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

长期以来，脂肪组织一直被认为是严格调节能量代谢和营养动态平衡的内分泌器官。营养过剩会导致WAT膨胀，从而影响脂肪细胞的生物学，最终导致严重的代谢紊乱，如肥胖和胰岛素抵抗。甲状腺激素(TH)对能量代谢和产热有重要影响，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 Finger Protein 423(Zfp423)被确定为脂肪细胞系建立和维持的重要转录因子。在小鼠中，Zfp423的表达调节前脂肪细胞的承诺和分化，这些前脂肪细胞驻留在脂肪组织的血管系统中，并有助于与高脂饮食相关的白色脂肪细胞的增殖。在成熟脂肪细胞中，Zfp423通过抑制产热基因程序来维持白色脂肪细胞的储能状态。在我们自己的初步工作中，我们发现了第一个证据，即连接的TRβ通过转录失活抑制Zfp423的表达。因此，我们的工作假设是TH通过调节Zfp423的表达来调节前脂肪细胞对脂肪谱系的承诺。因此，TH的缺乏通过Zfp423介导的抑制产热基因程序脂肪细胞而使前脂肪细胞向储存能量的白色表型分化。该假说将在四个针对特定目标的工作包中得到验证：(I)评估TH和Zfp423诱导的前体脂肪细胞的相互作用以及脂肪细胞的谱系；(Ii)评估脂肪组织特异性去除Zfp423在成年甲状腺功能低下小鼠中的代谢后果，尤其是对于适应性产热；(Iii)评估Zfp423通过靶向激活TRβ而在转录水平上拮抗Zfp423的可能性，从而挽救甲状腺功能减退症中的适应性产热；(Iv)研究TH功能障碍对ZFP 423表达的二级机制，尤其是ZFP 423在减肥后脂肪组织重构中的调节。总体而言，我们希望我们提出的研究将对TH调节脂肪组织可塑性的机制提供更好的理解，从而可能为肥胖症的治疗提供新的治疗方法。

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.