| First Author | Soylu-Kucharz R | Year | 2022 |
| Journal | iScience | Volume | 25 |
| Issue | 2 | Pages | 103771 |
| PubMed ID | 35146388 | Mgi Jnum | J:322625 |
| Mgi Id | MGI:6870388 | Doi | 10.1016/j.isci.2022.103771 |
| Citation | Soylu-Kucharz R, et al. (2022) IKKbeta signaling mediates metabolic changes in the hypothalamus of a Huntington disease mouse model. iScience 25(2):103771 |
| abstractText | Huntington disease (HD) is a neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin (HTT) gene. Metabolic changes are associated with HD progression, but underlying mechanisms are not fully known. As the IKKbeta/NF-kappaB pathway is an essential regulator of metabolism, we investigated the involvement of IKKbeta, the upstream activator of NF-kappaB in hypothalamus-specific HD metabolic changes. We expressed amyloidogenic N-terminal fragments of mutant HTT (mHTT) in the hypothalamus of mice with brain-specific ablation of IKKbeta (Nestin/IKKbeta(lox/lox)) and control mice (IKKbeta(lox/lox)). We assessed effects on body weight, metabolic hormones, and hypothalamic neuropathology. Hypothalamic expression of mHTT led to an obese phenotype only in female mice. CNS-specific inactivation of IKKbeta prohibited weight gain in females, which was independent of neuroprotection and microglial activation. Our study suggests that mHTT in the hypothalamus causes metabolic imbalance in a sex-specific fashion, and central inhibition of the IKKbeta pathway attenuates the obese phenotype. |
