Fat-On-A-Chip Models for Research and Discovery in Obesity and Its Metabolic Comorbidities

Abstract

The obesity epidemic and its associated comorbidities present a looming challenge to health care delivery throughout the world. Obesity is characterized as a sterile inflammatory process within adipose tissues leading to dysregulated secretion of bioactive adipokines such as adiponectin and leptin, as well as systemic metabolic dysfunction. The majority of current obesity research has focused primarily on preclinical animal models in vivo and two-dimensional cell culture models in vitro. Neither of these generalized approaches is optimal due to interspecies variability, insufficient accuracy with respect to predicting human outcomes, and failure to recapitulate the three-dimensional (3D) microenvironment. Consequently, there is a growing demand and need for more sophisticated microphysiological systems to reproduce more physiologically accurate human white and brown/beige adipose depots. To address this research need, human and murine cell lines and primary cultures are being combined with bioscaffolds to create functional 3D environments that are suitable for metabolically active adipose organoids in both static and perfusion bioreactor cultures. The development of these technologies will have considerable impact on the future pace of discovery for novel small molecules and biologics designed to prevent and treat metabolic syndrome and obesity in humans. Furthermore, when these adipose tissue models are integrated with other organ systems they will have applicability to obesity-related disorders such as diabetes, nonalcoholic fatty liver disease, and osteoarthritis. Impact statement The current review article summarizes the advances made within the organ-onchip field, as it pertains to adipose tissue models of obesity and obesity-related syndromes, such as diabetes, non-alcoholic fatty liver disease, and osteoarthritis. As humanized 3D adipose-derived constructs become more accessible to the research community, it is anticipated that they will accelerate and enhance the drug discovery pipeline for obesity, diabetes, and metabolic diseases by reducing the preclinical evaluation process and improving predictive accuracy. Such developments, applications, and usages of existing technologies can change the paradigm of personalized medicine and create substantial progress in our approach to modern medicine.

Keywords: ADMET; ASC; BAT; WAT; fat-on-a-chip; microphysiological system.

FIG. 1.

Left: This design represents the microscale compartmentalized cell culture system used in Viravaidya and Shuler in which wells and channels were etched onto a silicon chip. The wells were then seeded with cell types corresponding to different organ systems. The result allows for simulation of complex pharmacokinetic mechanisms, such as bioaccumulation. Middle: The structure in the middle represents the automated 16-channel microfluidic multiplexer used by Li et al. to dynamically stimulate and interrogate cells of interest. The red lines represent control channels, which can be used to automatically control exposure to the fluids loaded into the reservoirs (black circles). Right: Fat-on-a-chip technology allows for multiple instances of an experiment to be run simultaneously with massive parallelization, as seen in Wu et al.