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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

Targeting of different TH cell populations and stereological assessment of dopaminergic cells in the hypothalamus at 12 months post-injection.(A–C) The orthogonal projections of Z-stack image series show the co-localization of TH+ cells (red) with GFP transgene (green) in the A13, A14 and A12 hypothalamic regions of animals injected with rAAV5-GFP vector. (D–G) Photomicrographs representing the A13, A12, and A14 TH+ cell populations in the hypothalamus at the 12 month time-point. (H–J) Stereological estimation of the number of A13, A14 and A12 TH+ cells in the hypothalamus (n = 7–11/group, *p < 0.05, one-way ANOVA followed by Tukey’s posthoc test). Data is presented as mean ± SEM. 3V = 3rd ventricle; MFB = medial forebrain bundle. Scale bar in A–C = 20 μm; D–G = 200 μm.
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f2: Targeting of different TH cell populations and stereological assessment of dopaminergic cells in the hypothalamus at 12 months post-injection.(A–C) The orthogonal projections of Z-stack image series show the co-localization of TH+ cells (red) with GFP transgene (green) in the A13, A14 and A12 hypothalamic regions of animals injected with rAAV5-GFP vector. (D–G) Photomicrographs representing the A13, A12, and A14 TH+ cell populations in the hypothalamus at the 12 month time-point. (H–J) Stereological estimation of the number of A13, A14 and A12 TH+ cells in the hypothalamus (n = 7–11/group, *p < 0.05, one-way ANOVA followed by Tukey’s posthoc test). Data is presented as mean ± SEM. 3V = 3rd ventricle; MFB = medial forebrain bundle. Scale bar in A–C = 20 μm; D–G = 200 μm.

Mentions: Next, we wanted to confirm that the A12, A13 and A14 cell groups were all transfected by the rAAV5 vectors and investigate whether there was a selective sensitivity of the A13 group to expression of mutant HTT. As wild-type HTT has been shown to have metabolic effects2029, we were also interested in studying the long-term consequences of wild-type HTT expression in the hypothalamus. To control for aberrant protein overexpression, we included a group injected with a vector encoding the green fluorescent protein (GFP) that also served as an extra control group. The animals were kept up to 12 months post-injection, and the pattern of expression was analyzed using confocal microscopy. The fluorescence imaging of the GFP expressing brain sections showed that all three dopaminergic cell populations in the hypothalamus were transfected (Fig. 2A–C).


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)

Targeting of different TH cell populations and stereological assessment of dopaminergic cells in the hypothalamus at 12 months post-injection.(A–C) The orthogonal projections of Z-stack image series show the co-localization of TH+ cells (red) with GFP transgene (green) in the A13, A14 and A12 hypothalamic regions of animals injected with rAAV5-GFP vector. (D–G) Photomicrographs representing the A13, A12, and A14 TH+ cell populations in the hypothalamus at the 12 month time-point. (H–J) Stereological estimation of the number of A13, A14 and A12 TH+ cells in the hypothalamus (n = 7–11/group, *p < 0.05, one-way ANOVA followed by Tukey’s posthoc test). Data is presented as mean ± SEM. 3V = 3rd ventricle; MFB = medial forebrain bundle. Scale bar in A–C = 20 μm; D–G = 200 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4588570&req=5

f2: Targeting of different TH cell populations and stereological assessment of dopaminergic cells in the hypothalamus at 12 months post-injection.(A–C) The orthogonal projections of Z-stack image series show the co-localization of TH+ cells (red) with GFP transgene (green) in the A13, A14 and A12 hypothalamic regions of animals injected with rAAV5-GFP vector. (D–G) Photomicrographs representing the A13, A12, and A14 TH+ cell populations in the hypothalamus at the 12 month time-point. (H–J) Stereological estimation of the number of A13, A14 and A12 TH+ cells in the hypothalamus (n = 7–11/group, *p < 0.05, one-way ANOVA followed by Tukey’s posthoc test). Data is presented as mean ± SEM. 3V = 3rd ventricle; MFB = medial forebrain bundle. Scale bar in A–C = 20 μm; D–G = 200 μm.
Mentions: Next, we wanted to confirm that the A12, A13 and A14 cell groups were all transfected by the rAAV5 vectors and investigate whether there was a selective sensitivity of the A13 group to expression of mutant HTT. As wild-type HTT has been shown to have metabolic effects2029, we were also interested in studying the long-term consequences of wild-type HTT expression in the hypothalamus. To control for aberrant protein overexpression, we included a group injected with a vector encoding the green fluorescent protein (GFP) that also served as an extra control group. The animals were kept up to 12 months post-injection, and the pattern of expression was analyzed using confocal microscopy. The fluorescence imaging of the GFP expressing brain sections showed that all three dopaminergic cell populations in the hypothalamus were transfected (Fig. 2A–C).

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