Human Molecular Genetics Advance Access published online on January 5, 2009
Human Molecular Genetics, doi:10.1093/hmg/ddn428
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adipose tissue dysfunction tracks disease progression in two Huntington's disease mouse models
1 Departments of Human Genetics and Medicine, University of California, Los Angeles, CA 90095 2 Neurology, Reed Neurological Research Centre, The David Geffen School of Medicine at UCLA, University of California, Los Angeles, CA 90095 3 Molecular Biology Institute, University of California, Los Angeles, CA 90095
* Correspondence: Karen Reue, PhD, Human Genetics Department, David Geffen School of Medicine at UCLA, Gonda 6506A, 695 Charles E. Young Drive South, Los Angeles, CA 90095. Tel (310) 794-5631. Fax (310) 794-5446. Email reuek{at}ucla.edu
Received October 15, 2008; Revised December 10, 2008; Accepted December 10, 2008
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 knockin 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
coactivator 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.
$ Current address: Department of Radiation Oncology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston TX 77030
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  M.-C. Chiang, H.-M. Chen, H.-L. Lai, H.-W. Chen, S.-Y. Chou, C.-M. Chen, F.-J. Tsai, and Y. Chern The A2A adenosine receptor rescues the urea cycle deficiency of Huntington's disease by enhancing the activity of the ubiquitin-proteasome system Hum. Mol. Genet., August 15, 2009; 18(16): 2929 - 2942. [Abstract] [Full Text] [PDF]
|
|