Adipose-specific Huntingtin knockout mice display alterations in response to metabolic challenges

Huntington’s disease (HD) is a fatal autosomal dominant disease, characterized by progressive motor, cognitive, and psychiatric phenotypes. HD results from a trinucleotide expansion (CAG) in the huntingtin gene (HTT), which causes abnormal function of mutant huntingtin protein (HTT). Although Huntington’s disease is classically considered a neurodegenerative disease, neither HD nor HTT expression is confined to the brain. HTT expression is found throughout the body, and so too are the toxic effects of the causal mutation in HD. This research is particularly interested in whole-body signs in HD, and aims to shine a light on the metabolic and molecular effects of Htt gene knockout in adipose tissues using mice harboring floxed Htt alleles and an Adipoq-Cre transgene (“HttAKO”). While previous work has described phenotypes arising from mutant huntingtin expression in adipose tissue, it is unclear whether these phenotypes are due to toxic gain-of-function or loss of wild-type functions. Subtle differences between wild-type and a mutant Htt allele can be exacerbated when met with metabolic challenges, and likewise, Htt knockout alleles may require metabolic challenges to uncover phenotypes that are subtle or non-existent at baseline. In order to address this question, wild-type (Htt+/+) and HttAKO/AKO mice will be characterized and compared in response to a series of metabolic challenges. We will discuss the effects of a glucose challenge and prolonged fast on gene and protein expression in these knockout mice. We will also present RNA sequencing data which highlights the additional genetic changes in response to Htt knockout in adipose tissues