International Journal of Molecular Sciences Review Does C-C Motif Chemokine Ligand 2 (CCL2) Link Obesity to a Pro-Inflammatory State? Sebastian Dommel 1 and Matthias Blüher 1,2,* 1 Medical Department III—Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, Germany Liebigstr. 20, 04103 Leipzig, Germany; [email protected] 2 Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG), Helmholtz Zentrum München, University of Leipzig and University Hospital Leipzig, 04103 Leipzig, Germany * Correspondence: [email protected]; Tel.: +49-341-9715984 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. Keywords: adipokine; adipose tissue; obesity; inflammation; chemokine Citation: Dommel, S.; Blüher, M. Does C-C Motif Chemokine Ligand 2 (CCL2) Link Obesity to a Pro-Inflammatory State?. Int. J. Mol. 1. Introduction Sci. 2021, 22, 1500. https://doi.org/ Accumulation of adipose tissue (AT) is the major symptom of obesity. Until about 10.3390/ijms22031500 25 years ago, AT was regarded as an energy storage organ that additionally acts as isolation for the inner organs [1]. Due to the discovery of its endocrine function in the late 1980s, Academic Editor: Maria our understanding of AT changed fundamentally [2]. Since then, hundreds of bioactive Gisella Cavallo components secreted by AT have been found [3,4]. Those AT-derived secretory factors Received: 1 December 2020 including leptin, adiponectin, adipsin, plasminogen activator inhibitor-1 (PAI1), comple- Accepted: 29 January 2021 α Published: 2 February 2021 ment components, or cytokines such as tumor necrosis factors (e.g., TNF- ) or chemokines (e.g., CCL2) have been described with the term “adipokines” [5]. biologically active molecules secreted from adipose tissue Publisher’s Note: MDPI stays neutral In 1999, Funahashi et al. defined “ ” with regard to jurisdictional claims in as “adipocytokines” [6]. However, this term is potentially misleading because it suggests published maps and institutional affil- that all AT-secreted substances are cytokines. While this is true for some AT-secreted iations. molecules (e.g., IL-6 or TNF-α), the majority is of non-cytokine origin. Although Trayhurn and Wood recommended to use the term “’adipokine’ [ ... ] to describe a protein that is secreted from [ ... ] adipocytes”, commonly all AT-produced and -secreted substances are named “adipokines”, independent of whether they are secreted primarily from adipocytes or other AT cell types [7]. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. Adipokines are a heterogenous group of peptides including hormones, growth factors, This article is an open access article and cytokines which differ in their physiological functions. Adipokines play an important distributed under the terms and role in the regulation of energy homeostasis, appetite, satiety, lipid metabolism and glu- conditions of the Creative Commons cose homeostasis, blood pressure and vascular homeostasis, angiogenesis, and immune Attribution (CC BY) license (https:// response [8]. Whereas adipocyte-secreted adiponectin and leptin circulate in the blood creativecommons.org/licenses/by/ as endocrine factors, it was demonstrated that some adipokines mainly have a para or 4.0/). autocrine functions within AT without a contribution to inter-organ tissue crosstalk [9]. Int. J. Mol. Sci. 2021, 22, 1500. https://doi.org/10.3390/ijms22031500 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, 1500 2 of 20 Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 2 of 21 Serum concentrations of several adipokines reflect body energy stores, fat mass and dis- tribution, systemic insulin sensitivity, glucose tolerance, a pro-inflammatory state, and other phenotypeor autocrine characteristics functions within [4,10 AT–16 without]. As examples,a contribution leptin to inter-organ serum concentrations tissue crosstalk [9]. are proportionallySerum secreted concentrations to body of fatseveral mass adipokines [17], where reflect circulating body energy adiponectin stores, fat mass are and typically dis- lower in individualstribution, systemic with obesityinsulin sensitivity, compared gluc toose those tolerance, who a are pro-inflammatory lean [18]. Additionally, state, and several immune-modulatingother phenotype characteristics adipokines, [4,10–16]. such as As IL-6, examples, IL-8, CXCL5,leptin serum or CCL2, concentrations are elevated are in the obeseproportionally state [9,19]. secreted These changesto body fat in mass adipokines’ [17], where secretion circulating pattern adiponectin can beare explainedtypically lower in individuals with obesity compared to those who are lean [18]. Additionally, sev- by AT remodeling, a process in which quantitative and qualitive changes in the cellular eral immune-modulating adipokines, such as IL-6, IL-8, CXCL5, or CCL2, are elevated in compositionthe of obese AT occurstate [9,19]. in response These changes to excessive in adipok weightines’ secretion gain [20 pattern]. can be explained by AT is aAT complex remodeling, organ a process composed in which of severalquantitative cell and types qualitive (Figure changes1). Adipocytes in the cellular account com- for up to 80%position of AT of volume, AT occur but in response reflect onlyto excessive 20–40% weight of cell gain number. [20]. AT consists of adipose- derived stem cellsAT is (ADSCs), a complex preadipocytes, organ composed endothelialof several cell cells,types (Figure and leukocytes 1). Adipocytes [21, 22account]. Very recently, single-nucleusfor up to 80% of RNA-sequencing AT volume, but reflect (snRNA-seq) only 20–40% of analysis cell number. of mouse AT consists and of human adi- adipose tissuepose-derived revealed stem a subpopulation cells (ADSCs), preadipocytes, of adipocytes endothelial that regulates cells, and thermogenesis leukocytes [21,22]. [23 ]. Very recently, single-nucleus RNA-sequencing (snRNA-seq) analysis of mouse and hu- Dependingman on theiradipose type, tissue different revealed AT-cellsa subpopulation produce of adipocytes distinct adipokinethat regulates patterns. thermogenesis There- fore, knowing[23]. theDepending cellular on origin their fortype, adipokine different AT-c productionells produce is important distinct adipokine to dissect patterns. which cell type mightTherefore, be enriched knowing the and/or cellular activated origin for inad AT.ipokine For production example, is adipocytes important to exhibit dissect a quantitativelywhich distinct cell type adipokine might be enriched pattern and/or in the acti functionvated in AT. of For the example, fat-depot adipocytes (subcutaneous exhibit (sc) and viscerala quantitatively (vis)) origin. distinct Adiponectinadipokine pattern and in leptinthe function are predominantly of the fat-depot (subcutaneous expressed in sc AT [24].(sc) In contrast,and visceral IL-6 (vis)) [25 origin.], omentin Adiponectin [26], visfatinand leptin [27 are], andpredominantly RBP4 exhibit expressed higher in sc vis AT [24]. In contrast, IL-6 [25], omentin [26], visfatin [27], and RBP4 exhibit higher vis than than sc production [28]. Adipsin [29], lipocalin 2 [30], and TNF-α [31] are secreted in both sc production [28]. Adipsin [29], lipocalin 2 [30], and TNF-α [31] are secreted in both de- depots in comparablepots in comparable amounts. amounts. Using Using single-cell single-cell or singleor single nuclei nuclei transcriptomics, transcriptomics, it itis isnow now possible topossible discriminate to discriminate adipocyte adipocyte subpopulations subpopulatio withinns within one one depot, depot, as as wellwell as more more than than 10 different10 AT different cell types AT cell which types differwhich indiffer their in their metabolic metabolic and and transcriptional transcriptional properties properties including theincluding identification the identification of differences of differences in cellular in cellular adipokine adipokine sources sources [ 23[23,32–34].,32–34]. Figure 1. Adipose tissue cells secrete distinct adipokines. Adipose tissue consists of a variety of cell Figure 1. Adipose tissue cells secrete distinct adipokines. Adipose tissue consists of a variety of cell types, such as adipo- cytes, preadipocytes,types, such adipose as tissue-derived adipocytes, preadipocytes,stem cells, and several adipose immune tissue-derived cells which produce stem cells, and secrete and several cell-type- immune specific adipokines.cells which +/−, higher/lower produce andsecreted secrete in sc cell-type-specificor vis. c-KIT, KIT proto-oncogene,