Alterations in the hypothalamic melanocortin pathway in amyotrophic lateral sclerosis
| Autor: | Vercruysse, Pauline, Sinniger, Jérôme, Dreyhaupt, Jens, Grehl, Torsten, Hermann, Andreas, Grosskreutz, Julian, Witting, Anke, Van Den Bosch, Ludo, Spreux-Varoquaux, Odile, Group, GERP ALS Study, Ludolph, Albert C, Dupuis, Luc, El Oussini, Hajer, Borisow, Nadja, Holm, Theresa, Maier, Andre, Meyer, Thomas, Budde, Paula, Gruhn, Kai, Bewersdorff, Malte, Heneka, Michael, Storch, Alexander, Scekic-Zahirovic, Jelena, Frank, Tobias, Göricke, Bettina, Weishaupt, Jochen, Eger, Katharina, Hanisch, Frank, Zierz, Stephan, Boeck, Anna-Lena, Dengler, Reinhard, Koerner, Sonja, Kollewe, Katja, Dieterlé, Stéphane, Petri, Susanne, Prell, Tino, Ringer, Thomas, Zinke, Jan, Anneser, Johanna, Borasio, Gian Domenico, Chahli, Christine, Winkler, Andrea S, Boentert, Matthias, Stubbe-Draeger, Bianca, Young, Peter, Bogdahn, Ulrich, Franz, Steffen, Haringer, Verena, Weidner, Norbert, Benecke, Reiner, Meister, Stefanie, Prudlo, Johannes, Wittstock, Matthias, Dorst, Johannes, Hendrich, Corinna, Sperfeld, Anne-Dorte, Weiland, Ulrike, Neidhardt, Sabine, Schrank, Berthold, Beck, Marcus, Kraft, Peter, Toyka, Klaus, Ulzheimer, Jochen, Wessig, Carsten, Kassubek, Jan, Fischer, Wilhelm |
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| Přispěvatelé: | Mécanismes Centraux et Périphériques de la Neurodégénérescence, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hannover Medical School [Hannover] (MHH), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Martin-Luther-University Halle-Wittenberg, University of Ulm (UUlm), Ruhr-Universität Bochum [Bochum], Technische Universität Dresden = Dresden University of Technology (TU Dresden), German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Jena University Hospital [Jena], Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), GERP ALS Study Group: Nadja Borisow, Theresa Holm, Andre Maier, Thomas Meyer, Paula Budde, Torsten Grehl, Kai Gruhn, Malte Bewersdorff, Michael Heneka, Andreas Hermann, Alexander Storch, Tobias Frank, Bettina Göricke, Jochen Weishaupt, Katharina Eger, Frank Hanisch, Stephan Zierz, Anna-Lena Boeck, Reinhard Dengler, Sonja Koerner, Katja Kollewe, Susanne Petri, Julian Grosskreutz, Tino Prell, Thomas Ringer, Jan Zinke, Johanna Anneser, Gian Domenico Borasio, Christine Chahli, Andrea S Winkler, Matthias Boentert, Bianca Stubbe-Draeger, Peter Young, Ulrich Bogdahn, Steffen Franz, Verena Haringer, Norbert Weidner, Reiner Benecke, Stefanie Meister, Johannes Prudlo, Matthias Wittstock, Johannes Dorst, Corinna Hendrich, Albert C Ludolph, Anne-Dorte Sperfeld, Ulrike Weiland, Sabine Neidhardt, Berthold Schrank, Marcus Beck, Peter Kraft, Klaus Toyka, Jochen Ulzheimer, Carsten Wessig., Dieterle, Stéphane |
| Rok vydání: | 2015 |
| Předmět: |
MESH: Signal Transduction
0301 basic medicine Male Pro-Opiomelanocortin calorie intake [SDV]Life Sciences [q-bio] MESH: Thiazolidinediones MESH: Synapses MESH: Spatial Memory [SCCO]Cognitive science Mice MESH: Riluzole 0302 clinical medicine Superoxide Dismutase-1 MESH: Transcription Factor RelA Sod1 protein mouse thiazolinediones genetics [Superoxide Dismutase] MESH: Pro-Opiomelanocortin MESH: Animals Amyotrophic lateral sclerosis MESH: Superoxide Dismutase therapeutic use [Riluzole] MESH: Superoxide Dismutase-1 2. Zero hunger Riluzole Leptin digestive oral and skin physiology SOD1 protein human metabolism [Hypothalamus] 3. Good health [SDV] Life Sciences [q-bio] genetics [Amyotrophic Lateral Sclerosis] Female Melanocortin hormones hormone substitutes and hormone antagonists medicine.drug Signal Transduction medicine.medical_specialty drug effects [Signal Transduction] MESH: Mice Transgenic MESH: Pioglitazone metabolism [Superoxide Dismutase] SOD1 Hypothalamus Mice Transgenic drug effects [Hypothalamus] pharmacology [Thiazolidinediones] Biology TARDBP pathology [Hypothalamus] 03 medical and health sciences Proopiomelanocortin MESH: Mice Inbred C57BL MESH: Rats Long-Evans Internal medicine physiology [Signal Transduction] medicine metabolism [Pro-Opiomelanocortin] Animals Humans ddc:610 weight loss MESH: Mice MESH: Humans therapeutic use [Thiazolidinediones] drug therapy [Amyotrophic Lateral Sclerosis] Pioglitazone genetics [Pro-Opiomelanocortin] Superoxide Dismutase metabolism [Amyotrophic Lateral Sclerosis] Amyotrophic Lateral Sclerosis pharmacology [Riluzole] [SCCO] Cognitive science medicine.disease MESH: Hypothalamus MESH: Male Mice Inbred C57BL 030104 developmental biology Endocrinology biology.protein Thiazolidinediones Neurology (clinical) MESH: Female 030217 neurology & neurosurgery |
| Zdroj: | Brain 139(4), 1106-1122 (2016). doi:10.1093/brain/aww004 Brain-A Journal of Neurology Brain-A Journal of Neurology, Oxford University Press (OUP), 2016, 139 (4), pp.1106-1122. ⟨10.1093/brain/aww004⟩ Brain-A Journal of Neurology, 2016, 139 (4), pp.1106-1122. ⟨10.1093/brain/aww004⟩ |
| ISSN: | 1460-2156 0006-8950 |
| DOI: | 10.1093/brain/aww004 |
| Popis: | International audience; Amyotrophic lateral sclerosis, the most common adult-onset motor neuron disease, leads to death within 3 to 5 years after onset. Beyond progressive motor impairment, patients with amyotrophic lateral sclerosis suffer from major defects in energy metabolism, such as weight loss, which are well correlated with survival. Indeed, nutritional intervention targeting weight loss might improve survival of patients. However, the neural mechanisms underlying metabolic impairment in patients with amyotrophic lateral sclerosis remain elusive, in particular due to the lack of longitudinal studies. Here we took advantage of samples collected during the clinical trial of pioglitazone (GERP-ALS), and characterized longitudinally energy metabolism of patients with amyotrophic lateral sclerosis in response to pioglitazone, a drug with well-characterized metabolic effects. As expected, pioglitazone decreased glycaemia, decreased liver enzymes and increased circulating adiponectin in patients with amyotrophic lateral sclerosis, showing its efficacy in the periphery. However, pioglitazone did not increase body weight of patients with amyotrophic lateral sclerosis independently of bulbar involvement. As pioglitazone increases body weight through a direct inhibition of the hypothalamic melanocortin system, we studied hypothalamic neurons producing proopiomelanocortin (POMC) and the endogenous melanocortin inhibitor agouti-related peptide (AGRP), in mice expressing amyotrophic lateral sclerosis-linked mutant SOD1(G86R). We observed lower Pomc but higher Agrp mRNA levels in the hypothalamus of presymptomatic SOD1(G86R) mice. Consistently, numbers of POMC-positive neurons were decreased, whereas AGRP fibre density was elevated in the hypothalamic arcuate nucleus of SOD1(G86R) mice. Consistent with a defect in the hypothalamic melanocortin system, food intake after short term fasting was increased in SOD1(G86R) mice. Importantly, these findings were replicated in two other amyotrophic lateral sclerosis mouse models based on TDP-43 (Tardbp) and FUS mutations. Finally, we demonstrate that the melanocortin defect is primarily caused by serotonin loss in mutant SOD1(G86R) mice. Altogether, the current study combined clinical evidence and experimental studies in rodents to provide a mechanistic explanation for abnormalities in food intake and weight control observed in patients with amyotrophic lateral sclerosis. Importantly, these results also show that amyotrophic lateral sclerosis progression impairs responsiveness to classical drugs leading to weight gain. This has important implications for pharmacological management of weight loss in amyotrophic lateral sclerosis. |
| Databáze: | OpenAIRE |
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