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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

Early loss of A13 TH-immunopositive cells in the mutant HTT-expressing hypothalamus.(A–F) Representative images of TH immunohistochemistry showing the population of A13 TH+ cells in the hypothalamus after unilateral injections of either rAAV5-HTT853-18Q or rAAV5-HTT853-79Q at 6 weeks (A,B); 12 weeks (C,D) and 18 weeks post-injection (E,F). (G) Stereological estimation of the number of analysis of TH+ cells in the A13 area at 6; 12; and 18 weeks post-injection. Data is presented as a percentage of A13 TH+ neurons in relation to the uninjected side (n = 4–6 animals/group, *p < 0.05, unpaired t-test). 3V = 3rd ventricle. Scale bar in all panels = 200 μm.
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f1: Early loss of A13 TH-immunopositive cells in the mutant HTT-expressing hypothalamus.(A–F) Representative images of TH immunohistochemistry showing the population of A13 TH+ cells in the hypothalamus after unilateral injections of either rAAV5-HTT853-18Q or rAAV5-HTT853-79Q at 6 weeks (A,B); 12 weeks (C,D) and 18 weeks post-injection (E,F). (G) Stereological estimation of the number of analysis of TH+ cells in the A13 area at 6; 12; and 18 weeks post-injection. Data is presented as a percentage of A13 TH+ neurons in relation to the uninjected side (n = 4–6 animals/group, *p < 0.05, unpaired t-test). 3V = 3rd ventricle. Scale bar in all panels = 200 μm.

Mentions: First, we performed immunohistochemistry for 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). For this purpose, we used brain tissue from wild-type mice that were stereotactically injected with rAAV serotype 5 (rAAV5) vectors expressing the first 853 amino acids of HTT with 79Q (rAAV5-HTT853-79Q; disease causing mutant HTT) or 18Q (rAAV5-HTT853-18Q; wild-type variant) into the hypothalamus. We have previously shown that expression of 79Q in the hypothalamus led to rapid development of a severe metabolic phenotype16. Stereological estimates of the total number of A13 dopaminergic neurons present on the viral vector injected side revealed a significant loss in the 79Q group already 6 weeks post-injection compared to the uninjected side. Moreover, this loss in 79Q group coincided with weight gain onset, as compared to the 18Q animals16. Loss of TH positive (TH+) neurons in the A13 area of 79Q animals was estimated to be 37 ± 9%, 43 ± 11% and 55 ± 13% (at 6, 12 and 18 weeks post-injection, respectively) as compared to the uninjected side. Notably, this effect appeared to be specific to the mutant protein as no such reduction in TH+ numbers was present in the 18Q group (Fig. 1G). Hence, the TH+ population in the A13 area of the hypothalamus was severely affected by expression of mutant HTT.


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)

Early loss of A13 TH-immunopositive cells in the mutant HTT-expressing hypothalamus.(A–F) Representative images of TH immunohistochemistry showing the population of A13 TH+ cells in the hypothalamus after unilateral injections of either rAAV5-HTT853-18Q or rAAV5-HTT853-79Q at 6 weeks (A,B); 12 weeks (C,D) and 18 weeks post-injection (E,F). (G) Stereological estimation of the number of analysis of TH+ cells in the A13 area at 6; 12; and 18 weeks post-injection. Data is presented as a percentage of A13 TH+ neurons in relation to the uninjected side (n = 4–6 animals/group, *p < 0.05, unpaired t-test). 3V = 3rd ventricle. Scale bar in all panels = 200 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f1: Early loss of A13 TH-immunopositive cells in the mutant HTT-expressing hypothalamus.(A–F) Representative images of TH immunohistochemistry showing the population of A13 TH+ cells in the hypothalamus after unilateral injections of either rAAV5-HTT853-18Q or rAAV5-HTT853-79Q at 6 weeks (A,B); 12 weeks (C,D) and 18 weeks post-injection (E,F). (G) Stereological estimation of the number of analysis of TH+ cells in the A13 area at 6; 12; and 18 weeks post-injection. Data is presented as a percentage of A13 TH+ neurons in relation to the uninjected side (n = 4–6 animals/group, *p < 0.05, unpaired t-test). 3V = 3rd ventricle. Scale bar in all panels = 200 μm.
Mentions: First, we performed immunohistochemistry for 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). For this purpose, we used brain tissue from wild-type mice that were stereotactically injected with rAAV serotype 5 (rAAV5) vectors expressing the first 853 amino acids of HTT with 79Q (rAAV5-HTT853-79Q; disease causing mutant HTT) or 18Q (rAAV5-HTT853-18Q; wild-type variant) into the hypothalamus. We have previously shown that expression of 79Q in the hypothalamus led to rapid development of a severe metabolic phenotype16. Stereological estimates of the total number of A13 dopaminergic neurons present on the viral vector injected side revealed a significant loss in the 79Q group already 6 weeks post-injection compared to the uninjected side. Moreover, this loss in 79Q group coincided with weight gain onset, as compared to the 18Q animals16. Loss of TH positive (TH+) neurons in the A13 area of 79Q animals was estimated to be 37 ± 9%, 43 ± 11% and 55 ± 13% (at 6, 12 and 18 weeks post-injection, respectively) as compared to the uninjected side. Notably, this effect appeared to be specific to the mutant protein as no such reduction in TH+ numbers was present in the 18Q group (Fig. 1G). Hence, the TH+ population in the A13 area of the hypothalamus was severely affected by expression of mutant HTT.

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