| dc.description.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] | en_US |
