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

regulation and, in states of relative insulin deficiency such as
streptozotocin-induced diabetes and chronic fasting GLUT4 gene
expression is down-regulated, a situation that is reversed by insulin
treatment and refeeding (7). However, studies in cells failed to
establish a stimulatory role of insulin on GLUT4 expression,
suggesting that additional factors could be involved in this tissue. In
this regard, dexamethasone, a synthetic glucocorticoid, has been
shown to increase GLUT4 mRNA expression in myocytes, white
adipocytes and brown adipocytes, in these cells acting as a co-
regulator with insulin (8). This review is focused on examining
alterations on insulin action in states of insulin resistance associated
with obesity.

OBESITY, INFLAMATION AND INSULIN RESISTANCE

Type 2 diabetes mellitus is a complex metabolic disease with an
environmental and genetic component affecting over 5% of the
population in Western societies. This disease represents the final
stage of long existing metabolic disturbances with deleterious effects
on the vascular system, tissues and organs. Insulin resistance,
defined as a diminished ability of the cell to respond to the action
of insulin, is the most important pathophysiological feature in many
prediabetic states and, is the first detectable defect in type 2 diabetes.
The pathogenesis of type 2 diabetes involves abnormalities in both
insulin action and secretion. Insulin resistance is usually compen-
sated by hyperinsulinemia. Although moderate hyperinsulinemia
might be tolerated in the short term, chronic hyperinsulinemia
exacerbates insulin resistance and contributes directly to beta-cell
failure and diabetes (1). At the molecular level, insulin resistance
correlates with impaired insulin signalling in peripheral tissues
(Figure 2). Insulin resistance in adipose tissues leads to an increase
of lipolysis, with subsequent release of glycerol and free fatty acids
(FFA) into the circulation. It is widely accepted that increased
availability and utilization of FFA contribute to the development of
skeletal muscle insulin resistance, as well as to increased hepatic
glucose production (1). Both genetic and environmental factors can
contribute to develop insulin resistance and in the second group,
obesity has been proposed as an important contributor.

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