The transcription factor Prep1 regulates adipose tissue functions

Adipose tissue is crucial for maintaining energy and metabolichomeostasis and its functionality is closely related to the adipocytesdifferentiation state. Adipogenesis is regulated by several transcription factors.Prep1 is an homeodomain transcription factor belonging to the TALEproteins, which plays an important role in hematopoiesis, organogenesis anddevelopment. Previous studies have indicated that Prep1 hypomorphicheterozygous (Prep1i/+) mice, which express only 55-57% of protein, have acomplex metabolic phenotype. In fact, these mice present smaller butotherwise normally structured islets with reduced fasting and post-loadingplasma insulin levels and increased insulin sensitivity in skeletal muscle and inliver which is accompanied by protection from streptozotocin-induceddiabetes. In addition, Prep1 deficiency in mice induces a reduction of hepatictriglycerides synthesis and a protection from methionine and choline-deficientdiet-induced steatohepatitis.In this study, I focused my attention on the role of Prep1 on the regulation ofadipocyte differentiation and on the adipose tissue functionality.To understand the possible role of Prep1 in adipose tissue, I first evaluated thefeatures of adipose tissue of Prep1i/+ and WT mice. Prep1i/+mice show areduction of adipose tissue weight, a reduction of the area but no change in thenumber of adipocytes. In addition, expression of adipogenic markers, C/EBP,GLUT4 and FABP4, is increased in adipose tissue of Prep1i/+ mice, whilePPAR does not change. Consistent with these data, upon insulin stimulation,insulin receptor (IR), AKT and MAPK phosphorylation is increased in adiposetissue of Prep1 hypomorphic heterozygous mice. In addition, basal andinsulin- stimulated glucose-uptake is increased in adipocytes isolated fromadipose tissue of Prep1i/+ mice compared to the adipocytes from WT mice.The increased basal uptake is fully consistent with the higher expression ofGLUT4 on the plasma membrane of adipocytes of Prep1i/+ mice comparedwith that of control animals.To further study the function of Prep1 on adipocyte differentiation, I haveanalyzed Prep1 expression during different steps of adipogenesis in 3T3L1murine cells. Levels of Prep1 are progressively reduced during the conversionfrom 3T3L1 preadipocytes to adipocytes. Moreover, 3T3L1 adipocytes stablytransfected with Prep1 cDNA display reduced lipid accumulation, andexpression of C/EBP, GLUT4 and FABP4. Interestingly, insulin molecularsignaling 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 inpreventing adipose tissue dysfunctions. [edited by author]