Tissue engineered models of adipose tissue dysfunction to investigate obesity-related comorbidities

Emerging evidence suggests that adipose tissue is not just a fat depot but a metabolically active organ that plays a central role in connecting obesity with its comorbidities. Understanding the complex interactions between adipocytes and neighboring cell types in obesity requires models that accurately replicate adipocyte behavior within their natural environment. Three-dimensional (3D) adipocyte cultures mimic the native tissue microenvironment by incorporating the spatial architecture as well as cell-cell and cell-extracellular matrix interactions present<i>in vivo</i>, offering improved platforms for (patho)physiological adipose tissue modeling. 3D models of adipose tissue dysfunction enable the study of complex cellular crosstalk, such as adipocyte cancer cell interactions in breast, colorectal, bone, and pancreatic cancers; epicardial and pericardial adipocyte-myocardial cell dynamics in obesity-related cardiac dysfunction; and adipocyte-hepatocyte interactions in the development of non-alcoholic fatty liver disease, among other critical pathophysiological processes. In this review, we first discuss 3D models of adipose tissue and current strategies for mimicking the obesogenic microenvironment, including dietary stimulation of hyperlipidemia and hyperglycemia, as well as the incorporation of oxygen gradients, proinflammatory cytokines, and immune cells. Secondly, we examine 3D co-culture platforms that incorporate disease-associated/dysfunctional adipocytes with various cell types, such as cancer cells, cardiac cells, hepatocytes, immune cells, endothelial cells (EC), and fibroblasts, to model intercellular and interorgan crosstalk in obesity. Lastly, we provide insights into enhancing the physiological relevance of dysfunctional adipose tissue models and their co-culture systems while discussing future directions in tissue engineering aimed at improving clinical translation and reducing obesity related complications and mortality.