McCourt Andrew C, Jakobsson Lovisa, Larsson Sara, Holm Cecilia, Piel Sarah, Elmér Eskil, Björkqvist Maria
Brain Disease Biomarker Unit, Department of Experimental Medical Science, Lund University, BMC A10, 22184 Lund, Sweden.
Section for Diabetes, Metabolism and Endocrinology, Department of Experimental Medical Science, Lund University, BMC C11, 221 84 Lund, Sweden.
PLoS One. 2016 Aug 3;11(8):e0159870. doi: 10.1371/journal.pone.0159870. eCollection 2016.
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(HD)是一种致命的常染色体显性遗传神经退行性疾病,其特征不仅在于进行性认知、运动和精神障碍,还包括外周病理学变化。在人类HD患者和HD小鼠模型中,均有证据表明能量消耗增加、体重减轻,同时身体成分也发生改变。与白色脂肪组织(WAT)不同,棕色脂肪组织(BAT)以及WAT内的类棕色细胞表达线粒体蛋白解偶联蛋白1(UCP1)。UCP1可使细胞呼吸与ATP利用解离,从而导致储存的能量以热量形式释放。有研究表明,WAT中棕色/米色细胞的增生可增强能量消耗。因此,在本研究中,我们调查了R6/2 HD小鼠模型中WAT的基因表达谱、组织学外观、对冷刺激的反应及功能方面,并在全长Q175 HD小鼠模型中选择了WAT基因表达进行研究。R6/2小鼠的WAT含有明显更多的类棕色脂肪细胞区域,且其基因谱表明存在类棕色脂肪细胞,如Ucp1表达较高。与野生型WAT的产热反应相比,冷暴露诱导R6/2腹股沟WAT中Ucp1的表达程度明显更高。与此同时,WAT褐变的重要诱导因子转录因子(Zfp516和Pparα)的基因表达在R6/2腹股沟WAT中增加,并且Creb1被确定为HD中的关键转录因子。除了WAT中Ucp1表达增加外,在腹股沟R6/2 WAT中还发现由于解偶联活性增强导致线粒体氧消耗增加的趋势。从Q175小鼠获得的腹股沟WAT中复制了关键基因表达变化(Zfp516和Pparα表达增加)。总之,我们首次在此表明,HD小鼠的WAT经历了褐变过程,导致分子和功能改变,这可能有助于解释疾病进展过程中出现的体重减轻和代谢改变。