Pbx-regulating-protein 1 (Prep1) as a novel transcription factor linking immune system function and metabolism.

Prep1 is a transcription factor which plays an important role in organogenesis, in the regulation of energy homeostasis and metabolism. In particular, Prep1 has been recently demonstrated to inhibit insulin signaling, inducing insulin-resistance and contributing to steatohepatitis. Since accumulating evidence has shown that metabolic disorders are associated with immune system dysregulation, in this thesis we have characterized the role of Prep1 in the control of immune system function. We found a decreased secretion of pro-inflammatory cytokines/chemokines and enhanced anti-inflammatory cytokines release in the sera of Prep1-hypomorphic heterozygous mice (Prep1i/+), which express 55-57% of Prep1 protein. In addition, Prep1 deficiency significantly inhibited T cells proliferation and activation. These effects were associated with an impaired mTOR pathway activation, cell growth arrest and an altered metabolic profile of CD4+ T cells. On the other hand, regulatory T cells (Treg) from Prep1i/+ mice displayed higher proliferative capacity and increased suppressive activity, which determined in vivo protection of Prep1i/+ mice from high fat diet-induced metabolic alterations and hepatic inflammation. These observations unmask a previously unknown role of Prep1 in the regulation of adaptive immune response and provide a rationale for further investigating Prep1 as a possible target for immune-mediate metabolic disorders.