Chronic Adipose Tissue Inflammation Linking Obesity to Insulin Resistance and Type 2 Diabetes

Abstract

Obesity is one of the major health burdens of the 21st century as it contributes to the growing prevalence of its related comorbidities, including insulin resistance and type 2 diabetes. Growing evidence suggests a critical role for overnutrition in the development of low-grade inflammation. Specifically, chronic inflammation in adipose tissue is considered a crucial risk factor for the development of insulin resistance and type 2 diabetes in obese individuals. The triggers for adipose tissue inflammation are still poorly defined. However, obesity-induced adipose tissue expansion provides a plethora of intrinsic signals (e.g., adipocyte death, hypoxia, and mechanical stress) capable of initiating the inflammatory response. Immune dysregulation in adipose tissue of obese subjects results in a chronic low-grade inflammation characterized by increased infiltration and activation of innate and adaptive immune cells. Macrophages are the most abundant innate immune cells infiltrating and accumulating into adipose tissue of obese individuals; they constitute up to 40% of all adipose tissue cells in obesity. In obesity, adipose tissue macrophages are polarized into pro-inflammatory M1 macrophages and secrete many pro-inflammatory cytokines capable of impairing insulin signaling, therefore promoting the progression of insulin resistance. Besides macrophages, many other immune cells (e.g., dendritic cells, mast cells, neutrophils, B cells, and T cells) reside in adipose tissue during obesity, playing a key role in the development of adipose tissue inflammation and insulin resistance. The association of obesity, adipose tissue inflammation, and metabolic diseases makes inflammatory pathways an appealing target for the treatment of obesity-related metabolic complications. In this review, we summarize the molecular mechanisms responsible for the obesity-induced adipose tissue inflammation and progression toward obesity-associated comorbidities and highlight the current therapeutic strategies.

Keywords: adaptive immunity; adipose tissue inflammation; diabetes; inflammatory triggers; innate immune system; insulin resistance; low-grade inflammation; obesity.

FIGURE 1

Pathways linking local obesity-induced inflammation to systemic insulin resistance. Obesity results in the activation of the inflammatory signaling pathways mediated by JNK and nuclear factor-kappa B (NF-κB). Once activated, these pathways induce the production of several pro-inflammatory cytokines in adipocytes, which contribute to insulin resistance and pro-inflammatory macrophages infiltration. Activation of the JNK signaling pathway starts the transcription of pro-inflammatory genes and inhibits the insulin signaling pathway through the insulin receptor substrate-1 (IRS-1) inhibitory serine phosphorylation, which reduces the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB) signaling pathway. Instead, NF-κB signaling pathway activation culminates in the increased expression of several NF-κB target genes such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and monocyte chemotactic protein-1 (MCP-1), which leads to serine phosphorylation of IRS-1, therefore preventing insulin signaling. The inflammatory mediators including free fatty acids (FFA), IL-6, TNF-α, and MCP-1 also spread through systemic circulation and activate JNK and NF-κB signaling pathways in the liver and skeletal muscle, inhibiting systemic insulin signaling. GLUT4, glucose transporter type 4.

FIGURE 2

Obesity triggers inflammation. Obesity provides a plethora of intrinsic and extrinsic signals capable of triggering an inflammatory response in AT. These mechanisms are commonly considered the link between chronic caloric excess and adipose tissue inflammation. Some of these mechanisms include dysregulation of fatty acid homeostasis, increased adipose cell size and death, local hypoxia, mitochondrial dysfunction, endoplasmic reticulum (ER), and mechanical stress. These triggers converge on the activation of the c-Jun N-terminal kinase (JNK) and nuclear factor-kappa B (NF-κB) pathways, commonly considered signaling hubs. The activation of these pathways increases the production of pro-inflammatory cytokines and promotes the infiltration of pro-inflammatory M1 macrophages. TLR2, Toll like receptor 2; TLR4, Toll like receptor 4; FFA, free fatty acids; UPR, unfolded protein response; HIF-1α, hypoxia-inducible factor-1α; RhoA, ras homolog gene family, member A; TNF-α, tumor necrosis factor-α; IL-6, interleukin-6; MCP-1, monocyte chemotactic protein-1; ECM, extracellular matrix.