Role of metaflammation as asystemic manifestation of metabolic diseases

Abstract

Visceral obesity as acomponent of the metabolic syndrome is characterized by systemic and local inflammation, which can be quantified in organs (metaflammation). This process can be regarded as achronic, sterile, and low-grade state of inflammation without infection, trauma, tumor or autoimmunity. It is caused by an inflammation of the visceral adipose tissue (adipose inflammation or adipoflammation) due to adipocyte hypertrophy and hyperplasia with increased infiltration by monocytes and macrophages. Important is the presence of proinflammatory, so-called polarized M1 macrophages that are induced by interferon gamma (IFN-γ) and lipopolysaccharides (LPS) with secretion of interleukin (IL)-6, tumor necrosis factor (TNF) and IL‑1. In contrast, the anti-inflammatory, so-called polarized M2 macrophages induced by IL‑4 and IL-13 with secretion of IL‑8 and IL-10 decrease. In addition, the secreted adipokine pattern changes from anti-inflammatory to proinflammatory. Adipocyte necrosis, local hypoxia, dysregulated autophagy, activation of inflammasomes, modulation of toll-like receptors, and epigenetic factors play a complex role. This mechanism results in local insulin resistance and subsequently a systemic insulin resistance of peripheral organs as well as a spillover of local mediators of inflammation into the systemic circulation (measured as obesity C‑reactive protein, CRP). The activation of inflammatory signal transduction cascades leads to inhibitory phosphorylation of the insulin signaling pathway and a weakening of the effect of insulin. In parallel, ectopic lipid accumulation occurs in the liver, musculature, pancreas, pericardium and lungs. Diacylglycerol (DAG) activates specific isoforms of protein kinaseC (εin the liver and τin the musculature), which in turn lead to inhibition of the insulin signaling pathway. Insulin resistance in obesity and type2 diabetes mellitus is an inflammatory disease. The aim of future translational approaches is an anti-inflammatory, molecularly individualized (precision medicine) treatment in adipose tissue (targeted therapy) and in organs of insulin resistance.