop11 was mainly detected in the hypothalamus and adipocytes, and was dramatically upregulated in these central and peripheral structures in obese mice. Urop11 was also expressed in human neural and lymphoid samples and its expression seemed to be regulated by the state of lymphocyte activation. Interestingly, Urop11 expression was strongly upregulated both in vivo in mouse hypothalamus and in vitro in mouse neural cell lines, after leptin treatment. Taken together, our data show that Urop11 is a target of leptin, the satiety factor produced by adipocytes, in physiological and pathological conditions, including obesity. This new gene can be considered a key molecule in the hypothalamic integration pathway and demonstrates the importance of Urop11 as a target of leptin action.

scholarly journals OR04-01 MRAP2 Regulates Energy Homeostasis by Promoting Primary Cilia Localization of MC4R

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Adelaide A Bernard ◽  
Irene Ojeda Naharros ◽  
Florence Bourgain Guglielmetti ◽  
Xinyu Yue ◽  
Christian Vaisse
Keyword(s):  
Body Weight ◽  
Primary Cilium ◽  
Energy Homeostasis ◽  
Primary Cilia ◽  
Small Population ◽  
The Body ◽  
Melanocortin Receptor ◽  
Hypothalamic Neurons

Abstract Genetic studies in humans and mice have demonstrated that the Melanocortin 4 Receptor (MC4R) is essential for adequate regulation of food intake and body weight. MC4R is expressed in a small population of hypothalamic neurons and very little is known about its molecular and cellular dynamics in vivo. We have recently demonstrated that MC4R localizes to and functions at the primary cilia of select hypothalamic neurons to control energy homeostasis. The primary cilium is a solitary hair-like organelle that serves as an antenna sensing extracellular environment. Defective primary cilia lead to a series of conditions known as ciliopathies, that can manifest through a variety of clinical features, including hyperphagia and obesity. Here we establish that the ciliary localization and the body weight regulating activity of MC4R is dependent on a single-pass transmembrane accessory protein: the Melanocortin Receptor Associated Protein 2 (MRAP2). Specifically, we show that deleting MRAP2 specifically from MC4R neurons (MC4RMRAP2-/-) leads to early onset obesity and hyperphagia. In vitro, co-expression of MRAP2 in ciliated IMCD3 cells increases MC4R localization to the primary cilium. We further demonstrate that MRAP2 and MC4R colocalize specifically at the primary cilium in vivo, and that MC4R fails to localize to the primary cilium when MRAP2 is deleted. These findings highlight the role of the primary cilium in the control of energy homeostasis, and the importance of accessory proteins for the localization of GPCRs to the primary cilium where they exert their function, in this case being critical for the regulation of energy homeostasis.

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