Loss of hypothalamic MCH decreases food intake in amyotrophic lateral sclerosis

被引:11
|
作者
Bolborea, Matei [1 ,2 ]
Vercruysse, Pauline [1 ]
Daria, Tselmen [3 ]
Reiners, Johanna C. [3 ,4 ]
Alami, Najwa Ouali [3 ]
Guillot, Simon J. [1 ]
Dieterle, Stephane [1 ]
Sinniger, Jerome [1 ]
Scekic-Zahirovic, Jelena [5 ,6 ]
Londo, Amela [5 ,6 ]
Arcay, Hippolyte [1 ]
Goy, Marc-Antoine [1 ]
de Tapia, Claudia Nelson [1 ]
Thal, Dietmar R. [6 ,7 ,8 ,9 ]
Shibuya, Kazumoto [10 ]
Otani, Ryo [10 ]
Arai, Kimihito [10 ]
Kuwabara, Satoshi [10 ]
Ludolph, Albert C. [5 ,11 ]
Roselli, Francesco [5 ,11 ]
Yilmazer-Hanke, Deniz [3 ]
Dupuis, Luc [1 ]
机构
[1] Univ Strasbourg, INSERM, Mecanismes centraux & peripher neurodegenerescenc, UMR S1118, S1118, Strasbourg, France
[2] Univ Warwick, Sch Life Sci, Gibbet Hill Rd, Coventry CV4 7AL, Warwickshire, England
[3] Ulm Univ, Dept Neurol, Clin Neuroanat Sect, Ulm, Germany
[4] Ulm Univ, Inst Neurobiochemistry, Ulm, Germany
[5] Ulm Univ, Dept Neurol, Neurol Clin, Ulm, Germany
[6] Ulm Univ, Inst Pathol, Lab Neuropathol, Ulm, Germany
[7] KU louvain, Dept Imaging & Pathol, Lab Neuropathol, Louvain, Belgium
[8] KU louvain, Leuven Brain Inst, Louvain, Belgium
[9] UZ Leuven, Dept Pathol, Louvain, Japan
[10] Chiba Univ, Dept Neurol, Sch Med, Chiba, Japan
[11] Deutsch Zentrum Neurodegenerat Erkrankungen DZNE, Ulm, Germany
关键词
MELANIN-CONCENTRATING HORMONE; BODY-MASS INDEX; SUPEROXIDE-DISMUTASE SOD1; MOUSE MODEL; MICE; PATHOLOGY; SURVIVAL; BRAIN; RISK; OVEREXPRESSION;
D O I
10.1007/s00401-023-02569-x
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
Amyotrophic lateral sclerosis (ALS) is associated with impaired energy metabolism, including weight loss and decreased appetite which are negatively correlated with survival. Neural mechanisms underlying metabolic impairment in ALS remain unknown. ALS patients and presymptomatic gene carriers have early hypothalamic atrophy. The lateral hypothalamic area (LHA) controls metabolic homeostasis through the secretion of neuropeptides such as orexin/hypocretin and melanin-concentrating hormone (MCH). Here, we show loss of MCH-positive neurons in three mouse models of ALS based on SOD1 or FUS mutations. Supplementation with MCH (1.2 mu g/d) through continuous intracerebroventricular delivery led to weight gain in male mutant Sod1(G86R) mice. MCH supplementation increased food intake, rescued expression of the key appetite-related neuropeptide AgRP (agouti-related protein) and modified respiratory exchange ratio, suggesting increased carbohydrate usage during the inactive phase. Importantly, we document pTDP-43 pathology and neurodegeneration in the LHA of sporadic ALS patients. Neuronal cell loss was associated with pTDP-43-positive inclusions and signs of neurodegeneration in MCH-positive neurons. These results suggest that hypothalamic MCH is lost in ALS and contributes to the metabolic changes, including weight loss and decreased appetite.
引用
收藏
页码:773 / 791
页数:19
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