Obesity is often described as a symptom of energy imbalance in which energy intake far exceeds energy output. However, over a decade ago, scientists determined that the obese state is also associated with low-grade chronic inflammation (Johnson et al. 2012), with macrophages being the main drivers of this inflammatory state (Weisberg et al. 2003).
At the onset of weight gain, there is a 4-5 fold increase in macrophages in adipose tissue (Xu et al. 2003). These cells ultimately account for 50% of the total cells, and have been shown to be the cause of both the development of insulin resistance and type 2 diabetes in obese individuals (Weisberg et al. 2006, Heilbronn and Campbell 2008).
The accumulation of fat is also linked to a significant shift in macrophage polarization from the anti-inflammatory M2 polarization to a pro-inflammatory M1 polarization in the obese adipose tissue (Johnson et al. 2012). An “M0” macrophage phenotype with a role in driving inflammation has also been identified in the obese state (Zeyda et al. 2010).
The differences between macrophages in the lean versus obese state also extend to their distribution within adipose tissue. In contrast to the lean state where M2 macrophages are evenly distributed throughout, in the obese state, M1 macrophages are situated around adipocytes (fat cells that compose adipose tissue) that are dead and form “crown-like structures” (CLSs). The macrophages in these CLSs have been directly linked to insulin resistance (Boutens and Stienstra 2016).
M1 macrophages in obese adipose tissue induce insulin resistance through mechanisms that involve toll-like receptor 4 (TLR-4) and nuclear factor kappa B (NF-κB) signaling (Arkan et al. 2005, Shi et al. 2006). Fatty acids, which are elevated in obesity, are the main factors that activate these inflammatory pathways in adipocytes and macrophages.
Upon activation by fatty acids, TLR-4 signaling in macrophages and adipocytes leads to subsequent activation of the JNK signaling cascade, which induces serine phosphorylation of insulin receptor substrate (IRS)-1 and IRS-2 (Shi et al. 2006, Hirosumi et al. 2002) and drives insulin resistance. Fatty acid activation of TLR-4 signaling can also indirectly activate the JNK signaling pathway through the secretion of pro-inflammatory cytokines such as tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 by activated macrophages and adipocytes (Hirosumi et al. 2002).
Fatty acids can also directly activate the NF-κB pathway in macrophages, and it has been shown that myeloid cell specific knockout of IKK-β function, which is upstream of NF-κB activation, resulted in protection from obesity development and insulin resistance (Arkan et al. 2005).
As obesity remains a significant public health concern worldwide, inhibiting macrophage infiltration into adipose tissue is being considered as a potential therapeutic strategy for obese patients, as well as for addressing obesity-associated insulin resistance and type 2 diabetes (Heilbronn and Campbell 2008).
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