28 Chapter 2 high levels of fatty acids are caused by increased basal lipolysis in adipose tissues and this elevated concentration has been proposed to serve as a stimulus for the entry and accumulation of macrophages in adipose tissue by increasing the local production and release of pro-inflammatory cytokines and chemokines (15). High concentrations of saturated free fatty acids will also induce pro-inflammatory effects through activation of Toll-like receptors (16). A consequence of this activation is the induction of the Jun N-terminal kinase and inhibitor of κB kinase (JNK/IKKκB) pathways, which is then followed by an inflammatory cascade. Both JNK and IKK are believed to promote insulin resistance because they phosphorylate serine/ threonine residues on insulin receptor substrate (IRS) proteins. By phosphorylating these residues, their phosphorylation by insulin receptors is blocked, which prevents the activation of insulin receptors by insulin. The result is inhibition of insulindriven signal transduction and downstream effects thus inhibiting glucose entry into the cell and its accumulation in the blood. MACROPHAGES AND INFLAMMATION IN OBESITY AND DMTII The inflammation related to obesity was first described in 1993 when Hotamisligil et al. showed that adipose tissue from obese rats expressed more tumor necrosis factor-α (TNF-α) (17) than adipose tissue from lean animals. Weisberg and colleagues further showed that TNF-α was not secreted by adipocytes but by macrophages and that the number of macrophages increased in adipose tissue during weight gain (10). Macrophages develop either from self-renewing fetal progenitors that can populate tissues before birth and maintain their numbers after birth or from circulating monocytes recruited to tissues after birth (18). Studies have shown a higher number of macrophages in white adipose tissue of obese subjects compared to people of normal BMI, going from 10% of total cells to more than 50% (19). The origin of these macrophages, either through local proliferation or monocyte recruitment, remains to be established in detail. A recent study in mice found that local proliferation of adipose tissue-resident macrophages at least contributes to macrophage accumulation during obesity too (20). Studies have shown that during obesity, triglyceride accumulation causes stress on adipocytes due to an increase in cell size and subsequent hypoxia (21). Capillary network development cannot keep up with fat mass expansion, resulting in adipocytes that are too far away from the vasculature to be efficiently supplied with oxygen (22). This leads to higher expression of hypoxia-inducible factor, adipocyte activation, and production and subsequent release of free fatty acids and pro-inflammatory mediators such as interleukin-1β (IL-1β), IL-6, macrophage migration inhibitory factor (MIF), monocyte chemoattractant protein 1 (MCP-1, also
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