A51 Genetically altering metabolism by leptin-deficiency affects peripheral disease features in the R6/2 mouse model of huntington´s disease

Abstract

Background Accumulating evidence suggests altered energy metabolism, with a hyper-catabolic state, as a key feature of Huntington´s disease pathology. Interestingly, it has been suggested that a higher BMI can postpone onset and slow down the progression rate in human HD. The R6/2 mouse model of HD mirrors human HD and in addition to central pathological changes, the mice exhibit progressive weight loss, skeletal muscle atrophy, altered glucose metabolism and body composition, as well as increased oxygen consumption. Ob/Ob mice are leptin deficient; they eat more and have a slower energy metabolism leading to increased body weight and fat mass. An amyotrophic lateral sclerosis (ALS) mouse model on a leptin deficient background has been shown to have normalized energy expenditure, improved motor function, decreased motor neuronal loss as well as enhanced survival, suggesting a slower rate of the disease progression. Aim In this study, we therefore aim to investigate whether a higher BMI and a slower energy metabolism, can affect HD disease progression in the R6/2 mouse model. Methods We generated a novel mouse model, R6/2;Ob/Ob, and evaluated body weight and composition, as well as the effects in central and peripheral target tissues using real-time PCR, histological and stereological analysis. Results Crossing the R6/2 mouse with Ob/Ob mice (R6/2;Ob/Ob mice) results in a dramatic body weight increase compared to R6/2 mice (of both male and female mice). Energy metabolism features, as well as central and peripheral pathology, is currently evaluated. Conclusion Our findings suggest that it is possible to affect energy metabolism features and body weight in R6/2 mice.