Obesity and inflammation

The above data explain why an insulin-resistant state may be pro-inflammatory. They do not, however, explain the origin of insulin resistance. Mutations of the genes involved in insulin signal transduction provide one approach to the study of this issue in humans and in mice with specific gene knockouts. Such lesions are of interest but are too infrequent to provide a basis for the understanding of the pathogenesis of insulin resistance at large in humans. Thus, some recent observations on the interference of insulin signal transduction by inflammatory mechanisms are of great interest because obesity is a pro-inflammatory state (Figure 2.2).

Even if we accept that inflammatory mechanisms are involved in the patho-genesis of interference with insulin signal transduction and of insulin resistance itself, how does inflammation arise? Over the past decade, obesity has been associated with inflammation. This association was first proposed in a landmark paper by Hotamisligil et al. in which TNFa was shown to be constitutively expressed by adipose tissue, to be hyper-expressed in obesity, and to mediate insulin resistance in the major animal models of obesity.38 This seminal paper also demonstrated that the neutralization of TNFa with soluble TNFa receptors resulted in the restoration of insulin sensitivity. Thus, the TNFa pro-inflammatory cytokine was the mediator of insulin resistance. Although the infusion of soluble TNFa receptors in humans has not reproduced the results observed in mice,39 Hotamisligil's paper laid the foundation of the concept that inflammatory mechanisms may have a role to play in the pathogenesis of insulin resistance.

More data have now accumulated to reinforce the concept that obesity is an inflammatory state in humans. Increased plasma concentrations of TNFa, IL-6, CRP, MIF, and other inflammatory mediators were demonstrated in obese subjects.3740-44 Adipose tissue has been shown to express most of these pro-inflammatory mediators. It has also been shown that macrophages residing in adipose tissue may also be sources of pro-inflammatory factors and may also modulate the secretory activities of adipocytes.45

Tonic vasconstriction -abnormal vascular reactivity - j vascular flow reserve

| Cardio-protection

I NO bioavailability t ADMA

Larger infarcts t Tendency to CHF

Platelet Hyperaggregability

I NO I PGL, t ROS generation t Oxidative stress

Novel features of metabolic syndrome on the basis of the vascular and other effects of insulin

Pro-apoptotic state t Infarct size

Atherosclerosis f NADPH oxidase f Mitochondrial superoxide

CHD Stroke

Chronic pro-inflammatory state

Pro-thrombotic state t NFkB I IkB t MIF t CRP t TNFa t TF

Anti-fibrinolytic state t PAl-1

FIGURE 2.2 Extension of metabolic syndrome based on novel actions of insulin. (Source: From Dandona, P. et al., Circulation 111, 1448, 2005.)

Tissue macrophages are derived from monocytes in blood. Recently, the mononuclear cells of obese patients, of which monocytes constitute a fraction, have also been shown to be in an inflammatory state, expressing increased amounts of pro-inflammatory cytokines and related factors.46 In addition, these cells have been shown to have significantly increased binding of NFkB, the key pro-inflammatory transcription factor, and an increase in the intranuclear expression of p65 (Rel A), the major protein component of NFkB. These cells also express diminished amounts of IkB^, the inhibitor of NFkB. Evidence of inflammation clearly exists in various cells and in plasma in obesity.

In addition to TNFa and IL-6, the major adipocyte cytokines, three other important proteins, leptin, adiponectin, and resistin, need mention. While leptin is known for its function as a satiety signal that inhibits feeding, it has additional roles as a regulator of sexual function and as an immune modulator. It is also proinflammatory and induces platelet aggregation.47-49 Thus, its elevated concentrations may contribute to the pro-inflammatory state of obesity and to atherogenesis in the long term. On the other hand, adiponectin, secreted in abundance by adipocytes in normal subjects, is anti-inflammatory and thus potentially anti-atherogenic. In contrast to leptin, its concentration falls with weight gain and in obesity.50,51 It has been suggested that a low adiponectin concentration may be a marker for atherosclerosis and coronary heart disease.52 Furthermore, in several experimental models, it has been shown to be protective to the arterial endothelium.

Resistin, discovered as a gene suppressed by rosiglitazone in mouse adipose tissue, earned its name because it induced insulin resistance.53 Thiazolidenediones (TZDs) suppress resistin concentrations in humans while inducing an increase in adiponectin concentration consistent with the anti-inflammatory effects of these drugs. Furthermore, it has been shown that the increase in adiponectin and the decrease in resistin occur early after rosiglitazone treatment along with manifestations of other anti-inflammatory effects prior to any changes in plasma concentrations of insulin, glucose, or FFAs. Thus, these early anti-inflammatory effects are independent of the metabolic effects of TZDs.54

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