ReviewImmunity as a link between obesity and insulin resistance
Introduction
Two-thirds of adults in the United States are either overweight or obese (Flegal et al., 2010). Moreover, childhood obesity rates have tripled over the last three decades (Ogden and Carroll, 2010). Obesity is also an emerging health problem worldwide, with approximately 1.6 billion and 400 million adults being overweight and obese, respectively in 2005 (WHO, 2011). Obesity increases the risk for type-2 diabetes (T2D) (Kahn et al., 2006). As a result, parallel to the rise in obesity rates, the prevalence of diabetes has also increased over the last few decades. Moreover, US regions with highest rates of obesity also exhibit highest rates of diabetes (CDC, 2007) and the number of US adults with T2D has more than tripled (5.5–18.0 million) between 1980 and 2008 (CDC, 2009).
Obese individuals also develop insulin resistance and the metabolic syndrome, also known as pre-diabetes, which can later progress to diabetes. Indeed, recent evidence has causally linked obesity to T2D (Kahn et al., 2006). Immune cell infiltration of adipose tissue giving rise to a chronic low-grade inflammation is in-part responsible for the pathogenesis of insulin resistance in obesity (Kalupahana et al., 2011a). Evidence for the role of immunity as a link between obesity and insulin resistance is reviewed in this paper.
Section snippets
Insulin resistance and metabolic syndrome
Insulin resistance is defined as an inadequate response by insulin-sensitive tissues (liver, skeletal muscle and adipose tissue) to normal circulating levels of insulin (Schenk et al., 2008). During fasting conditions, hepatic output of glucose helps to maintain normal blood glucose concentrations (Fig. 1). The liver produces glucose via glycogenolysis and gluconeogenesis. Following a meal, the intestine becomes the major source of glucose, which increases the glucose availability to the
Molecular mechanisms of insulin resistance
Insulin exerts its physiological actions on insulin-sensitive tissues via activation of a cascade of intracellular signaling events. Details of this insulin signaling have been previously reviewed (Cheng et al., 2010, Taniguchi et al., 2006). Briefly, insulin binding to its receptor (insulin receptor – IR) triggers autophosphorylation as well as tyrosine phosphorylation of downstream substrates including the insulin receptor substrates (IRS) (Fig. 2). The latter step is important in eliciting
Role of inflammation in pathogenesis of insulin resistance
At the cellular level, pro-inflammatory cytokines such as TNF-α and IL-6 impair insulin signaling (discussed above). Moreover, overactivation of inflammatory pathways in insulin-sensitive tissues gives rise to local and systemic insulin resistance (Cai et al., 2005). In humans, markers of systemic inflammation are strongly associated with insulin resistance (de Rooij et al., 2009) and predict the development of T2D (Festa et al., 2002). As discussed below, acute and chronic infusion of
Immunity as a link between adipose tissue dysfunction and insulin resistance
Adipose tissue is a dynamic and heterogeneous endocrine organ. It is comprised of adipocytes, an extra-cellular matrix, vascular and neural tissues and other cell types such as preadipocytes, fibroblasts, stem cells and immune cells such as macrophages and T lymphocytes (Ibrahim, 2010). Adipose tissue secretes numerous bioactive peptides collectively known as adipokines (Kim and Moustaid-Moussa, 2000, Olefsky and Glass, 2010). Examples include peptides involved in glucose homeostasis such as
Conclusions
Adipose tissue inflammation is a causal link between obesity and insulin resistance. In lean adipose tissue, the anti-inflammatory Treg cells and M2 macrophages maintain normal insulin sensitivity. Obesity leads to adipocyte hypertrophy, which subsequently reduces the aforementioned anti-inflammatory immune cells, with infiltration of proinflammatory CD8+ T cells, CD4+ Th1 cells and M1 macrophages, leading to the development of insulin resistance. Identification of mechanisms responsible for
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