Using Immune Cell/Adipocyte Co-Culture Models to Identify Inflammatory Paracrine Signaling Mechanisms: A Process Attenuated by Long-Chain N-3 Polyunsaturated Fatty Acids

Abstract

Obese adipose tissue (AT) is characterized by increased recruitment and infiltration of multiple immune cell populations, in particular T cells (CD4 + or CD8 + subsets) and macrophages, that interact with adipocytes through paracrine signaling (i.e., cross-talk). Adipocyte/ immune cell cross-talk results in increased inflammatory and chemoattractant mediator production that contributes to local (i.e., AT) and systemic metabolic dysfunction. Therefore, co-culture models of adipocytes and immune cell populations represent an important experimental approach to study how paracrine interactions between cell types promote obese AT inflammation and dysfunction, and to identify intervention strategies to attenuate this cellular cross-talk. In this commentary, we will discuss the development of physiologically relevant adipocyte (differentiated and mature 3T3-L1 pre-adipocyte cell line) and primary immune cell population (namely CD4 + T cells, CD8 + T cells and CD11b + macrophages) co-culture models that recapitulate the critical features of the obese AT microenvironment via i) culturing cellular ratios that reproduce the cellular abundance of immune cells observed in obese AT, and ii) stimulation with a concentration of lipopolysaccharide (LPS) that mimics circulating endotoxin levels in obese humans and rodents. The co-culture models discussed are comprised of i) a cell contact-dependent model wherein the cells are in direct physical contact, ii) a cell contact-independent model, wherein cells are physically separated by trans-well semi-permeable membrane that prevents physical cell contact but permits soluble mediators to cross, and iii) a cell contact-independent model where conditioned media is generated from intact primary AT, or adipocyte/immune cell co-cultures to influence another cell type. Finally, we summarize the utility of these co-culture models by discussing recent findings demonstrating how n-3 polyunsaturated fatty acids [eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)] derived from fish oil can attenuate inflammatory and chemotactic paracrine signaling between adipocytes and immune cell populations to improve AT function.