Journal Article

DZNE-2023-00534

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Loss of hypothalamic MCH decreases food intake in amyotrophic lateral sclerosis.

Bolborea, M. ; Vercruysse, P. ; Daria, T. ; Reiners, J. C. ; Alami, N. O. ; Guillot, S. J. ; Dieterlé, S. ; Sinniger, J. ; Scekic-Zahirovic, J.Extern* ; Londo, A. ; Arcay, H. ; Goy, M.-A. ; de Tapia, C. N. ; Thal, D. R. ; Shibuya, K. ; Otani, R. ; Arai, K. ; Kuwabara, S. ; Ludolph, A. C.DZNE* ; Roselli, F.DZNE* ; Yilmazer-Hanke, D. ; Dupuis, L.

2023
Springer Heidelberg

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Please use a persistent id in citations: doi:10.1007/s00401-023-02569-x

Abstract: 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 µg/d) through continuous intracerebroventricular delivery led to weight gain in male mutant Sod1G86R 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.

Keyword(s): Male (MeSH) ; Mice (MeSH) ; Animals (MeSH) ; Amyotrophic Lateral Sclerosis (MeSH) ; Superoxide Dismutase-1 (MeSH) ; Neuropeptides: metabolism (MeSH) ; Orexins (MeSH) ; Eating (MeSH) ; Weight Loss (MeSH) ; melanin-concentrating hormone ; Superoxide Dismutase-1 ; Neuropeptides ; Orexins

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Contributing Institute(s):

1. Clinical Study Center Ulm (Clinical Study Center ; Clinical Study Center Ulm)
2. Metabolic Changes (AG Roselli)

Research Program(s):

1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)
2. 352 - Disease Mechanisms (POF4-352) (POF4-352)

Appears in the scientific report 2023

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Database coverage:
; ; ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; DEAL Springer ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 10 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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