Limits...
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

The hallmarks of brain and systemic metabolic changes in mice selectively expressing the 79Q and the 18Q HTT variants in the hypothalamus.(A–C) Representative photomicrographs of hypothalami sections processed for orexin immunohistochemistry from mice 12 months post-injection. (D) Representative images from GFP immunohistochemistry showing the coverage of transgene expression in the hypothalamus. (E,F) Anti-huntingtin immunohistochemistry (sc87-67) demonstrating diffuse cytoplasmic staining in the 18Q group in contrast to the HTT inclusion formation in the 79Q group. (G,H) Anti-ubiquitin immunohistochemistry demonstrating absence of inclusion formation in GFP and 18Q group; and widespread ubiquitin positive inclusion formation in the 79Q group at 12 months (I). (J) Stereological assessment of the number of orexin+ cells at 12 months post-injection in the hypothalamus (n = 7–11/group). (K) Distinct changes in body weight over time monitored up to 12 months post-injection in animals expressing different HTT variants compared to controls (n = 20/group until 6 months, then n = 13–20/group). (L) Assessment with DEXA scan to show differences in percentage total body fat content between groups at 12 months (n = 10–19/group). (M–O) Evaluation of leptin, insulin and IGF-1 blood serum levels (n = 9–10/group). *p < 0.05 one- or two-way ANOVA followed by Tukey’s posthoc test. Data represented as mean ± SEM. Scale bar = 200 μm in (A–I) and 20 μm in high magnification images.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4588570&req=5

f3: The hallmarks of brain and systemic metabolic changes in mice selectively expressing the 79Q and the 18Q HTT variants in the hypothalamus.(A–C) Representative photomicrographs of hypothalami sections processed for orexin immunohistochemistry from mice 12 months post-injection. (D) Representative images from GFP immunohistochemistry showing the coverage of transgene expression in the hypothalamus. (E,F) Anti-huntingtin immunohistochemistry (sc87-67) demonstrating diffuse cytoplasmic staining in the 18Q group in contrast to the HTT inclusion formation in the 79Q group. (G,H) Anti-ubiquitin immunohistochemistry demonstrating absence of inclusion formation in GFP and 18Q group; and widespread ubiquitin positive inclusion formation in the 79Q group at 12 months (I). (J) Stereological assessment of the number of orexin+ cells at 12 months post-injection in the hypothalamus (n = 7–11/group). (K) Distinct changes in body weight over time monitored up to 12 months post-injection in animals expressing different HTT variants compared to controls (n = 20/group until 6 months, then n = 13–20/group). (L) Assessment with DEXA scan to show differences in percentage total body fat content between groups at 12 months (n = 10–19/group). (M–O) Evaluation of leptin, insulin and IGF-1 blood serum levels (n = 9–10/group). *p < 0.05 one- or two-way ANOVA followed by Tukey’s posthoc test. Data represented as mean ± SEM. Scale bar = 200 μm in (A–I) and 20 μm in high magnification images.

Mentions: Stereological analyses of the numbers of TH+ neurons in the A12-A14 groups confirmed that the A13 group was selectively affected by the expression of mutant HTT (Fig. 2D–J). The A12 and A14 groups remained unaffected despite the long-term follow-up and persistence of transgene expression (Fig. 2I,J). This data shows that the A13 TH population is highly vulnerable to overexpression of mutant HTT, a property not shared by the two other neighboring dopaminergic cell populations. Interestingly, at 12 months post-injection there was a measureable effect of wild-type HTT overexpression on the A13 cell group (Fig. 2H). The vulnerability of the A13 group to HTT overexpression mirrored the sensitivity of the orexin population, known to be affected in the HD hypothalamus121630 (Fig. 3A–C,J).


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)

The hallmarks of brain and systemic metabolic changes in mice selectively expressing the 79Q and the 18Q HTT variants in the hypothalamus.(A–C) Representative photomicrographs of hypothalami sections processed for orexin immunohistochemistry from mice 12 months post-injection. (D) Representative images from GFP immunohistochemistry showing the coverage of transgene expression in the hypothalamus. (E,F) Anti-huntingtin immunohistochemistry (sc87-67) demonstrating diffuse cytoplasmic staining in the 18Q group in contrast to the HTT inclusion formation in the 79Q group. (G,H) Anti-ubiquitin immunohistochemistry demonstrating absence of inclusion formation in GFP and 18Q group; and widespread ubiquitin positive inclusion formation in the 79Q group at 12 months (I). (J) Stereological assessment of the number of orexin+ cells at 12 months post-injection in the hypothalamus (n = 7–11/group). (K) Distinct changes in body weight over time monitored up to 12 months post-injection in animals expressing different HTT variants compared to controls (n = 20/group until 6 months, then n = 13–20/group). (L) Assessment with DEXA scan to show differences in percentage total body fat content between groups at 12 months (n = 10–19/group). (M–O) Evaluation of leptin, insulin and IGF-1 blood serum levels (n = 9–10/group). *p < 0.05 one- or two-way ANOVA followed by Tukey’s posthoc test. Data represented as mean ± SEM. Scale bar = 200 μm in (A–I) and 20 μm in high magnification images.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f3: The hallmarks of brain and systemic metabolic changes in mice selectively expressing the 79Q and the 18Q HTT variants in the hypothalamus.(A–C) Representative photomicrographs of hypothalami sections processed for orexin immunohistochemistry from mice 12 months post-injection. (D) Representative images from GFP immunohistochemistry showing the coverage of transgene expression in the hypothalamus. (E,F) Anti-huntingtin immunohistochemistry (sc87-67) demonstrating diffuse cytoplasmic staining in the 18Q group in contrast to the HTT inclusion formation in the 79Q group. (G,H) Anti-ubiquitin immunohistochemistry demonstrating absence of inclusion formation in GFP and 18Q group; and widespread ubiquitin positive inclusion formation in the 79Q group at 12 months (I). (J) Stereological assessment of the number of orexin+ cells at 12 months post-injection in the hypothalamus (n = 7–11/group). (K) Distinct changes in body weight over time monitored up to 12 months post-injection in animals expressing different HTT variants compared to controls (n = 20/group until 6 months, then n = 13–20/group). (L) Assessment with DEXA scan to show differences in percentage total body fat content between groups at 12 months (n = 10–19/group). (M–O) Evaluation of leptin, insulin and IGF-1 blood serum levels (n = 9–10/group). *p < 0.05 one- or two-way ANOVA followed by Tukey’s posthoc test. Data represented as mean ± SEM. Scale bar = 200 μm in (A–I) and 20 μm in high magnification images.
Mentions: Stereological analyses of the numbers of TH+ neurons in the A12-A14 groups confirmed that the A13 group was selectively affected by the expression of mutant HTT (Fig. 2D–J). The A12 and A14 groups remained unaffected despite the long-term follow-up and persistence of transgene expression (Fig. 2I,J). This data shows that the A13 TH population is highly vulnerable to overexpression of mutant HTT, a property not shared by the two other neighboring dopaminergic cell populations. Interestingly, at 12 months post-injection there was a measureable effect of wild-type HTT overexpression on the A13 cell group (Fig. 2H). The vulnerability of the A13 group to HTT overexpression mirrored the sensitivity of the orexin population, known to be affected in the HD hypothalamus121630 (Fig. 3A–C,J).

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