Characterizing the mechanisms controlling the rate of adipogenesis in vitro and in vivo

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Obesity constitutes a public health problem and enhances the risk for cardiovascular disease and metabolic disorders such as insulin resistance. Since adipose tissue is essential for the homeostatic control of metabolism, dysregulated expansion of adipose tissue affects the whole body. In obesity fat depots increase by differentiation of fat cells in a process called adipogenesis. Detailed understanding of the regulatory circuits underlying adipogenesis is missing and could enable to find ways to therapeutically control growth of adipose tissue in pathological conditions. Upon healthy conditions tissue size is preserved by balancing cell proliferation, differentiation and cell death. Hence, adipocytes renew in the human body at a rate of 10% per year. As all preadipocytes in the human body are subjected to the same differentiation stimuli it remains elusive why not the whole population of proliferating preadipocytes differentiates into non-dividing and lipid accumulating adipocytes. The laboratory of Dr. Mary Teruel addressed this question and realized that adipogenesis is controlled by a highly dynamic and interconnected regulatory network. They developed unique single cell imaging techniques, computational modeling, and targeted proteomics approaches, which revealed that preadipocytes in cell culture differentiate into terminal non-dividing adipocytes through an all-or-none, bistable switch mechanism, which is driven by seven feedback loops between critical regulator proteins and PPARgamma, the master transcriptional regulator of adipocyte differentiation. This regulatory network coupled with variation in protein expression provides a tunable system to maintain low rates of terminal adipocyte differentiation. This project aims to prove that this ultra-high feedback loop architecture is relevant in vivo. In my experimental strategy, I will employ the AdipoChaser mouse model which allows determining the exact timeframe of de novo adipogenesis by permanent labeling of mature adipocytes. I will investigate in vivo relevant feedback regulators in terms of timing, sequential order, and connectivity in following cell culture experiments. To evaluate how expression levels and timing of the feedback regulator proteins affect rates of adipogenesis upon physiological stimuli, I will apply gain and loss of function strategies of different feedback mediators in allograft models to quantitate differentiation rates in vivo. Results from this study will highlight which feedback mediators are essential to keep adipocyte differentiation rates low and thus, at least in part, answer the key question how organisms maintain adipose tissue size. In addition this study will provide a better understanding of the regulatory mechanism underlying adipogenesis, which may contribute to attempts to therapeutically control adipogenesis in metabolic disease.