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

Soylu-Kucharz R, Adlesic N, Baldo B, Kirik D, Petersén Å - Sci Rep (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Translational Neuroendocrine Research Unit, Department of Experimental Medical Sciences, Lund University, Sweden.

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.

No MeSH data available.


Related in: MedlinePlus

Gene expression changes in the metabolism-regulating dopaminergic circuitry to brown adipose tissue induced by mutant HTT expression in the hypothalamus.(A) mRNA levels of Y1, TH and NPY in the hypothalamus at 8 weeks post-injection (n = 7/group, *p < 0.05, one-way ANOVA followed by Tukey’s post-hoc test). Data was normalized to mRNA of actb and gapdh house keeping genes and presented as a fold change in relation to uninjected animals. (B) Similar mRNA levels of HTT853-18Q and HTT853-79Q after the injections of the viral vectors in the hypothalamus. The data is presented as fold change of HTT853-18Q (n = 5–7/group, ns, unpaired t-test). (C–E) Qualitative analysis of BAT at 18 weeks post-injection. The Oil Red O staining shows the increased prevalence of intracellular lipid droplets (red) and reduced number of nuclei (blue) in rAAV5-HTT853-79Q group compared to uninjected and rAAV5-HTT853-18Q animals. (F) Assessment of mRNA level changes in BAT in animals injected in the hypothalamus with either rAAV5-HTT853-18Q or rAAV5-HTT853-79Q. Data is presented as mean ± SEM of fold change in relation to uninjected animals after normalization to mRNA levels of actb and rlp13a housekeeping genes (n = 6/group, *p < 0.05, Kruskal-Wallis test followed by Dunn’s multiple comparison test). 3V = 3rd ventricle. Scale bar = 50 μm in all panels.
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f4: Gene expression changes in the metabolism-regulating dopaminergic circuitry to brown adipose tissue induced by mutant HTT expression in the hypothalamus.(A) mRNA levels of Y1, TH and NPY in the hypothalamus at 8 weeks post-injection (n = 7/group, *p < 0.05, one-way ANOVA followed by Tukey’s post-hoc test). Data was normalized to mRNA of actb and gapdh house keeping genes and presented as a fold change in relation to uninjected animals. (B) Similar mRNA levels of HTT853-18Q and HTT853-79Q after the injections of the viral vectors in the hypothalamus. The data is presented as fold change of HTT853-18Q (n = 5–7/group, ns, unpaired t-test). (C–E) Qualitative analysis of BAT at 18 weeks post-injection. The Oil Red O staining shows the increased prevalence of intracellular lipid droplets (red) and reduced number of nuclei (blue) in rAAV5-HTT853-79Q group compared to uninjected and rAAV5-HTT853-18Q animals. (F) Assessment of mRNA level changes in BAT in animals injected in the hypothalamus with either rAAV5-HTT853-18Q or rAAV5-HTT853-79Q. Data is presented as mean ± SEM of fold change in relation to uninjected animals after normalization to mRNA levels of actb and rlp13a housekeeping genes (n = 6/group, *p < 0.05, Kruskal-Wallis test followed by Dunn’s multiple comparison test). 3V = 3rd ventricle. Scale bar = 50 μm in all panels.

Mentions: Given that NPY from the arcuate nucleus negatively regulates TH expression via, as proposed previously, Y1 receptors expressed on the TH+ neurons in the A13 cell population2344 we investigated if the effects mediated by mutant HTT included alterations in Y1 receptor mRNA levels. We found that in 79Q group the mRNA levels of both Y1 receptor and TH were significantly downregulated compared to the 18Q group (Y1: ~22% loss; TH: ~24% loss) and an uninjected control group (Y1: ~27% loss; TH: ~32% loss) (Fig. 4A). qRT-PCR analysis confirmed similar mRNA levels of HTT expression in the 79Q and 18Q groups (Fig. 4B).


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

Soylu-Kucharz R, Adlesic N, Baldo B, Kirik D, Petersén Å - Sci Rep (2015)

Gene expression changes in the metabolism-regulating dopaminergic circuitry to brown adipose tissue induced by mutant HTT expression in the hypothalamus.(A) mRNA levels of Y1, TH and NPY in the hypothalamus at 8 weeks post-injection (n = 7/group, *p < 0.05, one-way ANOVA followed by Tukey’s post-hoc test). Data was normalized to mRNA of actb and gapdh house keeping genes and presented as a fold change in relation to uninjected animals. (B) Similar mRNA levels of HTT853-18Q and HTT853-79Q after the injections of the viral vectors in the hypothalamus. The data is presented as fold change of HTT853-18Q (n = 5–7/group, ns, unpaired t-test). (C–E) Qualitative analysis of BAT at 18 weeks post-injection. The Oil Red O staining shows the increased prevalence of intracellular lipid droplets (red) and reduced number of nuclei (blue) in rAAV5-HTT853-79Q group compared to uninjected and rAAV5-HTT853-18Q animals. (F) Assessment of mRNA level changes in BAT in animals injected in the hypothalamus with either rAAV5-HTT853-18Q or rAAV5-HTT853-79Q. Data is presented as mean ± SEM of fold change in relation to uninjected animals after normalization to mRNA levels of actb and rlp13a housekeeping genes (n = 6/group, *p < 0.05, Kruskal-Wallis test followed by Dunn’s multiple comparison test). 3V = 3rd ventricle. Scale bar = 50 μm in all panels.
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f4: Gene expression changes in the metabolism-regulating dopaminergic circuitry to brown adipose tissue induced by mutant HTT expression in the hypothalamus.(A) mRNA levels of Y1, TH and NPY in the hypothalamus at 8 weeks post-injection (n = 7/group, *p < 0.05, one-way ANOVA followed by Tukey’s post-hoc test). Data was normalized to mRNA of actb and gapdh house keeping genes and presented as a fold change in relation to uninjected animals. (B) Similar mRNA levels of HTT853-18Q and HTT853-79Q after the injections of the viral vectors in the hypothalamus. The data is presented as fold change of HTT853-18Q (n = 5–7/group, ns, unpaired t-test). (C–E) Qualitative analysis of BAT at 18 weeks post-injection. The Oil Red O staining shows the increased prevalence of intracellular lipid droplets (red) and reduced number of nuclei (blue) in rAAV5-HTT853-79Q group compared to uninjected and rAAV5-HTT853-18Q animals. (F) Assessment of mRNA level changes in BAT in animals injected in the hypothalamus with either rAAV5-HTT853-18Q or rAAV5-HTT853-79Q. Data is presented as mean ± SEM of fold change in relation to uninjected animals after normalization to mRNA levels of actb and rlp13a housekeeping genes (n = 6/group, *p < 0.05, Kruskal-Wallis test followed by Dunn’s multiple comparison test). 3V = 3rd ventricle. Scale bar = 50 μm in all panels.
Mentions: Given that NPY from the arcuate nucleus negatively regulates TH expression via, as proposed previously, Y1 receptors expressed on the TH+ neurons in the A13 cell population2344 we investigated if the effects mediated by mutant HTT included alterations in Y1 receptor mRNA levels. We found that in 79Q group the mRNA levels of both Y1 receptor and TH were significantly downregulated compared to the 18Q group (Y1: ~22% loss; TH: ~24% loss) and an uninjected control group (Y1: ~27% loss; TH: ~32% loss) (Fig. 4A). qRT-PCR analysis confirmed similar mRNA levels of HTT expression in the 79Q and 18Q groups (Fig. 4B).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Translational Neuroendocrine Research Unit, Department of Experimental Medical Sciences, Lund University, Sweden.

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.

No MeSH data available.


Related in: MedlinePlus