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

Moreover, TNF-a-induced insulin resistance on glucose uptake in
brown adipocytes seems to be due to the hypophosphorylation of the
IR and IRS-2 in response to insulin, resulting in an impairment of
IRS-2-associated PI3K activity (41). As a further step, we have
identified ceramide production as one of the mediators of insulin-
resistance by TNF-a and exogenously added C2-ceramide inhibited
AKT activity throughout a ceramide-activated phosphatase (41).
Furthermore, de novo ceramide generation produced by chronic
treatment with TNF-a induces insulin resistance on GLUT4 gene
expression in brown adipocytes by interfering C/EBPa acumulation
(42). Moreover, stress kinases activated in response to TNF-a, meanly
ERK and p38MAPKs also contribute to insulin resistance in brown
adipocyte primary cultures (43).

Recently, a significant enhancement of PTP1B mRNA, protein
and activity was observed in brown adipocytes treated with TNF-<
(44). As expected, the lack of PTP1B these cells confered protection
against TNF-a-induced insulin resistance on glucose uptake and
insulin signalling (44). Therefore, modulation of genes such as
PTP1B might contribute to the pathogenesis of TNF-<-induced insulin
resistance in murine brown adipocytes.

Accordingly, a complex mechanism impairs the normal response
to insulin on GLUT4 translocation in brown adipocytes in the
presence of TNF-a including 1) potential serine/treonine phosphory-
lation of IRS-2 by MAPKs, weakening the tyrosine phosphorylation
induced by insulin, 2) generation of ceramide and activation of PP2A
maintaining AKT in an inactive dephosphorylated state and 3)
modulation of PTP1B protein expression and activity, as summarized
in Figure 4.

PPAR? AND LXR AGONISTS AMELIORATE TNF-a-INDUCED
INSULIN RESISTANCE IN BROWN ADIPOCYTES

Nuclear receptors, such as retinoic acid receptor, peroxisome
proliferator activated receptors (PPAR), and liver X receptor (LXR),
comprise a superfamily of related proteins, which act as transcription
factors to activate expression of target genes in response to binding
of ligands. Thiazolidinediones (TZD), such as pioglitazone and

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