Metabolic Inflammation and Insulin Resistance in Obesity

Abstract

Obesity is becoming an epidemic in the United States and worldwide and increases risk for many diseases, particularly insulin resistance, type 2 diabetes mellitus, and cardiovascular disease. The mechanisms linking obesity with these diseases remain incompletely understood. Over the past 2 to 3 decades, it has been recognized that in obesity, inflammation, with increased accumulation and inflammatory polarization of immune cells, takes place in various tissues, including adipose tissue, skeletal muscle, liver, gut, pancreatic islet, and brain and may contribute to obesity-linked metabolic dysfunctions, leading to insulin resistance and type 2 diabetes mellitus. Therapies targeting inflammation have shed light on certain obesity-linked diseases, including type 2 diabetes mellitus and atherosclerotic cardiovascular disease, but remain to be tested further and confirmed in clinical trials. This review focuses on inflammation in adipose tissue and its potential role in insulin resistance associated with obesity.

Keywords: adipose tissue; diabetes mellitus; inflammation; insulin resistance; obesity.

Figure 1.. Regulation of inflammation in adipose tissue (AT).

In lean conditions, AT is enriched with type 2 immune cells, including alternatively activated M2-like macrophages (M2), innate lymphoid type 2 cells (ILC2), regulatory T cells (Treg), T helper type 2 cells (Th2), eosinophils, and others, which interact with each other by producing type 2 cytokines such as interleukin-4 (IL-4), IL-5, and IL-13 and also by direct contact via interactions of cell surface molecules, to maintain a type 2 immune environment. With the development of obesity, particularly induced by high-fat diet (HFD), dietary saturated fatty acids, along with AT hypoxia, danger-associated molecular patterns (DAMPs), and “metabolic endotoxemia” with increased plasma levels of lipopolysaccharide (LPS) that develop in obesity, may promote type 1 inflammation in AT, with increased inflammation in adipocytes and elevated number and type 1 inflammatory polarization or “metabolically activated” activation of a variety of immune cells, including macrophages, T cells, B cells, neutrophils, and others, which produce a large number of type 1 inflammatory molecules and also interact directly with each other to induce a type 1 inflammatory environment in AT. ICAM-1 indicates intercellular adhesion molecule–1; ICOS, inducible costimulator; ICOSL, inducible costimulator ligand; IFNγ, interferon-γ; ILC, innate lymphoid cells; iNKT, invariant natural killer T cells; LFA-1, leukocyte function-associated antigen–1; MCP-1, monocyte chemoattractant protein–1; MHC, major histocompatibility complex; MPO, myeloperoxidase; NK, natural killer cells; RANTES, regulated on activation, normal T cell expressed and secreted; TCR, T-cell receptor; and TNFα, tumor necrosis factor–α. (Illustration Credit: Ben Smith).

Figure 2.. Impact of inflammation on AT metabolism and remodeling.

A. In lean conditions, with a type 2 immune environment, various immune cells through different mechanisms contribute to maintenance of normal AT functions including adipocyte insulin sensitivity and beige adipogenesis. B. In obesity, type 1 inflammatory or metabolically activated immune cells may contribute to AT dysfunctions by adversely regulating adipocyte metabolism and AT remodeling, including induction of insulin resistance in adipocytes, suppression of beige adipogenesis, and induction of dysfunctional AT remodeling. Studies also show that in obesity, adipocyte inflammation may be essential for healthy AT expansion and remodeling and that lipid storage within AT macrophages may protect against obesity-linked adipocyte dysfunctions. ECM indicates extracellular matrix; MET-ENK, methionine-enkephalin; MMPs, matrix metalloproteinases; NE, norepinephrine; TGFβ, transforming growth factor–β; and VCAM-1, vascular cell adhesion molecule–1. (Illustration Credit: Ben Smith).