Hypothalamic overexpression of mutant huntingtin causes dysregulation of brown adipose tissue

Abstract

Expression of mutant huntingtin (htt) protein has been shown to cause metabolic imbalance in animal models of Huntington disease (HD). The pathways involved are not fully understood but dysfunction of both the hypothalamus and brown adipose tissue (BAT) has been implicated. Here we show that targeted expression of mutant HTT in the hypothalamus leads to loss of the A13 dopaminergic cell group located in the zona incerta and reduced mRNA expression of neuropeptide Y1 receptor in the hypothalamus. Furthermore, this is accompanied by downregulation of uncoupling protein 1 expression and PPARγ coactivator-1 alpha in BAT and a rapid body weight gain. Taken together, our data might provide a mechanistic link between expression of mutant HTT, reduced activity of a hypothalamic dopaminergic pathway and dysfunction of BAT and in part explain the development of an obese phenotype in HD mouse models.

SIRT1 is increased in affected brain regions and hypothalamic metabolic pathways are altered in Huntington disease

“…We further show a reduction in orexin and prodynorphin mRNA levels in the 79Q group compared to both the 18Q and the control group as well as in the 18Q group compared to the uninjected control group (Figure b , c ). This is in line with our previously reported results in this model . There was also a significant reduction in mRNA levels of TH in the 79Q group (Figure d ).…”

“…Female mice of the FVB/N strain (The Jackson Laboratories, Bar Harbor, MA, USA) were stereotactically injected at 2 months of age into the hypothalamus with rAAV vectors expressing either a mutant or a wild‐type HTT variant. The viral vectors have been described in detail previously . Briefly, we used pseudotyped rAAV2/5 vectors, where the HTT gene fragment was flanked by inverted terminal repeats of the AAV2 packaged in an AAV5 capsid (referred to as rAAV5 elsewhere).…”

Hypothalamic Alterations in Neurodegenerative Diseases and Their Relation to Abnormal Energy Metabolism

“…Interestingly, inactivation of mutant huntingtin in the hypothalamus prevented the development of the metabolic alterations in the BACHD mice, indicating that mutant huntingtin can alter energy metabolism by affecting hypothalamic pathways. Indeed, selective hypothalamic overexpression of mutant huntingtin of both short and longer fragment lengths in wild-type mice using recombinant adeno-associated viral (rAAV) vectors led to increased food intake and the development of severe metabolic alterations (Hult et al, 2011 ; Soylu-Kucharz et al, 2015 ). Furthermore, selective expression of mutant huntingtin fragments in the hypothalamus led to similar alterations in metabolism-regulating peripheral tissues such as brown adipose tissue as has previously been described in mouse models ubiquitously expressing mutant huntingtin (Weydt et al, 2006 ; Soylu-Kucharz et al, 2015 ).…”

Peripheral Expression of Mutant Huntingtin is a Critical Determinant of Weight Loss and Metabolic Disturbances in Huntington’s Disease

“…Nevertheless, given the wide expression of mHTT in HD subjects and the involvement of multiple tissues in the maintenance of adequate body weight 74 , we cannot rule out the implication of other regulatory systems or an indirect signal from neurodegeneration in hypothalamus 85 in the development of metabolic abnormalities and emaciation in HD. In few mouse model studies, it has been noted that selective expression of mHTT in the hypothalamus could lead to metabolic dysfunctions such as body weight changes and disturbances in the peripheral tissues like brown adipose tissue 35,86 . The available evidence, however, indicates the adipose tissue and liver to be the major determinants of these peripheral manifestations.…”