Adipocyte Dysfunction And Insulin Resistance

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Adipose tissue plays a key role in directing whole-body glucose disposal, although it accounts for only about 10% of insulin-stimulated glucose disposal. There is now substantial evidence that factors that regulate adipocyte function can ultimately lead to insulin sensitization in muscle. Along these lines, the discovery of the peroxisome proliferator-activated receptors (PPARs) in the early 1990s has revolutionized

Figure 4.6 CD68+ macrophages in human white adipose tissue. A hypertrophic adipocyte is surrounded by macrophages. Adipose tissue recruits macrophages for reasons that are not entirely clear. However, the local inflammatory milieu is thought to (a) increase adipocyte lipolysis as cytokines downregulate insulin signaling and (b) change the secretion of adipokines such as leptin and adiponectin. Photomicrograph courtesy of Barbara Kozak, PhD

Figure 4.6 CD68+ macrophages in human white adipose tissue. A hypertrophic adipocyte is surrounded by macrophages. Adipose tissue recruits macrophages for reasons that are not entirely clear. However, the local inflammatory milieu is thought to (a) increase adipocyte lipolysis as cytokines downregulate insulin signaling and (b) change the secretion of adipokines such as leptin and adiponectin. Photomicrograph courtesy of Barbara Kozak, PhD

our understanding of fat and carbohydrate metabolism and their interaction. In particular, a large body of evidence has accumulated suggesting that PPARy is a master regulator in the formation of fat cells and their ability to function normally in the adult21,22. PPARy is induced during adipocyte differentiation and ectopic expression of PPARy in non-adipogenic cells effectively converts them into mature adipocytes23,24. Thus, the discovery and study of the PPARs have contributed greatly to the evidence supporting the role of the adipocyte as having a major effect on skeletal muscle glucose uptake. First, there is evidence that activation of PPARy in adipose tissue improves its ability to store lipids, thereby reducing 'ectopic' fat storage in liver and muscle21. If this metabolic pathway is activated, lipid repartitioning on a whole-body level will occur increasing the triglyceride content of adipose tissue, lowering free fatty acids and triglycerides in the circulation, liver and muscle, resulting in improved insulin sensitivity. In essence, activation of this pathway will improve the 'lipotoxicity' as described for muscle. Furthermore, adipocytes are derived from pluripotent stem cell precursors and individuals who have a low capacity for proliferation and/or differentiation of precursors into mature fat-storing adipocytes are susceptible to hypertrophy of the existing adipocytes under conditions of energy excess25. Thus, adipocyte hypertrophy (i.e. large fat cells) is indicative of a failure to proliferate and/or differentiate, a failure to accommodate an increased energy flux resulting in ectopic (intracellular) storage in sites such as muscle, liver and pancreas, and correlates better with insulin resistance than any other measure of adiposity26,27 (Figure 4.6).

A second mechanism by which improvement in adipocyte function can improve insulin sensitivity is by altering the release of signaling molecules from fat (adipocytokines) that have metabolic effects in other tissues27-28. For example, it is well known that adipocytokines, such as leptin, tumor necrosis factor-a (TNF-a), resistin and adiponectin, have profound metabolic effects. It has been observed that PPARy

Obesity Inflammation

Obesity Inflammation

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Figure 4.7 The humoral theory of insulin resistance. In this model, insulin resistance results from pathophysiologic levels of circulating factors that are potentially derived from several different cell types. The possible role of adipocytes, macrophages (in adipose tissue, liver and elsewhere), and hepatocytes is shown, along with secreted factors that modulate insulin action at the cellular level. MCP, monocyte chemoattractant protein; IL, interleukin; TNF-a, tumor necrosis factor-a; PAI-1, plasminogen activator inhibitor type 1; RBP, retinol binding protein. From reference 29, with permission agonists may inhibit the expression of TNF-a and resistin which promote insulin resistance, whereas they may stimulate the production of adiponectin, which promotes fatty acid oxidation and insulin sensitivity in muscle and liver28 (Figure 4.7). In addition, substantial evidence has accumulated that chronic activation of the proinflammatory pathway in insulin target tissues and in macrophages may underlie the obesity-related component of these insulin-resistant states (Figure 4.8).

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