title: Hypothalamic overexpression of mutant huntingtin causes dysregulation of brown adipose tissue.
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.
authors.affiliation: Translational Neuroendocrine Research Unit, Department of Experimental Medical Sciences, Lund University, Sweden.
authors.forename: Rana
authors.initials: R
authors.lastname: Soylu-Kucharz
authors.affiliation: Translational Neuroendocrine Research Unit, Department of Experimental Medical Sciences, Lund University, Sweden.
authors.forename: Natalie
authors.initials: N
authors.lastname: Adlesic
authors.affiliation: Translational Neuroendocrine Research Unit, Department of Experimental Medical Sciences, Lund University, Sweden.
authors.forename: Barbara
authors.initials: B
authors.lastname: Baldo
authors.affiliation: Brain Repair and Imaging in Neural Systems (B.R.A.I.N.S.) Unit, Department of Experimental Medical Sciences Lund University, Sweden.
authors.forename: Deniz
authors.initials: D
authors.lastname: Kirik
authors.affiliation: Translational Neuroendocrine Research Unit, Department of Experimental Medical Sciences, Lund University, Sweden.
authors.forename: Åsa
authors.initials: Å
authors.lastname: Petersén
mesh_terms: D002001:Adipose Tissue, Brown / Q000378:metabolism*; D000818:Animals; D002452:Cell Count; D000229:Dependovirus / Q000235:genetics; D059290:Dopaminergic Neurons / Q000378:metabolism; D015870:Gene Expression; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D000071058:Huntingtin Protein; D007031:Hypothalamus / Q000378:metabolism* / Q000473:pathology; D007150:Immunohistochemistry; D051379:Mice; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009474:Neurons / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics*; D010641:Phenotype; D013997:Time Factors; D019076:Transgenes; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics / Q000378:metabolism
chemical_list: C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D014446:Tyrosine 3-Monooxygenase