Transplantation of committed pre-adipocytes from brown adipose tissue improves whole-body glucose homeostasis
Revati S. Dewal, Felix T. Yang, Lisa A. Baer, Pablo Vidal, Diego Hernández‐Saavedra, Nickolai P. Seculov, Adhideb Ghosh, Falko Noé, Olivia Togliatti, Lexis Hughes, Megan K. DeBari, Michael D. West, Richard Soroko, Hal Sternberg, Nafees N. Malik, Estella Puchulu-Campanella, Huabao Wang, Pearlly S. Yan, Christian Wolfrum, Rosalyn D. Abbott, Kristin I. Stanford
Abstract
Obesity and its co-morbidities including type 2 diabetes are increasing at epidemic rates in the U.S. and worldwide. Brown adipose tissue (BAT) is a potential therapeutic to combat obesity and type 2 diabetes. Increasing BAT mass by transplantation improves metabolic health in rodents, but its clinical translation remains a challenge. Here, we investigated if transplantation of 2-4 million differentiated brown pre-adipocytes from mouse BAT stromal fraction (SVF) or human pluripotent stem cells (hPSCs) could improve metabolic health. Transplantation of differentiated brown pre-adipocytes, termed "committed pre-adipocytes" from BAT SVF from mice or derived from hPSCs improves glucose homeostasis and insulin sensitivity in recipient mice under conditions of diet-induced obesity, and this improvement is mediated through the collaborative actions of the liver transcriptome, tissue AKT signaling, and FGF21. These data demonstrate that transplantation of a small number of brown adipocytes has significant long-term translational and therapeutic potential to improve glucose metabolism.