Brain Disease Biomarker Unit, Wallenberg Neuroscience Center, Department of Experimental Medical Science, Lund University, BMC A10, 221 84 Lund, Sweden.
Brain Disease Biomarker Unit, Wallenberg Neuroscience Center, Department of Experimental Medical Science, Lund University, BMC A10, 221 84 Lund, Sweden.
Mol Metab. 2022 Mar;57:101439. doi: 10.1016/j.molmet.2022.101439. Epub 2022 Jan 7.
In Huntington's disease (HD), the disease-causing huntingtin (HTT) protein is ubiquitously expressed and causes both central and peripheral pathology. In clinical HD, a higher body mass index has been associated with slower disease progression, indicating the role of metabolic changes in disease pathogenesis. Underlying mechanisms of metabolic changes in HD remain poorly understood, but recent studies suggest the involvement of hypothalamic dysfunction. The present study aimed to investigate whether modulation of hypothalamic HTT levels would affect metabolic phenotype and disease features in HD using mouse models.
We used the R6/2 and BACHD mouse models that express different lengths of mutant HTT to develop lean- and obese phenotypes, respectively. We utilized adeno-associated viral vectors to overexpress either mutant or wild-type HTT in the hypothalamus of R6/2, BACHD, and their wild-type littermates. The metabolic phenotype was assessed by body weight measurements over time and body composition analysis using dual-energy x-ray absorptiometry at the endpoint. R6/2 mice were further characterized using behavioral analyses, including rotarod, nesting-, and hindlimb clasping tests during early- and late-time points of disease progression. Finally, gene expression analysis was performed in R6/2 mice and wild-type littermates in order to assess transcriptional changes in the hypothalamus and adipose tissue.
Hypothalamic overexpression of mutant HTT induced significant gender-affected body weight gain in all models, including wild-type mice. In R6/2 females, early weight gain shifted to weight loss during the corresponding late stage of disease despite increased fat accumulation. Body weight changes were accompanied by behavioral alterations. During the period of early weight gain, R6/2 mice displayed a comparable locomotor capacity to wild-type mice. When assessing behavior just prior to weight loss onset in R6/2 mice, decreased locomotor performance was observed in R6/2 females with hypothalamic overexpression of mutant HTT. Transcriptional downregulation of beta-3 adrenergic receptor (B3AR), adipose triglyceride lipase (ATGL), and peroxisome proliferator-activated receptor-gamma (PPARγ) in gonadal white adipose tissue was accompanied by distinct alterations in hypothalamic gene expression profiles in R6/2 females after mutant HTT overexpression. No significant effect on metabolic phenotype in R6/2 was seen in response to wild-type HTT overexpression.
Taken together, our findings provide further support for the role of HTT in metabolic control via hypothalamic neurocircuits. Understanding the specific central neurocircuits and their peripheral link underlying metabolic imbalance in HD may open up avenues for novel therapeutic interventions.
亨廷顿病（HD）中，致病的亨廷顿蛋白（HTT）广泛表达，导致中枢和外周病理。在临床 HD 中，较高的体重指数与疾病进展较慢相关，表明代谢变化在疾病发病机制中的作用。HD 中代谢变化的潜在机制仍知之甚少，但最近的研究表明下丘脑功能障碍的参与。本研究旨在使用小鼠模型研究调节下丘脑 HTT 水平是否会影响 HD 的代谢表型和疾病特征。
我们使用表达不同长度突变 HTT 的 R6/2 和 BACHD 小鼠模型分别开发出瘦和肥胖表型。我们利用腺相关病毒载体在 R6/2、BACHD 及其野生型同窝仔鼠的下丘脑过表达突变或野生型 HTT。通过在终点时使用双能 X 射线吸收法进行体重测量和身体成分分析来评估代谢表型。在疾病进展的早期和晚期时间点，R6/2 小鼠进一步进行行为分析，包括旋转棒、筑巢和后肢抓握测试。最后，在 R6/2 小鼠及其野生型同窝仔鼠中进行基因表达分析，以评估下丘脑和脂肪组织中的转录变化。
突变 HTT 的下丘脑过表达在所有模型中，包括野生型小鼠，均诱导出显著的性别影响体重增加。在 R6/2 雌性中，尽管脂肪堆积增加，但早期体重增加转变为晚期疾病时的体重减轻。体重变化伴随着行为改变。在 R6/2 小鼠早期体重增加期间，其运动能力与野生型小鼠相当。当评估 R6/2 小鼠体重减轻开始前的行为时，在 R6/2 雌性中观察到具有突变 HTT 下丘脑过表达的运动能力下降。在 R6/2 雌性的生殖白色脂肪组织中，β-3 肾上腺素能受体（B3AR）、脂肪甘油三酯脂肪酶（ATGL）和过氧化物酶体增殖物激活受体-γ（PPARγ）的转录下调伴随着下丘脑基因表达谱的明显改变在突变 HTT 过表达后。R6/2 对野生型 HTT 过表达的代谢表型无明显影响。
总之，我们的发现为 HTT 通过下丘脑神经回路控制代谢提供了进一步的支持。了解 HD 中代谢失衡的特定中枢神经回路及其外周联系可能为新的治疗干预开辟途径。
