Microphysiological System Recapitulating the Pathophysiology of Adipose Tissue in Obesity

Abstract
A growing body of evidence has indicated that white adipose tissue (AT) remodeling is a major trigger for obesity-associated metabolic complications. However, the scarcity of translational models is an obstacle to the development of medicines that act on adipose restoration. Here, we describe a microphysiological system (MPS) that emulates the unique features of reprogrammed AT as a new in vitro tool for studying AT pathophysiology in obesity. The AT MPS contained mature adipocytes embedded in an extracellular matrix (ECM) hydrogel interfaced with AT microvascular endothelium, which was constantly perfused with fresh media. The unique biochemical signals due to the remodeled ECM in obesity were recapitulated using a decellularized AT ECM (AT dECM) hydrogel, which preserves the features of altered ECM composition in obesity. The mature adipocytes embedded in the AT dECM hydrogel maintained their function and morphology for a week without dedifferentiation. Using the AT MPS, we successfully modeled inflammation-induced AT microvascular dysfunction, the recruitment of immune cells due to the upregulation of cell adhesion molecules, and higher cancer cell adhesion as an indicator of metastasis, which are observed in obese individuals. The AT MPS may therefore represent a promising platform for understanding the dynamic cellular interplay in obesity-induced AT remodeling and validating the efficacy of drugs targeting AT in obesity. STATEMENT OF SIGNIFICANCE: The lack of translational in vitro white adipose tissue (AT) models is one of the main obstacles for understanding the obesity-induced reprogramming and the development of medicines. We report herein the AT microphysiological system (MPS), which recapitulates obesity and normal conditions and yields cell- and AT dECM-derived signals, thereby allowing accurate comparative in vitro analyses. Using the AT MPS, we successfully modeled reprogrammed AT in obesity conditions, including inflammation-induced AT vascular dysfunction, the recruitment of immune cells, and higher cancer cell metastasis, which are observed in obese individuals. Our proposed adipose tissue model providing physiological relevance and complexity may therefore enhance the understanding of obesity-associated disorders and be used to investigate their underlying molecular mechanisms to develop pharmacologic treatment strategies.

A research team, led by Professor Tae-Eun Park in the Department of Biomedical Engineering at UNIST has reported a microphysiological system that emulates the pathophysiological characteristics of human white adipose tissue (WAT). The research team anticipates that their findings may enhance the understanding of obesity-associated disorders and be used to investigate their underlying molecular mechanisms to develop pharmacologic treatment strategies.

Figure 1. A microphysiological system (MPS) that emulates the unique features of reprogrammed AT as a new in vitro tool for studying AT pathophysiology in obesity.

Adipose tissue is a specialized connective tissue mainly composed of fat cells, known as adipocytes. Based on their origin, location, and function, these tissues are categorized into three different cell types—white, brown, and beige adipocytes. Among those,white adipose tissue (WAT) is the predominant type of fat in body. The main functions of WAT are storing energy, insulating body from extreme temperatures, cushioning vital organs, as well as secreting hornones and biological factors.

Despite their obvious advantages, too much white fat may lead to obesity, which is the number one cause of death worldwide. Furthermore, the massive expansion and remodeling of AT during obesity significantly contribute to vascular dysfunction, chronic inflammation, and systemic metabolic disorders, noted the research team. However, with the existing methods, there has been limited understanding of the pathophysiological mechanisms of obesity due to the lack of in vitro models mirroring AT dysfunction in obesity.

In this study, the research team reported the AT microphysiological system (MPS), which recapitulates obesity and normal conditions and yields cell- and AT dECM-derived signals, thereby allowing accurate comparative in vitro analyses. Using the AT MPS, they successfully modeled reprogrammed AT in obesity conditions, including inflammation-induced AT vascular dysfunction, the recruitment of immune cells, and higher cancer cell metastasis, which are observed in obese individuals.

Figure 2. Fabrication of physiologically relevant AT microenvironment in an MPS device.

“Our approach offers a perfusable vascular compartment interfaced with a 3D adipocyte construct in a microfluidic system; thus, obesity-associated systemic metabolic disorders may be further modeled by linking with other MPSs, such as the liver and pancreas,” noted the research team. “The unique AT MPS described here may enhance the understanding of obesity-associated disorders and be used to investigate their underlying molecular mechanisms to develop pharmacologic treatment strategies.”

Their findings have been published in the January 2023 issue of Acta Biomaterialia.

Journal Reference
Heejeong Yoon, Jeong Kon Seo, Tae-Eun Park, “Microphysiological system recapitulating the pathophysiology of adipose tissue in obesity,” Acta Biomater., (2023).