UC Berkeley

Obesity and the metabolic diseases that result from it continue to increase across the developing and developed world little slow down in sight. As such, novel mechanisms for the study and treatment of these metabolic outcomes are needed to combat the ever-increasing epidemic. Our lab has focused on the development of two mechanisms geared toward the understanding of adipose tissue’s role in these abnormal metabolic processes through the development of an in situ forming implant whose goal is to burn excess circulating glucose and lipids, and through the characterization of a microphysiological device (MPS) to model insulin resistance formation in adipocytes. We have found that our hyaluronic acid (HA)-based implants are ideal candidates to perform the three main goals of the therapeutic implant showing robust capabilities to perform the three main goals: recruit stem cells, differentiate those stem cells to a beige adipocyte fate, and then maintain activation of these cells over a long period of time. Using two well characterized chemistries, thiol-acrylate Michael addition and Strain Promoted Azide Alkyne click (SPAAC), we can tailor our hydrogels to the targeted niche using short adhesion peptides, growth factors, degradable crosslinkers, and compounds that bind receptors on a cell’s surface. To this end we have shown that molecular weight plays no role in adipocyte function in vitro, but altering the hydrogel in increase the loss, or viscous, modulus of a hydrogel can. In addition, peptides and growth factors seem to enhance the differentiation of the cells plated on these substrates in ways that may provide further tailoring opportunities down the road for this therapeutic. I also created a bifunctional HA version of our implant with the goal of pushing forward aim three of the hydrogel project. Modifying the HA backbone with a DBCO group would allow us to conjugate in a tri-azole modified compound like Mirabegron, a β3-adrenergic agonist responsible for the differentiation of beige adipocytes. I was able to illustrate the efficacy of this bi-chemical modification and determine the final ability of the gels to perform in both capacities, which will be crucial for the beige adipocyte therapeutic in the future. Finally, we created a MPS that reproduces obese metabolic disease states in adipose tissue using induced pluripotent stem cells (iPSC) to differentiate them toward adipocytes and macrophages, modelling the interactions and development of these two cell types to validate this method as a testable platform for insulin resistance.