The transcription factor Prep1 regulates adipose tissue functions

Abstract

Adipose tissue is crucial for maintaining energy and metabolic homeostasis and its functionality is closely related to the adipocytes differentiation state. Adipogenesis is regulated by several transcription factors. Prep1 is an homeodomain transcription factor belonging to the TALE proteins, which plays an important role in hematopoiesis, organogenesis and development. Previous studies have indicated that Prep1 hypomorphic heterozygous (Prep1i/+) mice, which express only 55-57% of protein, have a complex metabolic phenotype. In fact, these mice present smaller but otherwise normally structured islets with reduced fasting and post-loading plasma insulin levels and increased insulin sensitivity in skeletal muscle and in liver which is accompanied by protection from streptozotocin-induced diabetes. In addition, Prep1 deficiency in mice induces a reduction of hepatic triglycerides synthesis and a protection from methionine and choline-deficient diet-induced steatohepatitis. In this study, I focused my attention on the role of Prep1 on the regulation of adipocyte differentiation and on the adipose tissue functionality. To understand the possible role of Prep1 in adipose tissue, I first evaluated the features of adipose tissue of Prep1i/+ and WT mice. Prep1i/+mice show a reduction of adipose tissue weight, a reduction of the area but no change in the number of adipocytes. In addition, expression of adipogenic markers, C/EBPα, GLUT4 and FABP4, is increased in adipose tissue of Prep1i/+ mice, while PPARγ does not change. Consistent with these data, upon insulin stimulation, insulin receptor (IR), AKT and MAPK phosphorylation is increased in adipose tissue of Prep1 hypomorphic heterozygous mice. In addition, basal and insulin- stimulated glucose-uptake is increased in adipocytes isolated from adipose tissue of Prep1i/+ mice compared to the adipocytes from WT mice. The increased basal uptake is fully consistent with the higher expression of GLUT4 on the plasma membrane of adipocytes of Prep1i/+ mice compared with that of control animals. To further study the function of Prep1 on adipocyte differentiation, I have analyzed Prep1 expression during different steps of adipogenesis in 3T3L1 murine cells. Levels of Prep1 are progressively reduced during the conversion from 3T3L1 preadipocytes to adipocytes. Moreover, 3T3L1 adipocytes stably transfected with Prep1 cDNA display reduced lipid accumulation, and expression of C/EBPα, GLUT4 and FABP4. Interestingly, insulin molecular signaling pathway is less activated in presence of Prep1. All together these data suggest that Prep1 regulates adipocyte differentiation, giving a rationale to investigate Prep1 as possible new therapeutic agents in preventing adipose tissue dysfunctions. [edited by author]