Cell Metabolism
Volume 13, Issue 4, 6 April 2011, Pages 428-439
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Article
Mutant Huntingtin Causes Metabolic Imbalance by Disruption of Hypothalamic Neurocircuits

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Summary

In Huntington's disease (HD), the mutant huntingtin protein is ubiquitously expressed. The disease was considered to be limited to the basal ganglia, but recent studies have suggested a more widespread pathology involving hypothalamic dysfunction. Here we tested the hypothesis that expression of mutant huntingtin in the hypothalamus causes metabolic abnormalities. First, we showed that bacterial artificial chromosome-mediated transgenic HD (BACHD) mice developed impaired glucose metabolism and pronounced insulin and leptin resistance. Selective hypothalamic expression of a short fragment of mutant huntingtin using adeno-associated viral vectors was sufficient to recapitulate these metabolic disturbances. Finally, selective hypothalamic inactivation of the mutant gene prevented the development of the metabolic phenotype in BACHD mice. Our findings establish a causal link between mutant huntingtin expression in the hypothalamus and metabolic dysfunction, and indicate that metabolic parameters are powerful readouts to assess therapies aimed at correcting dysfunction in HD by silencing huntingtin expression in the brain.

Highlights

▴ Metabolic disturbances are present in transgenic mice for Huntington's disease ▴ BACHD mice develop glucose intolerance as well as insulin and leptin resistance ▴ Hypothalamic expression of a mutant huntingtin fragment causes metabolic changes ▴ Hypothalamic inactivation of mutant huntingtin prevents the metabolic phenotype

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These authors contributed equally to this work