An understanding of adipose tissue regulation has broad clinical implications, because obesity correlates with increased risk of diabetes, stroke, heart disease and cancer. Brown adipose tissue dissipates calories as heat through non-shivering thermogenesis, and its activity correlates positively with decreased metabolic syndrome in mice and humans, making it an appealing therapeutic target. Studies with bone morphogenetic protein (BMP) ligand and receptor null mice reveal an essential role for this signaling pathway in the development of brown adipogenic precursors and their differentiation into mature brown adipose tissue. BMPs signal through several distinct pathways, however, the precise roles that these pathways play in control of brown adipocyte development and function are not well understood, and represent promising therapeutic targets to address obesity and related co-morbidities.
The first aim of this proposal is to use mouse models to determine if genetic manipulation of the genes that underlie BMP signaling can be used to enhance brown adipogenesis and function. To do this, master regulator genes that control BMP signaling will be ablated specifically in brown adipogenic precursors to determine their function. Thermogenic activity will be studied in live mutant mice using sophisticated metabolic monitoring techniques under conditions of cold-induced stress. The results of these studies allow testing of these genes in human models of brown adipocytes to determine their therapeutic value. A major obstacle with the study of human brown adipocytes is that isolation of primary cells requires invasive methods of procurement, and isolated cells have limited renewability or must be immortalized to interrogate them fully. In addition, the diverse environmental influences on primary brown adipocytes from different individuals makes it more difficult to directly study genetic factors that may lead to disrupted brown adipose metabolism. Brown adipocytes that have been derived from induced pluripotent stem (iPS) cells using BMP ligands have the potential to enhance our understanding of brown adipocyte development, metabolism, and its genetic variation in humans.
The second aim of this proposal is to develop human iPS cell-derived brown adipose tissue models using advanced cellular purification and tissue culture techniques. Human iPS cells will be derived from patients in a non-invasive manner, which will greatly facilitate the derivation of brown adipose samples across large cohorts of the human population that can be studied under defined tissue culture environments. Human iPS cell-derived brown adipocytes will be optimized for maximum thermogenic capacity through small molecule manipulation of BMP signaling pathways, and expanded in 3-dimensional biopolymer scaffolds to test their ability to control diet induced obesity in immune-compromised mice after tissue engraftment. Overall, the results of these studies will elucidate mechanisms that underlie control of brown adipose tissue and may shed light on promising therapeutic target pathways that can aid in the fight against obesity and related co-morbidities in humans.
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