Prep1 Deficiency Induces Protection from Diabetes and Increased Insulin Sensitivity through a p160-Mediated Mechanism

Abstract

We have examined glucose homeostasis in mice hypomorphic for the homeotic transcription factor gene Prep1. Prep1-hypomorphic (Prep1^i/i) mice exhibit an absolute reduction in circulating insulin levels but normal glucose tolerance. In addition, these mice exhibit protection from streptozotocin-induced diabetes and enhanced insulin sensitivity with improved glucose uptake and insulin-dependent glucose disposal by skeletal muscle. This muscle phenotype does not depend on reduced expression of the known Prep1 transcription partner, Pbx1. Instead, in Prep1^i/i muscle, we find normal Pbx1 but reduced levels of the recently identified novel Prep1 interactor p160. Consistent with this reduction, we find a muscle-selective increase in mRNA and protein levels of PGC-1α, accompanied by enhanced expression of the GLUT4 transporter, responsible for insulin-stimulated glucose uptake in muscle. Indeed, using L6 skeletal muscle cells, we induced the opposite effects by overexpressing Prep1 or p160, but not Pbx1. In vivo skeletal muscle delivery of p160 cDNA in Prep1^i/i mice also reverses the molecular phenotype. Finally, we show that Prep1 controls the stability of the p160 protein. We conclude that Prep1 controls insulin sensitivity through the p160-GLUT4 pathway.

ACKNOWLEDGMENTS

This work was supported, in part, by the European Community's FP6 EUGENE2 (contract LSHM-CT-2004-512013) and FP7 PREPROBEDIA (grant 201681), by an EFSD/Lilly grant, by the Associazione Italiana per la Ricerca sul Cancro (AIRC), and by the Ministero dell'Università e della Ricerca Scientifica (PRIN and FIRB RBNE0155LB). The financial support of Telethon—Italy is gratefully acknowledged. V. M. Diaz was a recipient of a Marie Curie Fellowship from the EU.

We are grateful to A. Zabatta for helping with the morphometric analysis. The technical help of Salvatore Sequino is also acknowledged.