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

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.亨廷顿舞蹈症（Huntington’s disease, HD）是一种致命的常染色体显性遗传性神经退行性疾病，其特征不仅表现为渐进性的认知、运动与精神功能障碍，还伴随外周组织病理改变。在人类HD患者与HD小鼠模型中，均已观察到能量消耗增加与体重下降，同时伴随身体成分异常。与白色脂肪组织（white adipose tissue, WAT）不同，棕色脂肪组织（brown adipose tissue, BAT）及WAT内的棕色样细胞均表达线粒体蛋白解偶联蛋白1（uncoupling protein 1, UCP1）。UCP1可介导细胞呼吸与ATP合成解偶联，将储存的能量以热能形式释放。已有研究指出，WAT内棕色/米色细胞的增生可增强机体能量消耗。因此本研究探究了R6/2 HD小鼠模型中WAT的基因表达谱、组织学形态、冷刺激响应及功能特征，并检测了全长Q175 HD小鼠模型的WAT基因表达情况。结果显示，R6/2小鼠的WAT中棕色样脂肪细胞区域显著增多，且基因表达谱提示存在棕色样脂肪细胞特征，例如Ucp1表达水平显著升高。与野生型（wild type, WT）WAT的产热响应相比，冷暴露可显著上调R6/2小鼠腹股沟WAT中的Ucp1表达。与此同时，R6/2小鼠腹股沟WAT中参与WAT褐变的关键转录因子Zfp516与Pparα的基因表达水平升高，且Creb1被鉴定为HD发生过程中的核心转录因子。除WAT中Ucp1表达上调外，本研究还在R6/2小鼠腹股沟WAT中发现了因解偶联活性增强导致的线粒体耗氧量升高趋势。在Q175小鼠的腹股沟WAT中，关键基因表达变化（Zfp516与Pparα表达上调）得到了重复验证。综上，本研究首次证实HD小鼠的WAT发生褐变过程，由此产生的分子与功能改变可能参与疾病进展过程中观察到的体重下降与代谢异常。