Page 192 - 73_04

MARGARITA LORENZO Y COLS. ANAL. REAL ACAD. NAC. FARM.

mechanisms employed for TZD to increase insulin sensitivity are
still unclear. Rosiglitazone reduced FFA circulating levels and
potentiated insulin-stimulated AKT phosphorylation in WAT and
muscle from Zucker obese rats (46). Moreover, other evidence favors
TZD effects on glucose uptake by modulating changes at the level of
the expression of IRS-2, p85-PI3K, GLUT4 or GLUT1 either in white
adipocyte or muscle cells (46). However, several limitations with this
therapy, such as increased adiposity, secondary insulin resistance in
WAT, and pro- and anti-atherogenic effects, are currently emerging.

LXRa is expressed predominantly in liver, WAT, and ma-
crophages, and is activated by naturally produced oxysterols, as well
as by synthetic compounds such as T0901317 and GW3965 (47).
Although LXR function has been elucidated in detail with respect to
cholesterol and lipid metabolism, new findings have emerged LXR
as important regulators of glucose metabolism (47). Recent studies
have reported low plasma glucose, improved glucose tolerance and
increased glucose-induced insulin secretion by islets in genetic and
dietary models of type 2 diabetes treated with synthetic LXR
agonists. Several evidences suggest that LXR activity may be
important in WAT because these nuclear receptors are abundant in
subcutaneous fat preferentially (47), LXR expression is regulated by
the key adipocyte transcription factor PPAR? and many LXR target
genes are also highly expressed in adipocytes. Moreover, ligand
activation of LXR regulates the expression of GLUT4 either in vivo
as well as in murine and human adipocytes, through direct
interaction with a conserved LXR response element in the GLUT4
promoter. In addition, the ability of LXR ligands to regulate GLUT4
expression was abolished in mice lacking LXRs.

BAT is also a target tissue for nuclear receptors agonists since
highly expressed PPAR?, LXRa, and LXRß (47). In this regard, the
PPAR? agonist rosiglitazone up-regulates the expression of LPL, HSL
and UCP-1 in brown adipocytes (48) as well as produces insulin
sensitization by increasing the expression of IR and its tyrosine
kinase activity (49). The effectiveness of rosiglitazone to treat TNF-
a-induced insulin resistance in these cells was due to the fact that
this TZD impaired the activation of p38MAPK and ERK produced by
TNF-a, and restored the insulin signaling cascade leading to
normalization of insulin-induced glucose uptake (43). Furthermore,

1002