Hypothalamic overexpression of mutant huntingtin causes dysregulation of brown adipose tissue.

Rana Soylu-Kucharz,Åsa Petersén,Deniz Kirik,Natalie Adlesic,Barbara Baldo

doi:10.1038/srep14598

Rana Soylu-Kucharz, Åsa Petersén + Show 3 more

Open Access

https://doi.org/10.1038/srep14598

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Journal: Scientific reports	Publication Date: Sep 30, 2015
Citations: 17	License type: CC BY 4.0

Affiliation: Lund University

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.

Highlights

0 6 weeks 12 weeks 18 weeks with ubiquitous expression of mutant HTT, and were linked to metabolic defects[21]
We performed immunohistochemistry for tyrosine hydroxylase (TH) to investigate whether selective expression of mutant HTT in the hypothalamus has an effect on the A13 group in the zona incerta (Fig. 1A–F)
We used brain tissue from wild-type mice that were stereotactically injected with recombinant adeno-associated viral (rAAV) serotype 5 vectors expressing the first 853 amino acids of HTT with 79Q or 18Q into the hypothalamus

Summary

Introduction

0 6 weeks 12 weeks 18 weeks with ubiquitous expression of mutant HTT, and were linked to metabolic defects[21]. It was demonstrated that NPY from the arcuate nucleus negatively acts on the tyrosine hydroxylase (TH)-expressing population in the A13 area, which in turn regulates BAT23. In the study by Shi et al the upregulation of NPY led to reduced energy metabolism and obesity via reduced TH expression in the hypothalamus and decreased levels of UCP123. Based on the neurotoxicity of mutant HTT, we hypothesized that the protein would directly act on the hypothalamic dopaminergic population and thereby lead to obesity via hypofunction of BAT. We investigated how this metabolic circuitry was affected by targeted expression of HTT in the hypothalamus

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Results

Conclusion