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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

A proposed model of the effect of mutant HTT expression in the hypothalamus on the metabolic circuitry to BAT.BAT: brown adipose tissue; HTT: huntingtin; NPY: neuropeptide Y; PGC1-α: peroxisome proliferator-activated receptor gamma coactivator 1-alpha; TH: tyrosine hydroxylase; UCP1: uncoupling protein 1; WAT: white adipose tissue, Y1R: neuropeptide Y receptor Y1.
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f5: A proposed model of the effect of mutant HTT expression in the hypothalamus on the metabolic circuitry to BAT.BAT: brown adipose tissue; HTT: huntingtin; NPY: neuropeptide Y; PGC1-α: peroxisome proliferator-activated receptor gamma coactivator 1-alpha; TH: tyrosine hydroxylase; UCP1: uncoupling protein 1; WAT: white adipose tissue, Y1R: neuropeptide Y receptor Y1.

Mentions: We have previously shown that overexpression of the disease causing protein HTT selectively in the hypothalamus is sufficient to induce a rapid development of a severe metabolic phenotype with leptin and insulin resistance16. Here we provide further insight, showing that selective hypothalamic overexpression of mutant HTT directly leads to a reduction of the TH A13 group in the zona incerta with downstream negative effects on BAT (Fig. 5). Hence, targeted expression of mutant HTT in the hypothalamus is sufficient to cause dysregulation of BAT function, previously shown to be present in mouse models with ubiquitous expression of the mutant protein21.


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)

A proposed model of the effect of mutant HTT expression in the hypothalamus on the metabolic circuitry to BAT.BAT: brown adipose tissue; HTT: huntingtin; NPY: neuropeptide Y; PGC1-α: peroxisome proliferator-activated receptor gamma coactivator 1-alpha; TH: tyrosine hydroxylase; UCP1: uncoupling protein 1; WAT: white adipose tissue, Y1R: neuropeptide Y receptor Y1.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f5: A proposed model of the effect of mutant HTT expression in the hypothalamus on the metabolic circuitry to BAT.BAT: brown adipose tissue; HTT: huntingtin; NPY: neuropeptide Y; PGC1-α: peroxisome proliferator-activated receptor gamma coactivator 1-alpha; TH: tyrosine hydroxylase; UCP1: uncoupling protein 1; WAT: white adipose tissue, Y1R: neuropeptide Y receptor Y1.
Mentions: We have previously shown that overexpression of the disease causing protein HTT selectively in the hypothalamus is sufficient to induce a rapid development of a severe metabolic phenotype with leptin and insulin resistance16. Here we provide further insight, showing that selective hypothalamic overexpression of mutant HTT directly leads to a reduction of the TH A13 group in the zona incerta with downstream negative effects on BAT (Fig. 5). Hence, targeted expression of mutant HTT in the hypothalamus is sufficient to cause dysregulation of BAT function, previously shown to be present in mouse models with ubiquitous expression of the mutant protein21.

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