Another novel finding of the current study is the identification of transcriptional regulation of TH, the rate-limiting enzyme of the CA synthesis, by FoxO1. By binding directly to the promoter region of TH gene, FoxO1 might inhibit the transcription of TH gene, resulting in decreased TH expression. Consistent with the results from ChIP and luciferase analyses, FoxO1DAT KO mice showed significant increase in mRNA and protein levels of TH, which might, at least in part, drive the elevation of DA content in DA neurons. Since DA and noradrenergic neurons have closely reciprocal interactions52535455, elevated dopamine content might lead to increased norepinephrine level52 and hence together enhance sympathetic nervous system activity56. Many factors have been known to be involved in the control of TH transcription including the orphan nuclear receptor Nurr15758, transcription factors related to cAMP-protein kinase A (PKA) signalling59, and the heterogeneous nuclear ribonucleoprotein K (hnRNP-K)60. Examining whether FoxO1 is involved in the interaction or regulation with these factors in control of TH expression might be another area for future study.
