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Normalizing glucocorticoid levels attenuates metabolic and neuropathological symptoms in the R6/2 mouse model of huntington's disease.

ABSTRACT: Huntington's disease (HD) is a fatal genetic neurological disorder caused by a mutation in the human Huntingtin (HTT) gene. This mutation confers a toxic gain of function of the encoded mutant huntingtin (mHTT) protein, leading to widespread neuropathology including the formation of mHTT-positive inclusion bodies, gene dysregulation, reduced levels of adult dentate gyrus neurogenesis and neuron loss throughout many regions of the brain. Additionally, because HTT is ubiquitously expressed, several peripheral tissues are also affected. HD patients suffer from progressive motor, cognitive, psychiatric, and metabolic symptoms, including weight loss and skeletal muscle wasting. HD patients also show neuroendocrine changes including a robust, significant elevation in circulating levels of the glucocorticoid, cortisol. Previously, we confirmed that the R6/2 mouse model of HD exhibits elevated corticosterone (the rodent homolog of cortisol) levels and demonstrated that experimentally elevated corticosterone exacerbates R6/2 HD symptomology, resulting in severe and rapid weight loss and a shorter latency to death. Given that efficacious therapeutics are lacking for HD, here we investigated whether normalizing glucocorticoid levels could serve as a viable therapeutic approach for this disease. We tested the hypothesis that normalizing glucocorticoids to wild-type levels would ameliorate HD symptomology. Wild-type (WT) and transgenic R6/2 mice were allocated to three treatment groups: 1) adrenalectomy with normalized, WT-level corticosterone replacement (10??g/ml), 2) adrenalectomy with high HD-level corticosterone replacement (35??g/ml), or 3) sham surgery with no corticosterone replacement. Normalizing corticosterone to WT levels led to an improvement in metabolic rate in male R6/2 mice, as indicated by indirect calorimetry, including a reduction in oxygen consumption and normalization of respiratory exchange ratio values (p?

SUBMITTER: Dufour BD

PROVIDER: S-EPMC6320701 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Normalizing glucocorticoid levels attenuates metabolic and neuropathological symptoms in the R6/2 mouse model of huntington's disease.

Dufour Brett D BD McBride Jodi L JL

Neurobiology of disease 20181005

Huntington's disease (HD) is a fatal genetic neurological disorder caused by a mutation in the human Huntingtin (HTT) gene. This mutation confers a toxic gain of function of the encoded mutant huntingtin (mHTT) protein, leading to widespread neuropathology including the formation of mHTT-positive inclusion bodies, gene dysregulation, reduced levels of adult dentate gyrus neurogenesis and neuron loss throughout many regions of the brain. Additionally, because HTT is ubiquitously expressed, severa ...[more]

PMID: 30292559

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Project description:Huntington's disease (HD) is a fatal, autosomal dominantly inherited neurodegenerative disorder, characterised not only by progressive cognitive, motor and psychiatric impairments, but also of peripheral pathology. In both human HD and in mouse models of HD there is evidence of increased energy expenditure and weight loss, alongside altered body composition. Unlike white adipose tissue (WAT), brown adipose tissue (BAT), as well as brown-like cells within WAT, expresses the mitochondrial protein, uncoupling protein 1 (UCP1). UCP1 enables dissociation of cellular respiration from ATP utilization, resulting in the release of stored energy as heat. Hyperplasia of brown/beige cells in WAT has been suggested to enhance energy expenditure. In this study, we therefore investigated the gene expression profile, histological appearance, response to cold challenge and functional aspects of WAT in the R6/2 HD mouse model and selected WAT gene expression in the full-length Q175 mouse model of HD. WAT from R6/2 mice contained significantly more brown-like adipocyte regions and had a gene profile suggestive of the presence of brown-like adipocytes, such as higher Ucp1 expression. Cold exposure induced Ucp1 expression in R6/2 inguinal WAT to a markedly higher degree as compared to the thermogenic response in WT WAT. Alongside this, gene expression of transcription factors (Zfp516 and Pparα), important inducers of WAT browning, were increased in R6/2 inguinal WAT, and Creb1 was highlighted as a key transcription factor in HD. In addition to increased WAT Ucp1 expression, a trend towards increased mitochondrial oxygen consumption due to enhanced uncoupling activity was found in inguinal R6/2 WAT. Key gene expressional changes (increased expression of (Zfp516 and Pparα)) were replicated in inguinal WAT obtained from Q175 mice. In summary, for the first time, we here show that HD mouse WAT undergoes a process of browning, resulting in molecular and functional alterations that may contribute to the weight loss and altered metabolism observed with disease progression.

Dataset Information

Normalizing glucocorticoid levels attenuates metabolic and neuropathological symptoms in the R6/2 mouse model of huntington's disease.

Publications

Normalizing glucocorticoid levels attenuates metabolic and neuropathological symptoms in the R6/2 mouse model of huntington's disease.

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