Novel mechanisms for the stromal vascular fraction of brown adipose tissue to improve metabolic homeostasis

Ohio State University, Columbus OH

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Abstract

? DESCRIPTION (provided by applicant): Obesity and type 2 diabetes and are increasing dramatically worldwide. The increasing rates of obesity and type 2 diabetes have increased the importance of elucidating the molecular basis for obesity, as well as determining potential therapeutic treatments for this condition. Brown adipose tissue (BAT) is a thermogenic tissue that contains large amounts of mitochondria to dissipate chemical energy as heat. BAT has a high capacity for both glucose and lipid oxidation, making BAT a potential target to decrease plasma glucose and lipids, and a potential target to protect against obesity and lower the risk of diabetes. Transplantation of BAT improves glucose homeostasis in normal chow-fed mice, in a model of diet-induced obesity, and in a model of type 1 diabetes, and these improvements in glucose homeostasis are mediated by increases in circulating IL-6 and FGF21. An increase in brown-adipocytes in white adipose tissue (WAT) through environmental (i.e. cold, exercise) or genetic manipulation results in increased energy expenditure, improved glucose tolerance, and protection against weight gain. It is currently unclear if BAT transplantation confers metabolic benefits due to certain cell types being transplanted, or whether the mature brown adipocytes are required as appears to be the case with `browning' of WAT. Our exciting preliminary data show that transplantation of isolated human progenitor cells differentiated into brown adipocytes decreases body weight and improves insulin sensitivity and a mouse model. We have also shown that transplantation of the total stromal vascular fraction (SVF) of mouse BAT improves glucose tolerance, suggesting that the SVF of BAT is essential to the improvement in metabolic homeostasis after transplantation, although the mechanism for this improvement, and the cell-type responsible for this improved glucose homeostasis, are unclear. We have also generated preliminary data that demonstrate that the cell distribution of the SVF compartment of BAT is altered with exercise-training, although the functional consequence of this change is not understood. There are two specific aims: 1) Determine if transplantation of the specific cell-types of BAT SVF improve glucose homeostasis, if a specific cell-type is required for this effect, and whether IL-6 or FGF21 are required for this effect; and 2) Determine if the metabolic function of the SVF population of BAT is altered after exercise-training. This project will establish the role of specific components of the BAT SVF in improvements in glucose metabolism, how these components function to mediate the beneficial effects of BAT on glucose homeostasis, and if exercise improves the metabolic capacity of specific components of the SVF. These studies have the potential to lead to the development of a novel cell-based therapy to combat type 2 diabetes and obesity and, if translatable to humans, have great therapeutic implications.