Does C-C Motif Chemokine Ligand 2 (CCL2) Link Obesity to a Pro-Inflammatory State?

Abstract

The mechanisms of how obesity contributes to the development of cardio-metabolic diseases are not entirely understood. Obesity is frequently associated with adipose tissue dysfunction, characterized by, e.g., adipocyte hypertrophy, ectopic fat accumulation, immune cell infiltration, and the altered secretion of adipokines. Factors secreted from adipose tissue may induce and/or maintain a local and systemic low-grade activation of the innate immune system. Attraction of macrophages into adipose tissue and altered crosstalk between macrophages, adipocytes, and other cells of adipose tissue are symptoms of metabolic inflammation. Among several secreted factors attracting immune cells to adipose tissue, chemotactic C-C motif chemokine ligand 2 (CCL2) (also described as monocyte chemoattractant protein-1 (MCP-1)) has been shown to play a crucial role in adipose tissue macrophage infiltration. In this review, we aimed to summarize and discuss the current knowledge on CCL2 with a focus on its role in linking obesity to cardio-metabolic diseases.

Roles of CCL2-CCR2 Axis in the Tumor Microenvironment

“…In other words, the relationship between CCL2 and CCR2 is not completely one-to-one, but overlaps with multiple ligands and receptors [9]. The major signaling pathway of the CCL2-CCR2 axis is through intracellular Gproteins, and when CCL2 binds to CCR2, the α subunit dissociates from the intracellular G-protein [10,11]. The α subunit then inhibits adenylyl cyclase function, leading to a decrease in phosphate levels [10,11].…”

“…The major signaling pathway of the CCL2-CCR2 axis is through intracellular Gproteins, and when CCL2 binds to CCR2, the α subunit dissociates from the intracellular G-protein [10,11]. The α subunit then inhibits adenylyl cyclase function, leading to a decrease in phosphate levels [10,11]. The remaining βγ-subunit-bound conjugates promote nuclear transfer of nuclear-factor-κB (NF-κB) via Akt activation [10,11].…”

Contribution of Adipose Tissue Oxidative Stress to Obesity-Associated Diabetes Risk and Ethnic Differences: Focus on Women of African Ancestry

“…However, macrophages can also produce ROS (e.g., O 2 − , H 2 O 2 and OH − ), which provides positive feedback to upregulate T-helper 1 cell activation and further sustain a pro-inflammatory state [123]. Moreover, increased NOX2 activity following macrophage-induced ROS production may subsequently dysregulate the expression of inflammatory adipokines (e.g., reduced adiponectin, increased plasminogen activator inhibitor-1 (PAI-1), monocyte chemoattractant protein 1 (MCP-1) and IL-6) and decrease the production of antioxidant enzymes [18,64,74,124]. ROS and by-products of lipid peroxidation such as MDA further induce the attraction, infiltration and activation of macrophages into AT and inflammation [18,74].…”

On the Role of Paraoxonase-1, Chemokine (C-C motif) Ligand 2 and Metabolism in Oxidation, Inflammation and Disease. A 2021 Update

“…Increased expression of inflammatory mediators has been observed in visceral fat of individuals with obesity [102,103]. Other metabolic tissues, apart from adipose tissue, contribute to the severity of the disease and, in consequence, to macrophage trafficking and infiltration mediated by chemokines [99,104,105]. Generally, the concept of abnormal nutrient intake should consider not only the total amount of calories consumed, but also their quality.…”

“…In humans, body mass index correlates well with adipose tissue CCL2 expression [116,117]. CCL2 has been suggested to influence the function of adipocytes and to be the link between adipose tissue inflammation, insulin resistance and liver impairment [99,118,119]. The inflammatory reaction induced by CCL2 could contribute to deterioration of cell homeostasis and energy requirements in metabolic organs [53,118].…”