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2. Single cell tracing of Pomc neurons reveals recruitment of ‘Ghost’ subtypes with atypical identity in a mouse model of obesity

Author

Leon, Stéphane, Simon, Vincent, Lee, Thomas H., Steuernagel, Lukas, Clark, Samantha, Biglari, Nasim, Lesté-Lasserre, Thierry, Dupuy, Nathalie, Cannich, Astrid, Bellocchio, Luigi, Zizzari, Philippe, Allard, Camille, Gonzales, Delphine, Le Feuvre, Yves, Lhuillier, Emeline, Brochard, Alexandre, Nicolas, Jean Charles, Teillon, Jérémie, Nikolski, Macha, Marsicano, Giovanni, Fioramonti, Xavier, Brüning, Jens C., Cota, Daniela, and Quarta, Carmelo

Published
2024
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5. GLP-1-mediated delivery of tesaglitazar improves obesity and glucose metabolism in male mice

Author

Quarta, Carmelo, Stemmer, Kerstin, Novikoff, Aaron, Yang, Bin, Klingelhuber, Felix, Harger, Alex, Bakhti, Mostafa, Bastidas-Ponce, Aimee, Baugé, Eric, Campbell, Jonathan E., Capozzi, Megan, Clemmensen, Christoffer, Collden, Gustav, Cota, Perla, Douros, Jon, Drucker, Daniel J., DuBois, Barent, Feuchtinger, Annette, Garcia-Caceres, Cristina, Grandl, Gerald, Hennuyer, Nathalie, Herzig, Stephan, Hofmann, Susanna M., Knerr, Patrick J., Kulaj, Konxhe, Lalloyer, Fanny, Lickert, Heiko, Liskiewicz, Arek, Liskiewicz, Daniela, Maity, Gandhari, Perez-Tilve, Diego, Prakash, Sneha, Sanchez-Garrido, Miguel A., Zhang, Qian, Staels, Bart, Krahmer, Natalie, DiMarchi, Richard D., Tschöp, Matthias H., Finan, Brian, and Müller, Timo D.

Published
2022
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7. Functional heterogeneity of POMC neurons relies on mTORC1 signaling

Author

Saucisse, Nicolas, Mazier, Wilfrid, Simon, Vincent, Binder, Elke, Catania, Caterina, Bellocchio, Luigi, Romanov, Roman A., Léon, Stéphane, Matias, Isabelle, Zizzari, Philippe, Quarta, Carmelo, Cannich, Astrid, Meece, Kana, Gonzales, Delphine, Clark, Samantha, Becker, Julia M., Yeo, Giles S.H., Fioramonti, Xavier, Merkle, Florian T., Wardlaw, Sharon L., Harkany, Tibor, Massa, Federico, Marsicano, Giovanni, and Cota, Daniela

Published
2021
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12. Molecular Imaging of Neuroblastoma Progression in TH-MYCN Transgenic Mice

Author

Quarta, Carmelo, Cantelli, Erika, Nanni, Cristina, Ambrosini, Valentina, D’ambrosio, Daniela, Di Leo, Korinne, Angelucci, Silvia, Zagni, Federico, Lodi, Filippo, Marengo, Mario, Weiss, William A, Pession, Andrea, Tonelli, Roberto, and Fanti, Stefano

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Oncology and Carcinogenesis, Rare Diseases, Neuroblastoma, Pediatric, Pediatric Research Initiative, Neurosciences, Cancer, Biomedical Imaging, Animals, Antineoplastic Agents, Disease Models, Animal, Disease Progression, Fluorodeoxyglucose F18, Histocytochemistry, Linear Models, Mice, Mice, Transgenic, Molecular Imaging, N-Myc Proto-Oncogene Protein, Positron-Emission Tomography, Proto-Oncogene Proteins, Statistics, Nonparametric, Small animal PET, [F-18]FDG, TH-MYCN mice, Physiology, Nuclear Medicine & Medical Imaging, Clinical sciences
Abstract

PurposeTH-MYCN transgenic mice represent a valuable preclinical model of neuroblastoma. Current methods to study tumor progression in these mice are inaccurate or invasive, limiting the potential of this murine model. The aim of our study was to assess the potential of small animal positron emission tomography (SA-PET) to study neuroblastoma progression in TH-MYCN mice.ProcedureSerial SA-PET scans using the tracer 2-deoxy-2-[(18)F]fluoro-D-glucose ((18)F-FDG) have been performed in TH-MYCN mice. Image analysis of tumor progression has been compared with ex vivo evaluation of tumor volumes and histological features.Results[(18)F]FDG-SA-PET allowed to detect early staged tumors in almost 100 % of TH-MYCN mice positive for disease. Image analysis of tumor evolution reflected the modifications of the tumor volume, histological features, and malignancy during disease progression. Image analysis of TH-MYCN mice undergoing chemotherapy treatment against neuroblastoma provided information on drug-induced alterations in tumor metabolic activity.ConclusionsThese data show for the first time that [(18)F]FDG-SA-PET is a useful tool to study neuroblastoma presence and progression in TH-MYCN transgenic mice.

Published
2013

13. Functional identity of hypothalamic melanocortin neurons depends on Tbx3

Author

Quarta, Carmelo, Fisette, Alexandre, Xu, Yanjun, Colldén, Gustav, Legutko, Beata, Tseng, Yu-Ting, Reim, Alexander, Wierer, Michael, De Rosa, Maria Caterina, Klaus, Valentina, Rausch, Rick, Thaker, Vidhu V., Graf, Elisabeth, Strom, Tim M., Poher, Anne-Laure, Gruber, Tim, Le Thuc, Ophélia, Cebrian-Serrano, Alberto, Kabra, Dhiraj, Bellocchio, Luigi, Woods, Stephen C., Pflugfelder, Gert O., Nogueiras, Rubén, Zeltser, Lori, Grunwald Kadow, Ilona C., Moon, Anne, García-Cáceres, Cristina, Mann, Matthias, Treier, Mathias, Doege, Claudia A., and Tschöp, Matthias H.

Published
2019
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14. Molecular Integration of Incretin and Glucocorticoid Action Reverses Immunometabolic Dysfunction and Obesity

Author

Quarta, Carmelo, Clemmensen, Christoffer, Zhu, Zhimeng, Yang, Bin, Joseph, Sini S., Lutter, Dominik, Yi, Chun-Xia, Graf, Elisabeth, García-Cáceres, Cristina, Legutko, Beata, Fischer, Katrin, Brommage, Robert, Zizzari, Philippe, Franklin, Bernardo S., Krueger, Martin, Koch, Marco, Vettorazzi, Sabine, Li, Pengyun, Hofmann, Susanna M., Bakhti, Mostafa, Bastidas-Ponce, Aimée, Lickert, Heiko, Strom, Tim M., Gailus-Durner, Valerie, Bechmann, Ingo, Perez-Tilve, Diego, Tuckermann, Jan, Hrabě de Angelis, Martin, Sandoval, Darleen, Cota, Daniela, Latz, Eicke, Seeley, Randy J., Müller, Timo D., DiMarchi, Richard D., Finan, Brian, and Tschöp, Matthias H.

Published
2017
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15. Astrocytic Insulin Signaling Couples Brain Glucose Uptake with Nutrient Availability

Author

García-Cáceres, Cristina, Quarta, Carmelo, Varela, Luis, Gao, Yuanqing, Gruber, Tim, Legutko, Beata, Jastroch, Martin, Johansson, Pia, Ninkovic, Jovica, Yi, Chun-Xia, Le Thuc, Ophelia, Szigeti-Buck, Klara, Cai, Weikang, Meyer, Carola W., Pfluger, Paul T., Fernandez, Ana M., Luquet, Serge, Woods, Stephen C., Torres-Alemán, Ignacio, Kahn, C. Ronald, Götz, Magdalena, Horvath, Tamas L., and Tschöp, Matthias H.

Published
2016
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16. Adipocyte cannabinoid receptor CB1 regulates energy homeostasis and alternatively activated macrophages

Author

Ruiz de Azua, Inigo, Mancini, Giacomo, Kamal Srivastava, Raj, Aparisi Rey, Alejandro, Cardinal, Pierre, Tedesco, Laura, Zingaretti, Cristina Maria, Sassmann, Antonia, Quarta, Carmelo, Schwitter, Claudia, Conrad, Andrea, Wettschureck, Nina, Kiran Vemuri, V., Makriyannis, Alexandros, Hartwig, Jens, Mendez-Lago, Maria, Bindila, Laura, Monory, Krisztina, Giordano, Antonio, Cinti, Saverio, Marsicano, Giovanni, Offermanns, Stefan, Nisoli, Enzo, Pagotto, Uberto, Cota, Daniela, and Lutz, Beat

Subjects
Obesity -- Health aspects, Macrophages -- Research, Homeostasis -- Research, Cannabinoids -- Research, Adipose tissue -- Research, Health care industry
Abstract

Dysregulated adipocyte physiology leads to imbalanced energy storage, obesity, and associated diseases, imposing a costly burden on current health care. Cannabinoid receptor type-1 (CB1) plays a crucial role in controlling energy metabolism through central and peripheral mechanisms. In this work, adipocyte-specific inducible deletion of the CB1 gene (Ati-CB1-KO) was sufficient to protect adult mice from diet-induced obesity and associated metabolic alterations and to reverse the phenotype in already obese mice. Compared with controls, Ati-CB1-KO mice showed decreased body weight, reduced total adiposity, improved insulin sensitivity, enhanced energy expenditure, and fat depot-specific cellular remodeling toward lowered energy storage capacity and browning of white adipocytes. These changes were associated with an increase in alternatively activated macrophages concomitant with enhanced sympathetic tone in adipose tissue. Remarkably, these alterations preceded the appearance of differences in body weight, highlighting the causal relation between the loss of CB1 and the triggering of metabolic reprogramming in adipose tissues. Finally, the lean phenotype of Ati-CB1-KO mice and the increase in alternatively activated macrophages in adipose tissue were also present at thermoneutral conditions. Our data provide compelling evidence for a crosstalk among adipocytes, immune cells, and the sympathetic nervous system (SNS), wherein CB1 plays a key regulatory role., Introduction In mammals, 2 different types of adipose tissues coexist; these exert specific functions in the context of energy balance regulation. White adipose tissue (WAT) is the main site for [...]

Published
2017
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18. Coordinated targeting of cold and nicotinic receptors synergistically improves obesity and type 2 diabetes

Author

Clemmensen, Christoffer, Jall, Sigrid, Kleinert, Maximilian, Quarta, Carmelo, Gruber, Tim, Reber, Josefine, Sachs, Stephan, Fischer, Katrin, Feuchtinger, Annette, Karlas, Angelos, Simonds, Stephanie E., Grandl, Gerald, Loher, Daniela, Sanchez-Quant, Eva, Keipert, Susanne, Jastroch, Martin, Hofmann, Susanna M., Nascimento, Emmani B. M., Schrauwen, Patrick, Ntziachristos, Vasilis, Cowley, Michael A., Finan, Brian, Müller, Timo D., and Tschöp, Matthias H.

Published
2018
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19. Publisher Correction: Coordinated targeting of cold and nicotinic receptors synergistically improves obesity and type 2 diabetes

Author

Clemmensen, Christoffer, Jall, Sigrid, Kleinert, Maximilian, Quarta, Carmelo, Gruber, Tim, Reber, Josefine, Sachs, Stephan, Fischer, Katrin, Feuchtinger, Annette, Karlas, Angelos, Simonds, Stephanie E., Grandl, Gerald, Loher, Daniela, Sanchez-Quant, Eva, Keipert, Susanne, Jastroch, Martin, Hofmann, Susanna M., Nascimento, Emmani B. M., Schrauwen, Patrick, Ntziachristos, Vasilis, Cowley, Michael A., Finan, Brian, Müller, Timo D., and Tschöp, Matthias H.

Published
2018
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23. Activation of the sympathetic nervous system mediates hypophagic and anxiety-like effects of CB₁ receptor blockade

Author

Bellocchio, Luigi, Soria-Gómez, Edgar, Quarta, Carmelo, Metna-Laurent, Mathilde, Cardinal, Pierre, Binder, Elke, Cannich, Astrid, Delamarre, Anna, Häring, Martin, Martín-Fontecha, Mar, Vega, David, Leste-Lasserre, Thierry, Bartsch, Dusan, Monory, Krisztina, Lutz, Beat, Chaouloff, Francis, Pagotto, Uberto, Guzman, Manuel, Cota, Daniela, and Marsicano, Giovanni

Published
2013

27. CB 1 Signaling in Forebrain and Sympathetic Neurons Is a Key Determinant of Endocannabinoid Actions on Energy Balance

Author

Quarta, Carmelo, Bellocchio, Luigi, Mancini, Giacomo, Mazza, Roberta, Cervino, Cristina, Braulke, Luzie J., Fekete, Csaba, Latorre, Rocco, Nanni, Cristina, Bucci, Marco, Clemens, Laura E., Heldmaier, Gerhard, Watanabe, Masahiko, Leste-Lassere, Thierry, Maitre, Marlène, Tedesco, Laura, Fanelli, Flaminia, Reuss, Stefan, Klaus, Susanne, Srivastava, Raj Kamal, Monory, Krisztina, Valerio, Alessandra, Grandis, Annamaria, De Giorgio, Roberto, Pasquali, Renato, Nisoli, Enzo, Cota, Daniela, Lutz, Beat, Marsicano, Giovanni, and Pagotto, Uberto

Published
2010
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28. Hypothalamic bile acid-TGR5 signaling protects from obesity

Author

Castellanos-Jankiewicz, Ashley, Guzmán-Quevedo, Omar, Fénelon, Valérie S., Zizzari, Philippe, Quarta, Carmelo, Bellocchio, Luigi, Tailleux, Anne, Charton, Julie, Fernandois, Daniela, Henricsson, Marcus, Piveteau, Catherine, Simon, Vincent, Allard, Camille, Quemener, Sandrine, Guinot, Valentine, Hennuyer, Nathalie, Perino, Alessia, Duveau, Alexia, Maitre, Marlène, Leste-Lasserre, Thierry, Clark, Samantha, Dupuy, Nathalie, Cannich, Astrid, Gonzales, Delphine, Deprez, Benoit, Mithieux, Gilles, Dombrowicz, David, Bäckhed, Fredrik, Prevot, Vincent, Marsicano, Giovanni, Staels, Bart, Schoonjans, Kristina, and Cota, Daniela

Published
2021
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29. GLP-1-mediated delivery of the PPAR𝛼/𝛾 dual-agonist Tesaglitazar improves obesity and glucose metabolism in mice

Author

Quarta, Carmelo, primary, Stemmer, Kerstin, additional, Novikoff, Aaron, additional, Yang, Bin, additional, Klingelhuber, Felix, additional, Harger, Alexandra, additional, Bakhti, Mostafa, additional, Bastidas-Ponce, Aimée, additional, Bauge, Eric, additional, Clemmensen, Christoffer, additional, Colldén, Gustav, additional, Cota, Perla, additional, Drucker, Daniel, additional, García-Cáceres, Cristina, additional, Grandl, Gerald, additional, Hennuyer, Nathalie, additional, Herzig, Stephan, additional, Hofmann, Susanna, additional, Kulaj, Konxhe, additional, Lalloyer, Fanny, additional, Lickert, Heiko, additional, Maity, Gandhari, additional, Perez-Tilve, Diego, additional, Sanchez-Garrido, Miguel A., additional, Zhang, Qian, additional, Staels, Bard, additional, Krahmer, Natalie, additional, DiMarchi, Richard, additional, Tschoep, Matthias, additional, Finan, Brian, additional, and Müller, Timo, additional

Published
2021
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33. GLP-1-mediated delivery of the PPAR\uD835\uDEFC/\uD835\uDEFE dual-agonist Tesaglitazar improves obesity and glucose metabolism in mice

Author

Quarta, Carmelo, Stemmer, Kerstin, Novikoff, Aaron, Yang, Bin, Klingelhuber, Felix, Harger, Alexandra, Bakhti, Mostafa, Bastidas-Ponce, Aimée, Bauge, Eric, Clemmensen, Christoffer, Colldén, Gustav, Cota, Perla, Drucker, Daniel, García-Cáceres, Cristina, Grandl, Gerald, Hennuyer, Nathalie, Herzig, Stephan, Hofmann, Susanna, Kulaj, Konxhe, Lalloyer, Fanny, Lickert, Heiko, Maity, Gandhari, Perez-Tilve, Diego, Sanchez-Garrido, Miguel A., Zhang, Qian, Staels, Bard, Krahmer, Natalie, DiMarchi, Richard, Tschoep, Matthias, Finan, Brian, Müller, Timo, Quarta, Carmelo, Stemmer, Kerstin, Novikoff, Aaron, Yang, Bin, Klingelhuber, Felix, Harger, Alexandra, Bakhti, Mostafa, Bastidas-Ponce, Aimée, Bauge, Eric, Clemmensen, Christoffer, Colldén, Gustav, Cota, Perla, Drucker, Daniel, García-Cáceres, Cristina, Grandl, Gerald, Hennuyer, Nathalie, Herzig, Stephan, Hofmann, Susanna, Kulaj, Konxhe, Lalloyer, Fanny, Lickert, Heiko, Maity, Gandhari, Perez-Tilve, Diego, Sanchez-Garrido, Miguel A., Zhang, Qian, Staels, Bard, Krahmer, Natalie, DiMarchi, Richard, Tschoep, Matthias, Finan, Brian, and Müller, Timo

Published
2021

34. Short Article Hypothalamic bile acid-TGR5 signaling protects from obesity

Author

Castellanos-Jankiewicz, Ashley, Guzman-Quevedo, Omar, Fenelon, Valerie S., Zizzari, Philippe, Quarta, Carmelo, Bellocchio, Luigi, Tailleux, Anne, Charton, Julie, Fernandois, Daniela, Henricsson, Marcus, Piveteau, Catherine, Simon, Vincent, Allard, Camille, Quemener, Sandrine, Guinot, Valentine, Hennuyer, Nathalie, Perino, Alessia, Duveau, Alexia, Maitre, Marlene, Leste-Lasserre, Thierry, Clark, Samantha, Dupuy, Nathalie, Cannich, Astrid, Gonzales, Delphine, Deprez, Benoit, Mithieux, Gilles, Dombrowicz, David, Backhed, Fredrik, Prevot, Vincent, Marsicano, Giovanni, Staels, Bart, Schoonjans, Kristina, Cota, Daniela, Castellanos-Jankiewicz, Ashley, Guzman-Quevedo, Omar, Fenelon, Valerie S., Zizzari, Philippe, Quarta, Carmelo, Bellocchio, Luigi, Tailleux, Anne, Charton, Julie, Fernandois, Daniela, Henricsson, Marcus, Piveteau, Catherine, Simon, Vincent, Allard, Camille, Quemener, Sandrine, Guinot, Valentine, Hennuyer, Nathalie, Perino, Alessia, Duveau, Alexia, Maitre, Marlene, Leste-Lasserre, Thierry, Clark, Samantha, Dupuy, Nathalie, Cannich, Astrid, Gonzales, Delphine, Deprez, Benoit, Mithieux, Gilles, Dombrowicz, David, Backhed, Fredrik, Prevot, Vincent, Marsicano, Giovanni, Staels, Bart, Schoonjans, Kristina, and Cota, Daniela

Abstract

Bile acids (BAs) improve metabolism and exert anti-obesity effects through the activation of the Takeda G protein-coupled receptor 5 (TGR5) in peripheral tissues. TGR5 is also found in the brain hypothalamus, but whether hypothalamic BA signaling is implicated in body weight control and obesity pathophysiology remains unknown. Here we show that hypothalamic BA content is reduced in diet-induced obese mice. Central administration of BAs or a specific TGR5 agonist in these animals decreases body weight and fat mass by activating the sympathetic nervous system, thereby promoting negative energy balance. Conversely, genetic downregulation of hypothalamic TGR5 expression in the mediobasal hypothalamus favors the development of obesity and worsens established obesity by blunting sympathetic activity. Lastly, hypothalamic TGR5 signaling is required for the anti-obesity action of dietary BA supplementation. Together, these findings identify hypothalamic TGR5 signaling as a key mediator of a top-down neural mechanism that counteracts diet induced obesity.

Published
2021

35. CB1 and GLP-1 Receptors Cross Talk Provides New Therapies for Obesity

Author

Zizzari, Philippe, He, Rongjun, Falk, Sarah, Bellocchio, Luigi, Allard, Camille, Clark, Samantha, Lesté-Lasserre, Thierry, Marsicano, Giovanni, Clemmensen, Christoffer, Perez-Tilve, Diego, Finan, Brian, Cota, Daniela, Quarta, Carmelo, Zizzari, Philippe, He, Rongjun, Falk, Sarah, Bellocchio, Luigi, Allard, Camille, Clark, Samantha, Lesté-Lasserre, Thierry, Marsicano, Giovanni, Clemmensen, Christoffer, Perez-Tilve, Diego, Finan, Brian, Cota, Daniela, and Quarta, Carmelo

Abstract

Glucagon-like peptide 1 receptor (GLP-1R) agonists effectively improve glycemia and body weight in patients with type 2 diabetes and obesity but have limited weight-lowering efficacy and minimal insulin sensitizing action. In preclinical models, peripherally restricted cannabinoid receptor type 1 (CB1R) inhibitors, which are devoid of the neuropsychiatric adverse effects observed with brain-penetrant CB1R blockers, ameliorate obesity and its multiple metabolic complications. Using mouse models with genetic loss of CB1R or GLP-1R, we demonstrate that these two metabolic receptors modulate food intake and body weight via reciprocal functional interactions. In diet-induced obese mice, the coadministration of a peripheral CB1R inhibitor with long-acting GLP-1R agonists achieves greater reduction in body weight and fat mass than monotherapies by promoting negative energy balance. This cotreatment also results in larger improvements in systemic and hepatic insulin action, systemic dyslipidemia, and reduction of hepatic steatosis. Thus, peripheral CB1R blockade may allow safely potentiating the antiobesity and antidiabetic effects of currently available GLP-1R agonists.

Published
2021

38. CB1 and GLP-1 Receptors Cross Talk Provides New Therapies for Obesity

Author

Zizzari, Philippe, primary, He, Rongjun, additional, Falk, Sarah, additional, Bellocchio, Luigi, additional, Allard, Camille, additional, Clark, Samantha, additional, Lesté-Lasserre, Thierry, additional, Marsicano, Giovanni, additional, Clemmensen, Christoffer, additional, Perez-Tilve, Diego, additional, Finan, Brian, additional, Cota, Daniela, additional, and Quarta, Carmelo, additional

Published
2020
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39. CB1 and GLP-1 receptors cross-talk provides new therapies for obesity

Author

Admin, Ada, primary, Zizzari, Philippe, primary, He, Rongjun, primary, Falk, Sarah, primary, Bellocchio, Luigi, primary, Allard, Camille, primary, Clark, Samantha, primary, Lesté-Lasserre, Thierry, primary, Marsicano, Giovanni, primary, Clemmensen, Christoffer, primary, Perez-Tilve, Diego, primary, Finan, Brian, primary, Cota, Daniela, primary, and Quarta, Carmelo, primary

Published
2020
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40. Peripheral cannabinoid–1 receptor blockade potentiates the anti–obesity and anti–diabetic effects of GLP–1 mimetics

Author

Zizzari, Philippe, primary, He, Rongjun, additional, Bellocchio, Luigi, additional, Allard, Camille, additional, Clark, Samantha, additional, Thierry, Leste–lasserre, additional, Marsicano, Giovanni, additional, Perez–Tilve, Diego, additional, Finan, Brian, additional, Cota, Daniela, additional, and Quarta, Carmelo, additional

Published
2020
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41. OR33-06 Potential Role of Mutations in TBX3 in Human Weight Regulation

Author

Xu, Yanjun, primary, De Rosa, Maria Caterina, primary, Quarta, Carmelo, primary, Fisette, Alexander, primary, Rausch, Richard, primary, Fleischman, Amy Debra, primary, Tschöp, Matthias H, primary, García-Cáceres, Cristina, primary, Hirschhorn, Joel N, primary, Doege, Claudia A, primary, and Thaker, Vidhu V, primary

Published
2020
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42. POMC neurons functional heterogeneity relies on mTORC1 signaling

Author

Saucisse, Nicolas, primary, Mazier, Wilfrid, additional, Simon, Vincent, additional, Binder, Elke, additional, Catania, Caterina, additional, Bellocchio, Luigi, additional, Romanov, Roman A., additional, Matias, Isabelle, additional, Zizzari, Philippe, additional, Leon, Stephane, additional, Quarta, Carmelo, additional, Cannich, Astrid, additional, Meece, Kana, additional, Gonzales, Delphine, additional, Clark, Samantha, additional, Becker, Julia M., additional, Yeo, Giles S.H., additional, Merkle, Florian T., additional, Wardlaw, Sharon L., additional, Harkany, Tibor, additional, Massa, Federico, additional, Marsicano, Giovanni, additional, and Cota, Daniela, additional

Published
2020
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44. Preclinical evaluation of KIT/PDGFRA and mTOR inhibitors in gastrointestinal stromal tumors using small animal FDG PET

Author

Fanti Stefano, Castellucci Paolo, Di Battista Monica, Nannini Margherita, Boschi Stefano, Quarta Carmelo, Gnocchi Chiara, Landuzzi Lorena, Nanni Cristina, Nicoletti Giordano, Pantaleo Maria, Lollini Pier, Bellan Elena, Castelli Mauro, Rubello Domenico, and Biasco Guido

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background Primary and secondary drug resistance to imatinib and sunitinib in patients with gastrointestinal stromal tumors (GISTs) has led to a pressing need for new therapeutic strategies such as drug combinations. Most GISTs are caused by mutations in the KIT receptor, leading to upregulated KIT tyrosine kinase activity. Imatinib and nilotinib directly inhibit the kinase activity of KIT, while RAD001 (everolimus) inhibits mTOR. We report a preclinical study on drug combinations in a xenograft model of GIST in which effects on tumor dimensions and metabolic activity were assessed by small animal PET imaging. Methods Rag2-/-; γcommon -/- male mice were injected s.c. into the right leg with GIST 882. The animals were randomized into 6 groups of 6 animals each for different treatment regimens: No therapy (control), imatinib (150 mg/kg b.i.d.) by oral gavage for 6 days, then once/day for another 7 days, everolimus (10 mg/kg/d.) by oral gavage, everolimus (10 mg/kg/d.) + imatinib (150 mg/kg b.i.d.) by oral gavage for 6 days, then once/day for another 7 days, nilotinib (75 mg/kg/d.) by oral gavage, nilotinib (75 mg/kg/d.) + imatinib (150 mg/kg b.i.d) by oral gavage for 6 days, then once/day for another 7 days. Tumor growth control was evaluated by measuring tumor volume (cm3). Small animal PET (GE Explore tomography) was used to evaluate tumor metabolism and performed in one animal per group at base-line then after 4 and 13 days of treatment. Results After a median latency time of 31 days, tumors grew in all animals (volume 0,06-0,15 cm3) and the treatments began at day 38 after cell injection. Tumor volume control (cm3) after 13 days of treatment was > 0.5 for imatinib alone and nilotinib alone, and < 0.5 for the 2 combinations of drugs and for everolimus alone. The baseline FDG uptake was positive in all animals. FDG/SUV/TBR was strongly reduced over time by everolimus both as a single agent and in combination with imatinib respectively: 3.1 vs. 2.3 vs. 1.9 and 2.5 vs 2.3 vs 0. Conclusions As single agents, all drugs showed an anti-tumor effect in GIST xenografts but everolimus was superior. The everolimus plus imatinib combination appeared to be the most active regimen both in terms of inhibiting tumor growth and tumor metabolism. The integration of everolimus in GIST treatment merits further investigation.

Published
2010
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45. Astrocytic Insulin Signaling Couples Brain Glucose Uptake with Nutrient Availability

Author

Helmholtz Association, Technical University of Munich, German Research Foundation, García-Cáceres, Cristina, Quarta, Carmelo, Varela, Luis, Gao, Yuanqing, Gruber, Tim, Legutko, Beata, Jastroch, Martin, Johansson, Pia, Ninkovic, J., Yi, Chun-Xia, Thuc, Ophelia Le, Szigeti-Buck, Klara, Cai, Weikang, Meyer, Carola W., Pfluger, Paul T., Fernández García, Ana María, Luquet, Serge, Woods, Stephen C., Torres Alemán, Ignacio, Kahn, C. Ronald, Götz, Magdalena, Horvath, Tamas L., Tschöp, Matthias, Helmholtz Association, Technical University of Munich, German Research Foundation, García-Cáceres, Cristina, Quarta, Carmelo, Varela, Luis, Gao, Yuanqing, Gruber, Tim, Legutko, Beata, Jastroch, Martin, Johansson, Pia, Ninkovic, J., Yi, Chun-Xia, Thuc, Ophelia Le, Szigeti-Buck, Klara, Cai, Weikang, Meyer, Carola W., Pfluger, Paul T., Fernández García, Ana María, Luquet, Serge, Woods, Stephen C., Torres Alemán, Ignacio, Kahn, C. Ronald, Götz, Magdalena, Horvath, Tamas L., and Tschöp, Matthias

Abstract

We report that astrocytic insulin signaling co-regulates hypothalamic glucose sensing and systemic glucose metabolism. Postnatal ablation of insulin receptors (IRs) in glial fibrillary acidic protein (GFAP)-expressing cells affects hypothalamic astrocyte morphology, mitochondrial function, and circuit connectivity. Accordingly, astrocytic IR ablation reduces glucose-induced activation of hypothalamic pro-opio-melanocortin (POMC) neurons and impairs physiological responses to changes in glucose availability. Hypothalamus-specific knockout of astrocytic IRs, as well as postnatal ablation by targeting glutamate aspartate transporter (GLAST)-expressing cells, replicates such alterations. A normal response to altering directly CNS glucose levels in mice lacking astrocytic IRs indicates a role in glucose transport across the blood-brain barrier (BBB). This was confirmed in vivo in GFAP-IR KO mice by using positron emission tomography and glucose monitoring in cerebral spinal fluid. We conclude that insulin signaling in hypothalamic astrocytes co-controls CNS glucose sensing and systemic glucose metabolism via regulation of glucose uptake across the BBB.

Published
2016

48. Hypothalamic leptin action is mediated by histone deacetylase 5

Author

Kabra, Dhiraj G., primary, Pfuhlmann, Katrin, additional, García-Cáceres, Cristina, additional, Schriever, Sonja C., additional, Casquero García, Veronica, additional, Kebede, Adam Fiseha, additional, Fuente-Martin, Esther, additional, Trivedi, Chitrang, additional, Heppner, Kristy, additional, Uhlenhaut, N. Henriette, additional, Legutko, Beata, additional, Kabra, Uma D., additional, Gao, Yuanqing, additional, Yi, Chun-Xia, additional, Quarta, Carmelo, additional, Clemmensen, Christoffer, additional, Finan, Brian, additional, Müller, Timo D., additional, Meyer, Carola W., additional, Paez-Pereda, Marcelo, additional, Stemmer, Kerstin, additional, Woods, Stephen C., additional, Perez-Tilve, Diego, additional, Schneider, Robert, additional, Olson, Eric N., additional, Tschöp, Matthias H., additional, and Pfluger, Paul T., additional

Published
2016
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49. Lack of Hypophagia in CB1 Null Mice is Associated to Decreased Hypothalamic POMC and CART Expression

Author

Universidade de Santiago de Compostela. Centro de Investigación en Medicina Molecular e Enfermidades Crónicas, Universidade de Santiago de Compostela. Departamento de Fisioloxía, Lage Fernández, Ricardo, Parisi, Claudia, Seoane Collazo, Patricia, Fernø, Johan, Mazza, Roberta, Bosch, Fátima, Seoane, Luisa M., Diéguez González, Carlos, Quarta, Carmelo, López Pérez, Miguel Antonio, Universidade de Santiago de Compostela. Centro de Investigación en Medicina Molecular e Enfermidades Crónicas, Universidade de Santiago de Compostela. Departamento de Fisioloxía, Lage Fernández, Ricardo, Parisi, Claudia, Seoane Collazo, Patricia, Fernø, Johan, Mazza, Roberta, Bosch, Fátima, Seoane, Luisa M., Diéguez González, Carlos, Quarta, Carmelo, and López Pérez, Miguel Antonio

Abstract

Background: Cumulative data indicate that the endocannabinoid system plays a major role in feeding behavior and energy balance. Genetic silencing of cannabinoid receptor type 1 (CB1) reduces body weight gain, independently of food intake. Methods: In this work, we investigated whether the hypothalamic neuropeptide expression pattern supports the absence of the anorexigenic response observed under constitutive CB1 ablation, by using neuronal CB1 conditional null mice (CamK-CB1-KO) and whole body CB1 null mice (CB1-KO). Results: Our data showed that both CB1 null models display a marked decrease in proopiomelanocortin (POMC) and cocaine-amphetamine-regulated transcript (CART) expression in the arcuate nucleus of the hypothalamus (ARC). Conclusions: This evidence suggests that a lack of hypophagia is associated with the suppression of ARC anorexigenic neuropeptides and that behavioral changes in food intake (or lack thereof) after constitutive CB1 ablation are likely mediated by impaired melanocortin and CART signaling in the hypothalamus.

Published
2015

50. Cardiovascular and sleep alterations in mice lacking the cannabinoid receptor 1

Author

BASTIANINI, STEFANO, BERTEOTTI, CHIARA, LO MARTIRE, VIVIANA CARMEN, MAZZA, ROBERTA, PAGOTTO, UBERTO, QUARTA, CARMELO, SILVANI, ALESSANDRO, ZOCCOLI, GIOVANNA, Bastianini S, Berteotti C, Lo Martire V, Mazza R, Pagotto U, Quarta C, Silvani A, and Zoccoli G

Subjects
MICE, ENDOCANNABINOID, HEART RATE, blood pressure control, SLEEP
Published
2012

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