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

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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.