Obesity, Inflammation, and Insulin Resistance
Section snippets
Adipose Tissue
In addition to containing adipocytes, adipose tissue is well vascularized and innervated and contains a connective tissue matrix and numerous immune cells including macrophages.2, 3 White adipose tissue (WAT) is most familiar as the type of fat in which triglyceride is stored and from which lipids are mobilized for systemic utilization when other tissues require energy. WAT is often subdivided into subcutaneous and abdominal depots, whose physiologies may be distinguished and whose roles in
Liver
The specialized anatomy of the liver provides a mechanism for the portal and arterial circulations to interact with both liver parenchyma (hepatocytes) and the many immune cells also located within the liver. The hepatocytes represent approximately two thirds of the total cells in liver. The remaining cells are diverse and include biliary epithelial cells, sinusoidal endothelial cells, Kupffer cells (resident macrophages), stellate cells (also called Ito or fat-storage cells), dendritic cells,
Obesity as a Proinflammatory State
Epidemiologic evidence for links between obesity and inflammation have existed for decades, although these findings were not appreciated in terms of the pathophysiologic conditions associated with obesity. For example, the levels of circulating fibrinogen and other acute phase reactants were found to be elevated in obesity.22, 23, 24 More recent epidemiologic studies have confirmed and extended these earlier findings by showing increases of additional acute phase reactants in obese subjects,
Potential Mechanisms for Inflammation-Induced Insulin Resistance
Two transcription factor-signaling pathways have been linked to the proinflammatory effects of obesity and insulin resistance: the NF-κB pathway, which is activated by inhibitor of NF-κB (IκB) kinase β (IKKβ), and the c-Jun NH2-terminal kinase (JNK) pathway. These pathways are activated by many of the same proinflammatory stimuli including cytokines such as TNF-α, which in addition to being activators of NF-κB are also NF-κB-regulated products. Both pathways are also activated by pattern
IL-6
The proinflammatory cytokine IL-6 was among the first to be implicated as a predictor or pathogenic mediator of insulin resistance and CVD. There are increased circulating levels of IL-6 in patients with T2D.58, 59 A human polymorphism in the Il6 gene, which causes a decrease in circulating IL-6 levels, is associated with increased insulin sensitivity.60 Concentrations of IL-6 decrease in parallel with weight loss and improvement of insulin resistance in patients undergoing bariatric surgery (
Drugs That Either Target or Reduce Inflammation as Potential Treatments for Insulin Resistance
The hypothesis that TNF-α is involved in the pathogenesis of insulin resistance and the availability of biologic TNF-α blocking reagents provided both rationale and means for the testing of pharmacologically-directed anti-inflammatory therapies. In support of this approach, the infusion of a TNF receptor IgG fusion protein was found to improve insulin sensitivity in mice.31 Because TNF-α targeted biologic reagents are in clinical use for treating patients with various inflammatory conditions
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Cited by (0)
Supported by NIH grants DK43123, DK45943, DK51729, DK73547, DK74556, and HL83813 for research in the authors’ laboratory. L.H. was supported by a postdoctoral fellowship from the Spanish Ministry of Education and Science.