Three-Dimensional Spheroid Cell Model of In Vitro Adipocyte Inflammation

Address correspondence to: Amol V. Janorkar, PhD, Department of Biomedical Materials Science, School of Dentistry, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216, E-mail: [email protected]

Introduction

In recent decades, obesity has increased steadily within the United States, thereby contributing to multiple systemic and metabolic diseases in men and women of all ages, races, and ethnicities.^1-3 In obese individuals, diets rich in carbohydrates and [omega]-6 fatty acids, but poor in antioxidants and [omega]-3 fatty acids,⁴ combined with a sedentary lifestyle, have been associated with chronic, low-grade systemic inflammation and overproduction of cytokines such as tumor necrosis factor alpha (TNF-[alpha]), interleukin (IL)-1, and IL-6.^5-8 These pro-inflammatory events have been proposed to result in the dysregulation of fatty acid metabolism (hyperlipidemia), glucose metabolism (hyperglycemia), and insulin resistance.⁶ Though common treatment for obesity involves a calorie-restricted diet and exercise,⁹ an optimal solution in severely obese cases would ideally include intervention at the cellular level. Indeed, such a goal has motivated studies aimed at characterizing the mechanisms regulating adipogenesis and inflammatory responses using various in vivo and in vitro model systems.^10-16

In keeping with the ability of fat tissue to respond to changes in fatty acid composition and pro-inflammatory stimuli, mature adipocytes express a number of plasma membrane-associated transporters, immune-related receptors, and intracellular signaling mediators that orchestrate responses to their changing microenvironment. For example, the transmembrane fatty acid transporter (FAT), CD36, is expressed by differentiated adipocytes and has been shown to mediate fatty acid uptake and glucose homeostasis via insulin sensitization¹⁷ as well as fatty acid egress and lipolysis.¹⁸ Likewise, CD40, a member of the TNF receptor superfamily, is expressed during adipose differentiation and has been shown to modulate the adipocyte inflammatory response and insulin resistance via an interaction with surrounding immune cells.^19,20 In terms of intracellular mediators, peroxisome proliferator-activated receptor-[gamma] (PPAR-[gamma])...