Identifies Zfp423 as a Transcriptional Regulator of Preadipocyte Determination

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The worldwide epidemic of obesity has increased the urgency to develop a deeper understanding of physiological systems related to energy balance and energy storage, including the mechanisms controlling the development of fat cells (adipocytes). The differentiation of committed preadipocytes to adipocytes is controlled by PPARγ and several other transcription factors1, but the molecular basis for preadipocyte determination is not understood. Using a new method for the quantitative analysis of transcriptional components, we identified the zinc-finger protein Zfp423 as a factor enriched in preadipose versus non-preadipose fibroblasts. Ectopic expression of Zfp423 in non-adipogenic NIH 3T3 fibroblasts robustly activates expression of Pparg in …show more content…
3e). To determine whether the SMAD-interaction domain of Zfp423 is required for this effect of the BMP proteins, we compared Pparg mRNA levels in BMP-treated control, Zfp423-expressing and Zfp423(ΔSBD)-expressing cell lines. Indeed, Zfp423-mutant-expressing cells failed to respond to the BMP signal to enhance Pparg gene expression further (Fig. 3f). In addition, although cells expressing full-length Zfp423 were capable of undergoing BMP-driven adipogenesis, cells expressing Zfp423(ΔSBD) or the empty viral vector did not undergo significant adipocyte differentiation when stimulated with low doses of BMP4 (Fig. 3g). Similar results were observed when we treated these same cell lines with BMP2 (Supplementary Fig. 12). These results indicate that the SMAD-binding domain of Zfp423 is not necessary for its activity in preadipocyte commitment under basal culture conditions, but it is absolutely required for Zfp423 modulation of adipogenic activity induced by BMPs.

To determine whether Zfp423 regulates adipose cell development in vivo, we examined the formation of adipocytes in Zfp423-deficient mice14. Zfp423-knockout mice show large defects in the development of the midline structures of the brain14, 21, and most of these Zfp423-/- mice died within 24 h of birth14, 21, 22. Although the few recovered postnatal Zfp423-/- mice showed noticeable defects in adipose mass (data not shown), we

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