Adipose tissue dysfunction tracks disease progression in two Huntington's disease mouse models

被引:92
作者
Phan, Jack [1 ,2 ]
Hickey, Miriam A. [3 ]
Zhang, Peixiang [1 ,2 ]
Chesselet, Marie-Francoise [3 ,4 ]
Reue, Karen [1 ,2 ,4 ]
机构
[1] Univ Calif Los Angeles, David Geffen Sch Med, Dept Human Genet, Reed Neurol Res Ctr, Los Angeles, CA 90095 USA
[2] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Reed Neurol Res Ctr, Los Angeles, CA 90095 USA
[3] Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurol, Reed Neurol Res Ctr, Los Angeles, CA 90095 USA
[4] Univ Calif Los Angeles, Inst Mol Biol, Los Angeles, CA 90095 USA
基金
美国国家卫生研究院;
关键词
ACTIVATED-RECEPTOR-GAMMA; EXPANDED CAG REPEAT; TRANSGENIC MICE; GENE-EXPRESSION; BODY-WEIGHT; TRANSCRIPTIONAL REPRESSION; MITOCHONDRIAL DYSFUNCTION; INDEPENDENT PREDICTOR; INSULIN SENSITIVITY; BEHAVIORAL DEFICITS;
D O I
10.1093/hmg/ddn428
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
In addition to the hallmark neurological manifestations of Huntington's disease (HD), weight loss with metabolic dysfunction is often observed in the later stages of disease progression and is associated with poor prognosis. The mechanism for weight loss in HD is unknown. Using two mouse models of HD, the R6/2 transgenic and CAG140 knock-in mouse strains, we demonstrate that adipose tissue dysfunction is detectable at early ages and becomes more pronounced as the disease progresses. Adipocytes acquire a 'de-differentiated' phenotype characterized by impaired expression of fat storage genes. In addition, HD mice exhibit reduced levels of leptin and adiponectin, adipose tissue-derived hormones that regulate food intake and glucose metabolism. Importantly, some of these changes occur prior to weight loss and development of some of the characteristic neurological symptoms. We demonstrate that impaired gene expression and lipid accumulation in adipocytes can be recapitulated by expression of an inducible mutant huntingtin transgene in an adipocyte cell line and that mutant huntingtin inhibits transcriptional activity of the PGC-1 alpha co-activator in adipocytes, which may contribute to aberrant gene expression. Thus, our findings indicate that mutant huntingtin has direct detrimental effects in cell types other than neurons. The results also indicate that circulating adipose-tissue-derived hormones may be accessible markers for HD prognosis and progression and suggest that adipose tissue may be a useful therapeutic target to improve standard of life for HD patients.
引用
收藏
页码:1006 / 1016
页数:11
相关论文
共 64 条
[1]   Safety testing of tebufenozide, a new molt-inducing insecticide, for effects on nontarget forest soil invertebrates [J].
Addison, JA .
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY, 1996, 33 (01) :55-61
[2]   Adipokines and the peripheral and neural control of energy balance [J].
Ahima, Rexford S. ;
Lazar, Mitchell A. .
MOLECULAR ENDOCRINOLOGY, 2008, 22 (05) :1023-1031
[3]   Adipose tissue as an endocrine organ [J].
Ahima, Rexford S. .
OBESITY, 2006, 14 :242-249
[4]   A cell-based screen for drugs to treat Huntington's disease [J].
Aiken, CT ;
Tobin, AJ ;
Schweitzer, ES .
NEUROBIOLOGY OF DISEASE, 2004, 16 (03) :546-555
[5]   Huntington's disease of the endocrine pancreas: Insulin deficiency and diabetes mellitus due to impaired insulin gene expression [J].
Andreassen, OA ;
Dedeoglu, A ;
Stanojevic, V ;
Hughes, DB ;
Browne, SE ;
Leech, CA ;
Ferrante, RJ ;
Habener, JF ;
Beal, MF ;
Thomas, MK .
NEUROBIOLOGY OF DISEASE, 2002, 11 (03) :410-424
[6]   Adipose tissue, inflammation, and cardiovascular disease [J].
Berg, AH ;
Scherer, PE .
CIRCULATION RESEARCH, 2005, 96 (09) :939-949
[7]   The R6/2 transgenic mouse model of Huntington's disease develops diabetes due to deficient β-cell mass and exocytosis [J].
Björkqvist, M ;
Fex, M ;
Renström, E ;
Wierup, N ;
Petersén, Å ;
Gil, J ;
Bacos, K ;
Popovic, N ;
Li, JY ;
Sundler, F ;
Brundin, P ;
Mulder, H .
HUMAN MOLECULAR GENETICS, 2005, 14 (05) :565-574
[8]   Genome-wide expression profiling of human blood reveals biomarkers for Huntington's disease [J].
Borovecki, F ;
Lovrecic, L ;
Zhou, J ;
Jeong, H ;
Then, F ;
Rosas, HD ;
Hersch, SM ;
Hogarth, P ;
Bouzou, B ;
Jensen, RV ;
Krainc, D .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2005, 102 (31) :11023-11028
[9]   Transcriptional signatures in Huntington's disease [J].
Cha, Jang-Ho J. .
PROGRESS IN NEUROBIOLOGY, 2007, 83 (04) :228-248
[10]   Minireview: Obesity and lipodystrophy - Where do the circles intersect? [J].
Chehab, Farid F. .
ENDOCRINOLOGY, 2008, 149 (03) :925-934