IKKβ signaling mediates metabolic changes in the hypothalamus of a Huntington's disease mouse model

Abstract

BackgroundHuntingtons disease (HD) is a neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin (HTT) gene. Metabolic changes are associated with HD progression, and underlying mechanisms are not fully known. As the IKK{beta}/NF-{kappa}B pathway is an essential regulator of metabolism, we investigated the involvement of IKK{beta}, the upstream activator of NF-{kappa}B in hypothalamus-specific HD metabolic changes. MethodsUsing viral vectors, we expressed amyloidogenic N-terminal fragments of mutant HTT (mHTT) fragments in the hypothalamus of mice without IKK{beta} in the CNS (IKK{beta}-/-) and control mice (IKK{beta}+/+). We assessed effects on body weight, metabolic hormones, and hypothalamic neuropathology. ResultsHypothalamic expression of mHTT led to an obese phenotype only in female mice. CNS-specific inactivation of IKK{beta} prohibited weight gain in females, which was independent of neuroprotection and microglial activation. ConclusionsThe expression of mHTT in the hypothalamus causes metabolic imbalance in a sex-specific fashion, and central inhibition of the IKK{beta} pathway attenuates the obese phenotype.