Thyroid hormones regulate Zfp423 expression in regionally distinct adipose depots through direct and cell-autonomous action

Highlights

• Thyroid hormones (TH) regulate Zfp423 expression in adipose depots

• This is mediated by distinct TR isoforms and a negative TRE within Zfp423 promoter

• TH deficiency induces the enrichment of Zfp423-expressing preadipocytes

• TH modulate ZFP423-dependent gene programs in adipogenesis

Summary

The hypothalamic pituitary thyroid axis is a major regulator of many differentiation processes, including adipose tissue. However, it remains unclear whether and how thyroid hormone (TH) signaling contributes to preadipocyte commitment and differentiation into mature adipocytes. Here, we show a cell-autonomous effect of TH on the transcriptional regulation of zinc finger protein 423 (Zfp423), an early adipogenic determination factor, in murine adipose depots. Mechanistically, binding of the unliganded TH receptor to a negative TH responsive element within the Zfp423 promoter activates transcriptional activity that is reversed upon TH binding. Zfp423 upregulation is associated with increased GFP⁺ preadipocyte recruitment in stromal vascular fraction isolated from white fat of hypothyroid Zfp423^GFP reporter mice. RNA sequencing identified Zfp423-driven gene programs that are modulated in response to TH during adipogenic differentiation. Collectively, we identified Zfp423 as a key molecule that integrates TH signaling into the regulation of adipose tissue plasticity.