Abstract
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.
Highlights
Huntington’s disease (HD) is a devastating autosomal dominant neurological disorder characterised by classical neurological symptoms, such as progressive cognitive, motor and psychiatric impairments [1]
We observed brown-like adipose tissue, as determined by presence of multilocular adipocytes, in discrete locations within subcutaneous white adipose tissue (WAT) depots obtained from R6/2 mice (Fig 1B)
Inducible brown-like adipocytes in white adipose tissue share the characteristics of high mitochondria content, uncoupling protein 1 (UCP1) expression and thermogenic capacity when activated
Summary
Huntington’s disease (HD) is a devastating autosomal dominant neurological disorder characterised by classical neurological symptoms, such as progressive cognitive, motor and psychiatric impairments [1]. The causal mutant gene (created by an expanded polyglutamine tract in exon 1 of the huntingtin gene) and the encoded protein are ubiquitously expressed throughout the body [2, 3] and HD central pathology is accompanied by complex peripheral pathology, including skeletal muscle atrophy, altered body composition and progressive weight loss [4,5,6]. Progressive weight loss is a feature of both human HD [7,8,9,10] and of HD mouse models [11]. The cause of HD weight loss is not fully known. Is that HD weight loss has been shown to be linked to the number of CAG repeats in the mutated gene [12]. Studies have indicated that body weight loss results from altered metabolism [10, 13], such as increased oxygen consumption [11]
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