Huntington’s disease (HD) is a neurodegenerative disorder that is clinically diagnosed by overt motor dysfunction, but metabolic defects such as insulin resistance and increased appetite often occur years before diagnosis. Triplet repeat expansion in the huntingtin gene (htt) is the primary cause of neuropathology but, because it is ubiquitously expressed, it has been hypothesised that mutant htt might also affect other tissues. Hult et al. now show that expression of mutant htt in the hypothalamus – a brain region central to regulating metabolism – causes metabolic abnormalities. Mice expressing a fragment of mutant htt selectively in the hypothalamus became obese, and developed insulin and leptin resistance. Furthermore, the development of metabolic abnormalities in transgenic mice expressing mutant htt ubiquitously could be prevented by hypothalamus-specific deletion of the gene in young mice. These findings establish a causal link between mutant htt in the hypothalamus and metabolic dysfunction, and suggest that metabolic readouts will be useful in assessing HD therapy involving silencing of htt in brain.
- Written by editorial staff. © 2011. Published by The Company of Biologists Ltd.
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