Huntington's disease (HD) is a neurodegenerative disease caused by the expansion 
of a CAG trinucleotide repeat in exon 1 of the huntingtin (HTT) gene. Here, we 
report that the transcript of the peroxisome proliferator-activated receptor-γ 
(PPARγ), a transcription factor that is critical for energy homeostasis, was 
markedly downregulated in multiple tissues of a mouse model (R6/2) of HD and in 
lymphocytes of HD patients. Therefore, downregulation of PPARγ seems to be a 
pathomechanism of HD. Chronic treatment of R6/2 mice with an agonist of PPARγ 
(thiazolidinedione, TZD) rescued progressive weight loss, motor deterioration, 
formation of mutant Htt aggregates, jeopardized global ubiquitination profiles, 
reduced expression of two neuroprotective proteins (brain-derived neurotrophic 
factor and Bcl-2) and shortened life span exhibited by these mice. By reducing 
HTT aggregates and, thus, ameliorating the recruitment of PPARγ into HTT 
aggregates, chronic TZD treatment also elevated the availability of the PPARγ 
protein and subsequently normalized the expression of two of its downstream 
genes (the glucose transporter type 4 and PPARγ coactivator-1 alpha genes). The 
protective effects described above appear to have been exerted, at least 
partially, via direct activation of PPARγ in the brain, as TZD was detected in 
the brains of mice treated with TZD and because a PPARγ agonist (rosiglitazone) 
protected striatal cells from mHTT-evoked energy deficiency and toxicity. We 
demonstrated that the systematic downregulation of PPARγ seems to play a 
critical role in the dysregulation of energy homeostasis observed in HD, and 
that PPARγ is a potential therapeutic target for this disease.