Inflammatory Alterations In Adipose Tissue With Obesity

The profile of adipokines synthesized and secreted in adipose tissue changes dramatically as individuals become obese. one of the first clues that adiposity alters adipose tissue function was that adiposity was associated with increased expression of inflammatory cytokines, in particular TNF-a and interleukin (IL)-6 (65). TNF-a is a member of a family of secreted proteins that are characteristically produced by immune cells. Cytokines can exert their effect locally via paracrine/autocrine signaling, as well as circulating in the blood to act on distal tissues. TNF-a was initially implicated in the pathogenesis of the cachexia associated with cancer and infectious diseases. In fact, one laboratory initially referred to TNF-a as cachetin (66). It was therefore an initial surprise to find that obese individuals had increased expression levels of TNF-a in their adipose tissue (67,68).

Subsequent studies demonstrated a second AT-derived cytokine, IL-6, to be elevated in the serum of obese individuals and significantly correlated with FFA levels (69). Interestingly, more than 90% of IL-6 in adipose tissue was produced by nonadipocyte cells. In 2003 two separate laboratories independently reported a key observation concerning the appearance of macrophages in obese adipose tissue (70,71). There was a strong correlation between macrophage numbers with increasing adipocyte cell size (essentially reflecting increasing amounts of adipocyte triglyceride) and obesity. Adipose tissue macrophages were found to secrete several cytokines, including TNF-a and IL-6, as well as bioactive mediators of nitric oxide. These cytokines and other inflammatory mediators produced by macrophages are thought to alter adipocyte metabolism and function, as well as adipokine profile (72,73), and are further discussed later in the "TFN-a" and "IL-6" sections.

Interestingly, macrophage infiltration in adipose tissue appeared to precede or coincide with significant insulin resistance in obese rodents. The underlying mechanism(s) of macrophage infiltration remains unclear. The immune factor, monocyte chemotactic protein (MCP)-1 is one factor that has been suggested to be involved in recruiting macrophages in adipose tissue (74). Macrophages in obese animals and humans have been described to predominantly localize and form granuloma-type structures around dead adipocytes (75). It remains unclear whether the necrotic adipocytes promote macrophage infiltration into adipose tissue or if the macrophages enter the adipose tissue and actually kill adipocytes. Regardless, the residual insoluble triglyceride droplet from dead adipocytes may be viewed by the body as analogous to a foreign body, as the macrophages appear to surround, sequester, and scavenge the residual lipid droplet in similar manner.

Future studies (including those in our own laboratory) are aimed at understanding the basis of macrophage infiltration, adipocyte cell death, and adipose tissue inflammation. New information regarding the inflammatory state in obese adipose tissue, as well as how inflammatory cells contribute to or are causal to obesity-related diseases, will be critical to future pharmacological intervention.

Obesity is associated with increased fatty acids, one of the products of adipocyte lipolysis. Fatty acids are released from adipose tissue and then enter the circulation. Increases in circulating levels of fatty acids have been demonstrated to promote insulin resistance in both skeletal muscle and liver, as well as increase hepatic gluconeogenesis (76,77). The role and regulation of fatty acids in metabolism and obesity are discussed in detail in Chapter 5 of this book.

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