Toll-Like Receptor, Lipotoxicity and Chronic inflammation: The Pathological Link Between Obesity and Cardiometabolic Disease

Abstract

The epidemic growth in the prevalence of obesity has made the impact of metabolic syndrome on cardiovascular events increasingly significant. Elevated visceral adiposity, the indispensable component of metabolic syndrome, is thought to play a primary role in the increasing incidence of cardiometabolic disorders. Importantly, obesity is not merely the simple expansion of adipose tissue mass; it also involves the activation of inflammatory processes within visceral adipose tissue. Adipose tissue inflammation on the one hand enhances the production of proinflammatory adipokines and on the other hand increases the release of free fatty acids via the activation of lipolysis. The adipokines and free fatty acids secreted from visceral fat then contribute to a cardiometabolic pathology. We herein summarize recent advances in our understanding of the mechanisms by which visceral obesity leads to the activation of inflammation in cardiovascular and metabolic tissues and promotes cardiometabolic disease. Our focus is on Toll-like receptor 4 signaling and free fatty acids as mediators of chronic inflammation in patients with metabolic syndrome and atherosclerosis.

Islet inflammation in type 2 diabetes and physiology

“…Several factors, including saturated FFAs, minimally modified LDL (mmLDL) cholesterol, advanced glycation end products of LDL cholesterol, and damage-associated molecular patterns (61) such as HSP60, S100 calcium-binding protein A8 (62), and high-mobility group B (HMGB) proteins (63) all reportedly activate TLRs in obese AT (64). Indeed, saturated FFAs have been reported to induce chemokine (Cxcl1 and Ccl3) expression within islets in vitro (12,46).…”

Contribution of Macrophage Polarization to Metabolic Diseases

“…The phenotype of adipose tissue macrophages (ATMs) is considered to be an M2-like phenotype; however, M1-like activation of ATMs is associated with the insulin resistance of adipocytes in obese patient and a murine obesity model 20) . Macrophage-derived TNF-, IL-6, MCP-1, IL-1 , and nitric oxide are suggested to be involved in the insulin resistance of adipocytes 24) . Saturated fatty acids (SFA) derived from adipocytes stimulate ATMs via TLR2/4 and Fetuin-A to express the M1 phenotype 24) , and cytokine secretion by activated Fig.…”

“…Macrophage-derived TNF-, IL-6, MCP-1, IL-1 , and nitric oxide are suggested to be involved in the insulin resistance of adipocytes 24) . Saturated fatty acids (SFA) derived from adipocytes stimulate ATMs via TLR2/4 and Fetuin-A to express the M1 phenotype 24) , and cytokine secretion by activated Fig. 1.…”

Acidification of the intimal fluid: the perfect storm for atherogenesis

“…Phospholipase A 2 (PLA 2 ) enzymes hydrolyze sn-2 ester bonds in glycerophospholipids, yielding lysophospholipids and FFAs, which have been shown to have proinfl ammatory effects (98)(99)(100)(101)(102). In addition, as noted above, the FFAs may contribute to extracellular acidifi cation.…”