A15 Hypothalamic expression of huntingtin causes distinct metabolic changes in the R6/2 and bachd mouse models of huntington’s disease

Background Underlying mechanisms of metabolic changes in Huntington’s disease are not fully known, but studies suggest involvement of hypothalamic dysfunction. In clinical HD, a higher body mass index has been associated with slower disease progression, indicating that metabolic changes may be involved in disease pathogenesis. Aim The aim was to investigate whether increased levels of hypothalamic huntingtin would affect metabolic phenotype and disease features in R6/2 and BACHD mouse models that respectively develop lean- and obese phenotypes. Methods We used adeno-associated viral vectors to overexpress either mutant or wild-type huntingtin in the hypothalamus of R6/2, BACHD and their wild-type littermates. Continuous analyses of body weight and body composition at endpoint were performed. We then further characterized disease features in R6/2 mice using rotarod, nesting- and clasping behavioral tests performed at early- and late timepoints of disease. Lastly, due to display of distinct weight changes after mutant huntingtin overexpression in R6/2 female mice, we examined food intake, followed by gene expression analyses in hypothalamus and adipose tissue. Results Hypothalamic overexpression of mutant huntingtin induced gender-specific body weight gain in all models, including wild-type mice. Early weight gain shifted to weight loss during late stage of disease in R6/2 female mice, and weight phenotypes were accompanied with behavioral alterations. Reduced nesting scores were detected in wild-type littermates during the period of early weight gain, and decreased rotarod performance in R6/2 and wild-types just prior to weight loss onset. Lastly, changes in gene expression profile of white adipose- and hypothalamic tissue were observed in both R6/2 and wild-types after mutant huntingtin overexpression. Conclusions Taken together, our findings provide further support for a role of huntingtin in metabolic control via hypothalamic neurocircuits.