Inflammatory concepts of obesity

Abstract

Obesity, long considered a condition characterized by the deposition of inert fat, is now recognized as a chronic and systemic inflammatory disease, where adipose tissue plays a crucial endocrine role through the production of numerous bioactive molecules, collectively known as adipokines. These molecules regulate carbohydrate and lipid metabolism, immune function and blood coagulability, and may serve as blood markers of cardiometabolic risk. Local inflammatory loops operate in adipose tissue as a consequence of nutrient overload, and crosstalk among its cellular constituents-adipocytes, endothelial and immune cells-results in the elaboration of inflammatory mediators. These mediators promote important systemic effects that can result in insulin resistance, dysmetabolism and cardiovascular disease. The understanding that inflammation plays a critical role in the pathogenesis of obesity-derived disorders has led to therapeutic approaches that target different points of the inflammatory network induced by obesity.

Figure 1

Adipose tissue inflammation in obesity. Whereas lean adipose tissue contains a population of resident inflammatory cells (1) and secretes various active substances, the obese adipose tissue (2) accumulates higher numbers of macrophages and T cells, producing copious amounts of inflammatory mediators, such as monocyte chemoattractant protein-1 (MCP-1) and interleukin-6 (IL-6), and less adiponectin (3). In the context of nutrient surplus and hypoxia, expanding adipocytes present endoplasmic reticulum (ER) stress (3), important trigger of inflammatory kinases, such as JNK and IKK, which can ultimately inhibit insulin signaling (further detail in the text) and activate inflammatory cascades and the production of inflammatory mediators. Existing evidence suggests that higher production of chemokines, such as MCP-1, within the obese adipose tissue could enhance local macrophage accumulation (4). Once in the tissue, monocyte-derived macrophages can be a fundamental source of tumor necrosis factor-alpha (TNFα), among other mediators. Cytokines like TNFα and other stimuli can cause further activation of inflammatory kinases (5). Several studies have demonstrated that T cells also accumulate in adipose tissue in the obese state (6). Interferon-gamma (IFNγ), a typical T-helper 1 cytokine, likely regulates local expression of TNFα, MCP-1, and other inflammatory mediators, suggesting a role for adaptive immunity in obesity pathophysiology. The spillover of adipokines, such as IL-6, into the circulation can also promote important systemic effects (7), such as increased production of liver-derived acute-phase inflammatory mediators and coagulation-related factors, most of them likely correlated with atherothrombosis.