Brown adipose tissue (BAT) possesses the inherent ability to dissipate metabolic energy as heat in a process termed non-shivering thermogenesis and thus could lend itself to novel anti-obesity treatment approaches. Strategies for expanding BAT fall into two general categories, pharmaceutical/genetic intervention to trigger endogenous BAT differentiation pathways or ex vivo generation/expansion of brown fat followed by implantation. Since pharmacological activation of differentiation pathways that might drive a white adipose tissue (WAT) to BAT transition, or "browning" of WAT, runs the risks of affecting differentiation and function of other tissues and offers poor control of the location and extend of BAT expansion, we will focus on the latter approach. Our overall strategy in this collaboration between the Stahl and Healy labs will be to leverage expertise in bioengineering of hydrogels and in metabolic biology to demonstrate the feasibility of a BAT base anti-obesity strategy that could be readily translated from the pre-clinical stage to actual application. The central hypothesis here is that a multidisciplinary approach of metabolic biology and tissue engineering can be utilized to develop an autologous transplantation approach to expand BAT mass and resting energy expenditure to combat obesity-associated disorders such as type-2 diabetes and hepatosteatosis. Our approach will focus on: 1) utilizing WAT as a readily available source of mesenchymal stem cells (MSC) and to optimize BAT differentiation conditions, without the introduction of transgenes, by combining soluble signaling factors with optimized adhesion ligands;2) development of 3D matrixes composed of bio-inspired hyaluronic acid (HyA) hydrogels that can be designed to enhance the differentiation of WAT-derived MSCs into BAT;3) to perform in vivo experiments with matrixes that have been tested ex vivo to further optimize for in vivo performance with a specific focus on determining tissue persistence, maintenance of BAT phenotype, cellular energetics, and whole animal metabolism as a function of matrix composition, growth factors, and implantation site;and 4) to demonstrate that optimized BAT-MACTs can indeed be used as a potent anti-obesity approach and facilitate the protection and reversal of obesity associated disorders.
Current approaches to treat obesity and associated disorders, such as diabetes and fatty liver disease, has proven inefficient based on the unabated rise of these diseases in the US and worldwide. Here we propose to develop and test in a preclinical setting a novel anti-obesity approach based on the expansion of a tissue type, brown fat, with a very high metabolic activity that might lead to the conversion of excess calories into heat.