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VOL. 73 (4), 987-1008, 2007 CONTRIBUTION OF TNF-a TO OBESITY...

INTRODUCTION

Insulin exerts a dominant role in regulating glucose homeostasis
though orchestrated effects on promotion of glucose uptake in
peripheral tissues such as muscle and fat, and suppressing hepatic
glucose uptake. Insulin initiates the biological effects in target cells
by binding to, and activating endogenous tyrosine kinase receptors.
Insulin receptors (IR) are believed to transduce signals by
phosphorylation on tyrosine residues of several cellular substrates
including insulin receptor substrate (IRS) proteins 1,2,3 and 4 (1). A
number of signalling pathways can be activated downstream of IRS
proteins. Molecules containing Src homology 2 domain, including
the regulatory subunits of phosphatidylinositol 3-kinase (PI3K), Grb-
2 and others, are recruited to the tyrosine phosphorylated IRSs and
transmit a cascade of signals, which consists in two major elements,
i.e., Ras/Raf/ extracelullar-signal regulated kinase (ERK) and PI3K/
AKT/p70S6 kinase pathways. A parallel mitogen-activated protein
kinase (MAPK), p38MAPK, has been shown to be stimulated by
insulin in several cell systems including skeletal muscle (2). On the
other had, the insulin signaling cascade is negatively regulated by
protein phosphatases, including tyrosine-, serine- and lipid-
phosphatases. Most notably, protein-tyrosine phosphatase (PTP)1B
acts dephosphorylating the phosphotyrosine residues of the IR and
IRS-1 (Figure 1).

Both muscle and fat are target tissues for insulin action. In
skeletal muscle insulin and insulin-like growth factors (IGF)s control
differentiation and regeneration of the tissue. The signaling pathways
that accompany the formation of myotubes in C2C12 cells involved
sequential activation of PI3K, AKT, P70S6 kinase and p38MAPK
cascade in parallel to the induction of muscle-specific proteins, with
a concomitant inhibition of ERK (3). Adipose tissues, including the
most abundant white adipose tissue (WAT) and the thermogenic one
(BAT) are also under insulin control. In fetal brown adipocytes
insulin and IGF-I, acting independently and thought the activation
of the IRS-PI3K signaling pathway, up-regulated the expression of
adipogenic-related genes at the transcriptional level, as reviewed (4).
In addition to adipogenesis, insulin/IGF-I are thermogenic factors
through the ability to increase the uncoupling-protein (UCP)-1 gene

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