Tfe3 and Tfeb transcriptionally regulate Pparγ2 expression in adipocytes and mediate adiponectin and glucose levels in mice.

Abstract Members of the MiT transcription factor family are pivotal regulators of several lineage-selective differentiation programs. We show that two of these, Tfeb and Tfe3, control the regulator of adipogenesis, Pparγ2. Knockdown of Tfeb or Tfe3 expression during in vitro adipogenesis causes dramatic downregulation of Pparγ2 expression as well as adipogenesis. Additionally, we found that these factors regulate Pparγ2 in mature adipocytes. Next, we demonstrated that Tfeb and Tfe3 act directly by binding to consensus E-boxes within the Pparγ transcriptional regulatory region. This transcriptional control also exists in vivo as we discovered that wildtype mice in the fed state increased their expression of Tfe3, Tf3b, and Pparγ in white adipose tissue. Furthermore, Tfe3KO mice in the fed state failed to upregulate Pparγ and adiponectin, a Pparγ dependent gene confirming the in vivo role for Tfe3. Lastly, we found that blood glucose is elevated and adiponectin serum levels suppressed in the Tfe3KO mice indicating that the Tfe3/Tfeb/Pparγ2 axis may contribute to whole body energy balance. Thus, we offer new insights into the upstream regulation of Pparγ by Tfe3/Tf3b and propose that targeting these transcription factors may offer opportunities to complement existing approaches for the treatment of diseases that have dysregulated energy metabolism.