Genetically altering organismal metabolism by leptin-deficiency benefits a mouse model of amyotrophic lateral sclerosis.
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.
Division of Neurology, Department of Pediatrics, Research Institute, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA, Neuroscience Graduate Group.
Maria A
MA
Lim
Neuroscience Graduate Group, Department of Animal Biology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Kendra K
KK
Bence
Division of Neurology, Department of Pediatrics, Research Institute, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Ishani
I
Sandesara
Laboratory for Integrative and Systems Physiology, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland.
Pénélope
P
Andreux
Laboratory for Integrative and Systems Physiology, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland.
Johan
J
Auwerx
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.
Jeff
J
Ishibashi
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.
Patrick
P
Seale
Division of Neurology, Department of Pediatrics, Research Institute, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA, Neuroscience Graduate Group, Department of Neurology and kalb@email.chop.edu.
Robert G
RG
Kalb
D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000473:pathology*; D000818:Animals; D001835:Body Weight; D004195:Disease Models, Animal; D004734:Energy Metabolism; D006801:Humans; D020738:Leptin / Q000172:deficiency*; D008297:Male; D051379:Mice; D009046:Motor Neurons / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics* / Q000378:metabolism*; D000072105:Superoxide Dismutase-1
D020738:Leptin; C000606290:SOD1 protein, human; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1