Abstract
Amyotrophic lateral sclerosis (ALS) is the most common adult motor neuron disease, causing motor neuron degeneration, muscle atrophy, paralysis, and death. Despite this degenerative process, a stable hypermetabolic state has been observed in a large subset of patients. Mice expressing a mutant form of Cu/Zn-superoxide dismutase (mSOD1 mice) constitute an animal model of ALS that, like patients, exhibits unexpectedly increased energy expenditure. Counterbalancing for this increase with a high-fat diet extends lifespan and prevents motor neuron loss. Here, we investigated whether lipid metabolism is defective in this animal model. Hepatic lipid metabolism was roughly normal, whereas gastrointestinal absorption of lipids as well as peripheral clearance of triglyceride-rich lipoproteins were markedly increased, leading to decreased postprandial lipidemia. This defect was corrected by the high-fat regimen that typically induces neuroprotection in these animals. Together, our findings show that energy metabolism in mSOD1 mice shifts toward an increase in the peripheral use of lipids. This metabolic shift probably accounts for the protective effect of dietary lipids in this model.
Highlights
Amyotrophic lateral sclerosis (ALS) is the most common adult motor neuron disease, causing motor neuron degeneration, muscle atrophy, paralysis, and death
This metabolic shift probably accounts for the protective effect of dietary lipids in this model
To assess whether this defect could be corrected by a highfat diet, we fed a group of mice 20% butter fat during 4 weeks and evaluated their lipid metabolism
Summary
Amyotrophic lateral sclerosis (ALS) is the most common adult motor neuron disease, causing motor neuron degeneration, muscle atrophy, paralysis, and death. Mice expressing a mutant form of Cu/Zn-superoxide dismutase (mSOD1 mice) constitute an animal model of ALS that, like patients, exhibits unexpectedly increased energy expenditure Counterbalancing for this increase with a high-fat diet extends lifespan and prevents motor neuron loss. Animal models of ALS displaying the major features of the human disease are transgenic mice overexpressing mutant forms of Cu/ Zn-superoxide dismutase (SOD1) [10,11,12], a free radicalscavenging enzyme that protects cells against oxidative stress and is mutated in a subset of patients with autosomal dominantly inherited ALS [13] Studies using these mice have postulated that mutant superoxide dismutase (mSOD1) triggers ALS by a non-cell-autonomous mechanism involving motor neurons themselves and other cells such as astrocytes and microglia [14, 15]. We recently observed systemic abnormalities occurring in animal models of ALS [6, 16]. mSOD1 mice are leaner than wild-type littermates, and their fat pads gradually deplete as a result of a prominent hypermetabolic trait mainly of muscular origin [6]
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