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Genetically altering organismal metabolism by leptin-deficiency benefits a mouse model of amyotrophic lateral sclerosis

Lim, Maria A. ; Bence, Kendra K. ; Sandesara, Ishani ; Andreux, Pénélope ; Auwerx, Johan ; Ishibashi, Jeff ; Seale, Patrick ; Kalb, Robert G.

In: Human Molecular Genetics, 2014, vol. 23, no. 18, p. 4995-5008

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    Titre
    • Genetically altering organismal metabolism by leptin-deficiency benefits a mouse model of amyotrophic lateral sclerosis
    Auteur
    • Lim, Maria A.. Division of Neurology, Department of Pediatrics, Research Institute, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
    • Bence, Kendra K.. Neuroscience Graduate Group
    • Sandesara, Ishani. Division of Neurology, Department of Pediatrics, Research Institute, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
    • Andreux, Pénélope. Laboratory for Integrative and Systems Physiology, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland
    • Auwerx, Johan. Laboratory for Integrative and Systems Physiology, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland
    • Ishibashi, Jeff. Institute for Diabetes, Obesity and Metabolism, Department of Cell and Developmental Biology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
    • Seale, Patrick. Institute for Diabetes, Obesity and Metabolism, Department of Cell and Developmental Biology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
    • Kalb, Robert G.. Division of Neurology, Department of Pediatrics, Research Institute, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
    Type de document
    • Postprint
    Langue
    • Anglais
    Publié dans
    • Human Molecular Genetics, 2014, vol. 23, no. 18, p. 4995-5008. Oxford University Press
    Autre version électronique
    Classification
    • Santé
    Identifiant OAI-PMH
    • oai:doc.rero.ch:302028
    Summary
    Amyotrophic lateral sclerosis (ALS) is a fatal, neurodegenerative disease that causes death of motor neurons. ALS patients and mouse models of familial ALS display organismal level metabolic dysfunction, which includes increased energy expenditure despite decreased lean mass. The pathophysiological relevance of abnormal energy homeostasis to motor neuron disease remains unclear. Leptin is an adipocyte-derived hormone that regulates whole-animal energy expenditure. Here, we report that placing mutant superoxide dismutase 1 (SOD1) mice in a leptin-deficient background improves energy homeostasis and slows disease progression. Leptin-deficient mutant SOD1 mice possess increased bodyweight and fat mass, as well as decreased energy expenditure. These observations coincide with enhanced survival, improved strength and decreased motor neuron loss. These results suggest that altering whole-body energy metabolism in mutant SOD1 mice can mitigate disease progression. We propose that manipulations that increase fat mass and reduce energy expenditure will be beneficial in the setting of motor neuron disease