| Obesity is the one of the most prevalent metabolic disorders of the twenty-first century. The expansion of white adipose tissue (WAT) occurs through increases in both the size (hypertrophy) and number of adipocytes (hyperplasia). Hyperplasia involves the recruitment, proliferation, and differentiation of locally derived precursor cells, or preadipocytes. The differentiation of preadipocytes into adipocytes is regulated by a network of transcription factors (TFs), notably peroxisome proliferator-activated receptor gamma (PPARgamma) and members of the CCAAT-enhancer-binding protein (C/EBP) family. These regulatory molecules act in coordination to activate the transcription of genes encoding metabolic, signaling and biosynthetic pathways that determine the adipocyte phenotype.;This thesis develops an integrated modeling framework to investigate the transcriptional regulation of metabolic pathways in the adipocyte. The first part constructed an adipocyte-specific model of isotopic label distribution to enhance the resolution of metabolic flux analysis (MFA). The second part applied the flux estimation tool to characterize targeted perturbations in adipocyte metabolism designed to reduce net TG storage. The third part formulated a model of regulatory interactions between the TF network and metabolic pathways.;In summary, this thesis investigated the first dynamic model of white adipocyte metabolism based on TF-dependent enzyme activity regulation. This model should provide a powerful new framework to integrate and interpret observations on the regulatory and metabolic processes leading to adipocyte formation and enlargement. Model calculations could be used, for example, to determine the effect of specific activators or inhibitors of a TF on the overall state of adipocyte metabolism, thus facilitating new drug target identification for obesity treatment. Model-based predictions on metabolic effects should be especially useful in studying combinatorial treatments involving multiple activators and/or inhibitors. The modeling and experimental approaches developed in this research are general with respect to the cell type, and thus broadly applicable to many other physiological and pathological phenomena that feature dynamic regulation of metabolic pathways. |
