title: Alterations in the hypothalamic melanocortin pathway in amyotrophic lateral sclerosis.
abstract: 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.
authors.affiliation: Inserm U1118, Mécanismes centraux et périphétiques de la neurodégénérescence, Strasbourg, F-67085 France Université de Strasbourg, Faculté de Médecine, UMRS1118, Strasbourg, F-67085 France Department of Neurology, University of Ulm, Germany.
authors.forename: Pauline
authors.initials: P
authors.lastname: Vercruysse
authors.affiliation: Inserm U1118, Mécanismes centraux et périphétiques de la neurodégénérescence, Strasbourg, F-67085 France Université de Strasbourg, Faculté de Médecine, UMRS1118, Strasbourg, F-67085 France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Sinniger
authors.affiliation: Inserm U1118, Mécanismes centraux et périphétiques de la neurodégénérescence, Strasbourg, F-67085 France Université de Strasbourg, Faculté de Médecine, UMRS1118, Strasbourg, F-67085 France.
authors.forename: Hajer
authors.initials: H
authors.lastname: El Oussini
authors.affiliation: Inserm U1118, Mécanismes centraux et périphétiques de la neurodégénérescence, Strasbourg, F-67085 France Université de Strasbourg, Faculté de Médecine, UMRS1118, Strasbourg, F-67085 France.
authors.forename: Jelena
authors.initials: J
authors.lastname: Scekic-Zahirovic
authors.affiliation: Inserm U1118, Mécanismes centraux et périphétiques de la neurodégénérescence, Strasbourg, F-67085 France Université de Strasbourg, Faculté de Médecine, UMRS1118, Strasbourg, F-67085 France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Dieterlé
authors.affiliation: Department of Neurology, Hannover Medical School, Hannover, Germany.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Dengler
authors.affiliation: Department of Neurology, Charité University Hospital, Berlin, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Meyer
authors.affiliation: Department of Neurology, University of Halle-Wittenberg, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Zierz
authors.affiliation: Department of Neurology, University of Ulm, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Kassubek
authors.affiliation: Department of Neurology, University of Ulm, Germany.
authors.forename: Wilhelm
authors.initials: W
authors.lastname: Fischer
authors.affiliation: Institute of Epidemiology and Medical Biometry, University of Ulm, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Dreyhaupt
authors.affiliation: Department of Neurology, BG University Hospital Bergmannsheil, Bochum, Germany.
authors.forename: Torsten
authors.initials: T
authors.lastname: Grehl
authors.affiliation: Department of Neurology, Technische Universität Dresden, and German Center for Neurodegenerative Disease (DZNE), Dresden, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Hermann
authors.affiliation: Department of Neurology, University Hospital, Jena, Germany.
authors.forename: Julian
authors.initials: J
authors.lastname: Grosskreutz
authors.affiliation: Department of Neurology, University of Ulm, Germany.
authors.forename: Anke
authors.initials: A
authors.lastname: Witting
authors.affiliation: Laboratory of Neurobiology, KU Leuven and Vesalius Research Center, VIB, Leuven, Belgium.
authors.forename: Ludo
authors.initials: L
authors.lastname: Van Den Bosch
authors.affiliation: Faculté de Médecine Paris-Ile de France-Ouest, France Université de Versailles Saint-Quentin-en-Yvelines, France Centre Hospitalier Versailles, Le Chesnay, France.
authors.forename: Odile
authors.initials: O
authors.lastname: Spreux-Varoquaux
authors.affiliation: Department of Neurology, University of Ulm, Germany ldupuis@unistra.fr albert-c.ludolph@uni-ulm.de.
authors.forename: Albert C
authors.initials: AC
authors.lastname: Ludolph
authors.affiliation: Inserm U1118, Mécanismes centraux et périphétiques de la neurodégénérescence, Strasbourg, F-67085 France Université de Strasbourg, Faculté de Médecine, UMRS1118, Strasbourg, F-67085 France ldupuis@unistra.fr albert-c.ludolph@uni-ulm.de.
authors.forename: Luc
authors.initials: L
authors.lastname: Dupuis
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D005260:Female; D006801:Humans; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D000077205:Pioglitazone; D011333:Pro-Opiomelanocortin / Q000235:genetics / Q000378:metabolism*; D019782:Riluzole / Q000494:pharmacology / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D000072105:Superoxide Dismutase-1; D045162:Thiazolidinediones / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: C000606290:SOD1 protein, human; D045162:Thiazolidinediones; D011333:Pro-Opiomelanocortin; D019782:Riluzole; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D000077205:Pioglitazone
keywords: amyotrophic lateral sclerosis; calorie intake; hypothalamus; thiazolinediones; weight loss