Inflammation in Obesity

Obesity has become a public health crisis in the United States and much of the world. More than a billion people worldwide are estimated to be overweight, and at least 30% of these, or 300 million, are obese.1 Obesity itself would be of little concern if it were not associated with the “metabolic syndrome,” a constellation of metabolic abnormalities that portend the development of type 2 diabetes mellitus, atherosclerosis and non-alcoholic fatty liver disease.2 The list of diseases associated with obesity is ever growing. This inspires the question of how obesity triggers these complications and what can be done to intervene in the progression from obesity to disease.
Low-grade, chronic inflammation is now widely recognized to be a salient feature of obesity and many of its accompanying pathologies. Studies of critically ill humans and animals have demonstrated that inflammation can profoundly alter metabolic function. Investigators have postulated that obesity-associated inflammation may induce similar metabolic shifts. As in other unhealthy states, the teleological role of the immune system is likely to clear the insult and return the organism to a healthy, functional state.3,4 However, during obesity, this restoration of tissue function does not occur. Rather, the elaboration of cytokines and other inflammatory mediators seems to lead to a downward spiral of tissue dysfunction in metabolic organs. Many scientific investigators and clinicians have been interested in the possibility that suppressing inflammation may lead to improvement of metabolic parameters in obese patients. Thus, substantial effort has been placed on understanding how obesity incites inflammation, with the hope that such knowledge will lead to the development of novel and much needed therapeutics.5
The components of the generic inflammatory response can be conceptually divided into four major categories: inducers (LPS, PolyIC), sensors (TLRs, NLRs), mediators (cytokines, eicosinoids) and effectors (cells that respond to inflammatory mediators),3 which are connected in a simple circuit (Fig. 1). In obesity, elevated free fatty acids, “metabolic endotoxemia,” local hypoxia, products of adipocyte death and endoplasmic reticulum stress have all been implicated as potential inducers of inflammation.6 These are thought to activate sensors such as NLRP3, TLRs, HIF-1α and NFκB within adipocytes, hepatocytes and tissue macrophages,5,7-10 leading to the elaboration of mediators such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6 and the recruitment of inflammatory cells to the white adipose tissue (WAT). The best appreciated of these are CD11c+ macrophages,11,12 although nearly every cell of the immune system—conventional T cells, innate-like lymphocytes, B cells and mast cells5—accumulates in obese WAT and has been implicated in the transition from healthy to inflamed fat. These cells release additional cytokines, which may act on adipocytes, myocytes or hepatocytes to induce insulin resistance and lipolysis.13 Conversely, a few cell types (Foxp3+CD4+ regulatory T cells and eosinophils, for example) may have a salutary influence on metabolic homeostasis in healthy WAT, and are reduced during obesity.