Understanding the significance of thyroid hormones in the context of adipocyte lineage determination by the transcription factor Zfp423.

了解甲状腺激素在转录因子 Zfp423 确定脂肪细胞谱系的背景下的重要性。

• 批准号: 417784217
• 负责人: Dr. Kerstin Krause
• 金额: --
• 依托单位: Klinik und Poliklinik für Endokrinologie, Nephrologie und Rheumatologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/417784217?language=en
• 关键词: Understanding; significance; thyroid; hormones; context

Adipose tissue (AT) has long been recognized as an endocrine organ which tightly regulates energy metabolism and nutritional homoeostasis. Overnutrition leads to WAT expansion thereby influencing adipocyte biology, which finally leads to serous metabolic disorders, as obesity and insulin resistance. Thyroid hormones (TH) critically influence energy metabolism and thermogenesis in particular by direct activation of gene transcription through binding to the thyroid hormone receptor (TR). Recently, the zing finger protein 423 (Zfp423) has been identified as an important transcription factor for the establishment and maintenance of the adipocyte lineage. In mice Zfp423 expression regulates commitment and differentiation of preadipocytes that reside in the adipose tissue vasculature and contribute to white adipocyte hyperplasia associated with high-fat diet feeding. In the mature adipocyte, Zfp423 acts to maintain the energy-storing status of the white adipocyte through suppression of the thermogenic gene program. In our own preliminary work we found first evidences that the liganded TRβ represses Zfp423 expression through transcriptional inactivation. Therefore, our working hypothesis is that TH regulate the commitment of preadipocytes to the adipose lineage through the modulation of Zfp423 expression. Thereby the absence of TH predisposes preadipocyte differentiation towards the energy storing white phenotype through Zfp423 mediated suppression of the thermogenic gene program adipocytes. The hypothesis will be tested in the four work packages addressing specific aims: (I) to evaluate the interaction of TH and Zfp423 induced preadipocyte commitment and determination of adipocyte lineage; (II) to evaluate the metabolic consequences of adipose-tissue-specific ablation of Zfp423 in adult hypothyroid mice particularly for adaptive thermogenesis; (III) to evaluate the possibility of the transcriptional antagonism of Zfp423 by targeted activation of TRβ to rescue adaptive thermogenesis in hypothyroidism; (IV) to dissect secondary mechanisms of TH dysfunction on ZFP423 expression, particularly the regulation of ZFP423in the context of human adipose tissue remodeling following weight loss. Overall, we expect that our proposed studies will provide a better understanding regarding the mechanisms by which TH regulate adipose tissue plasticity, thereby potentially suggesting new therapeutic approaches for the treatment of obesity.

脂肪组织（AT）长期以来被认为是严格调节能量代谢和营养稳态的内分泌器官。营养过剩导致 WAT 扩张，从而影响脂肪细胞生物学，最终导致浆液性代谢紊乱，如肥胖和胰岛素抵抗。甲状腺激素 (TH) 严重影响能量代谢和产热，特别是通过与甲状腺激素受体 (TR) 结合直接激活基因转录。最近，Zing指蛋白423（Zfp423）已被确定为建立和维持脂肪细胞谱系的重要转录因子。在小鼠中，Zfp423 的表达调节驻留在脂肪组织脉管系统中的前脂肪细胞的定向和分化，并导致与高脂肪饮食喂养相关的白色脂肪细胞增生。在成熟脂肪细胞中，Zfp423 通过抑制生热基因程序来维持白色脂肪细胞的能量储存状态。在我们自己的初步工作中，我们发现了配体 TRβ 通过转录失活抑制 Zfp423 表达的第一个证据。因此，我们的工作假设是 TH 通过调节 Zfp423 表达来调节前脂肪细胞对脂肪谱系的承诺。因此，TH 的缺失通过 Zfp423 介导的产热基因程序脂肪细胞的抑制，使前脂肪细胞易于分化为能量储存白色表型。该假设将在四个针对特定目标的工作包中进行测试：（I）评估 TH 和 Zfp423 诱导的前脂肪细胞定向和脂肪细胞谱系的确定的相互作用； (II) 评估成年甲状腺功能减退小鼠脂肪组织特异性消融 Zfp423 的代谢后果，特别是适应性生热作用； (III) 评估 Zfp423 通过靶向激活 TRβ 的转录拮抗作用来挽救甲状腺功能减退症适应性产热的可能性； (IV) 剖析 TH 功能障碍对 ZFP423 表达的次要机制，特别是在减肥后人类脂肪组织重塑背景下 ZFP423 的调节。总的来说，我们希望我们提出的研究能够更好地理解 TH 调节脂肪组织可塑性的机制，从而可能提出治疗肥胖的新治疗方法。