Increased peripheral lipid clearance in an animal model of amyotrophic lateral sclerosis

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.-Fergani, A

“Preconditioning” with latrepirdine, an adenosine 5′-monophosphate-activated protein kinase activator, delays amyotrophic lateral sclerosis progression in SOD1G93A mice

“…This is in accordance with a previously published study that documented increased AMPK activation at PND 90 in these mice (Lim et al 2012, Perera et al 2014. These data may mechanistically link AMPK activation with previously published bioenergetic abnormalities described in this mouse model (Dodge et al 2013, Kim et al 2011a, Fergani et al 2007, Dupuis et al 2004.…”

“…Late-stage SOD1 G93A mice also display decreased glucose uptake into skeletal muscle (Smittkamp et al 2014). Furthermore, SOD1 G93A and SOD1 G86R mice show a decrease in body weight and fat mass during disease progression, reduced levels of circulating triglycerides, and evidence of increased lipolysis (Dodge et al 2013, Kim et al 2011a, Fergani et al 2007, Dupuis et al 2004. ALS patients also exhibit higher resting levels of energy expenditure, weight loss, a hypermetabolic phenotype and increased lipolysis (Kasarskis et al 1996, Desport et al 2005, Dupuis et al 2008, Bouteloup et al 2009, Funalot et al 2009, Dodge et al 2013.…”

Mitochondrial Dysfunction and Decrease in Body Weight of a Transgenic Knock-in Mouse Model for TDP-43

“…7C). In the intestine, triglycerides are broken down into NEFA, this being the molecular species absorbed by enterocytes (52). Ad libitum fed females showed increased NEFA concentrations in mutants (Fig.…”

Reduced Activity of AMP-Activated Protein Kinase Protects against Genetic Models of Motor Neuron Disease

“…In nematodes, hermaphrodite reproduction is a complex process that involves the mobilization of lipids to generate, fertilize, and maintain oocytes and developing embryos (Kubagawa et al, 2006;Han et al, 2010). Interestingly, female G93A mSOD1 mice exhibit both bioenergetic abnormalities (Dupuis et al, 2004;Fergani et al, 2007), as well as decreased fertility (Jackson Laboratory) (Lim and Kalb, unpublished observations). In light of this, we wondered whether mSOD1 worms displayed reproductive abnormalities and, if so, whether ablation of aak-2 modified this phenotype.…”

“…Hypermetabolism in ALS patients cannot be ascribed to changes in forced vital capacity, muscle fasciculations, fever, hyperthyroidism, or infection (Desport et al, 2001). Similarly, transgenic mouse models overexpressing mutant copper zinc superoxide dismutase 1 (mSOD1) (G86R and G93A mice) show increased energy expenditure by indirect calorimetry, increased lipid and glucose clearance in skeletal muscle, and hypolipidemia (Dupuis et al, 2004;Fergani et al, 2007;Kim et al, 2011) (Lim and Kalb, unpublished observations). Metabolic defects have also been reported previously in another potential model of motor neuron disease.…”