Background Non-motor features of Huntington's disease (HD) include metabolic changes such as increased appetite, insulin resistance and changes in body weight. As mutant huntingtin (htt) is ubiquitously expressed in HD as well as in most animal models that recapitulate these features, it has not been possible to determine the underlying pathology. Metabolism is regulated by the hypothalamus and previous reports have suggested hypothalamic dysfunction in HD including loss of orexin (hypocretin), a neuropeptide involved in the control of sleep, metabolism and emotion.

Aims The aim of this study was to test if selective expression of mutant htt in the hypothalamus would lead to metabolic disturbances.

Methods We used adeno associated viral vectors as tools to deliver the first 853 amino acid fragment of either the wild-type or mutant form of the htt gene in the hypothalamus of mice.

Results We detected formation of htt inclusions and ubiquitinated aggregates in the absence of general cell loss, gliosis or microglia activation in the hypothalamus. Interestingly, selective hypothalamic expression of mutant htt, but not the wild-type form of htt expressed at a similar level, caused severe metabolic disturbances including glucose intolerance, insulin and leptin resistance as well as a significant increase in body fat and body weight. These changes were accompanied by loss of orexin.

Conclusions This study provides evidence for a causative relationship between the effects of mutant htt in the hypothalamus and the development of metabolic disturbances.