White Adipose Tissue Browning in the R6/2 Mouse Model of Huntington’s Disease

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.

Analysis of Tks4 Knockout Mice Suggests a Role for Tks4 in Adipose Tissue Homeostasis in the Context of Beigeing

“…The formation of beige cells in WAT has been observed in several transgenic mouse strains with a lean, reduced-adiposity phenotype [34,50]. In this study, we collected histological and gene expression data that provided evidence of WAT browning accompanied by a reduced body fat percentage in Tks4-KO mice.…”

“…Data were collected from two Tks4-KO and two WT samples, and the results are represented on a logarithmic scale. The differentially expressed genes were grouped according to their gene ontology similarities and clustered into pro-adipogenic, anti-adipogenic, and pro-brown functional groups [34]. We extracted the PPARγ target genes from the differentially expressed genes with the help of the PPARgene database, which lists the experimentally verified and computationally predicted PPARγ target genes [35].…”

Ghrelin rescues skeletal muscle catabolic profile in the R6/2 mouse model of Huntington’s disease

“…Alongside muscle atrophy, an altered body composition, accompanied by dysfunctional adipocytes, has been described in several HD mouse models 12 , 52 – 54 , and expression of mutant huntingtin in adipocytes has been shown to result in altered adipocyte function, such as reduced triglyceride storage within the adipocytes 53 . A feature of the HD hyper catabolic state has been suggested to be an abnormal fatty acid metabolism.…”

Ghrelin‐mediated improvements in the metabolic phenotype in the R6/2 mouse model of Huntington's disease

“…The ghrelin‐induced decrease in energy expenditure observed for R6/2 mice was likely related to ghrelin‐mediated modulation of the sympathetic nervous system . It has previously been suggested that R6/2 mice display increased sympathetic nervous tone, shown by increased browning of WAT …”