Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease for which there is no cure. Evidence of decreased glucose metabolism, hypermetabolism, malnutrition, and declining body mass index suggests that there may be increased use of fat as an energy substrate to supply increasing energy needs in ALS. Using human subjects and animal models, we assessed glucose and fatty acid metabolism in ALS.

A skeletal muscle biopsy from a patient presenting with symptoms at the Royal Brisbane and Women’s Hospital ALS clinic showed glycogen accumulation but no difference in lipid deposition. We also observed a decrease in the expression of genes that regulate glucose metabolism (in the absence of any change in fat content) in the hindlimb muscle of ALS mice first presenting with symptoms. As disease progressed, decreased fat mass occurred alongside an increase in the expression of genes encoding proteins and enzymes involved in the catabolism and mobilisation of fatty acids in white fat of ALS mice. By the late stage of disease, ALS mice had an increase in circulating ketones, and ex vivo explants of white fat had increased basal release of fatty acids. Our data suggests that to compensate for early and persistent defects in glucose metabolism, fat is released from (or not deposited into) storage at late stages of disease, and is used as an energy substrate. We are now assessing the neuroendocrine mechanisms that underpin these changes in energy use.