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Title: “Systems Biology of Human Adipocytes: From Genes and Molecular Networks to Heterogeneity and Metabolic Phenotypes” Committee: Simon Kasif, PhD – BU BME (Co-Advisor) C. Ronald Kahn, MD – HMS Medicine, Joslin Diabetes Center (Co-Advisor) Wilson Wong, PhD – BU BME (Chair) Mark Crovella, PhD – BU CS/ECE Trevor Siggers, PhD – BU Biology Abstract: Obesity and its co-morbidities are among the leading health problems facing the developed world. Multiple genetic and environmental factors are known to have a significant impact on obesity development, however, heterogeneity of adipose tissue also contributes to obesity and its complications. Regional variation in adipose tissue has been associated with disease risks. For example, accumulation of visceral white adipose tissue (VAT), when compared to accumulation of subcutaneous white adipose tissue (SAT), is associated with an increased risk of diabetes and metabolic syndrome. Accumulation of brown adipose tissue (BAT), when compared to accumulation of white adipose tissue (WAT), on the other hand, is associated with lower BMI and higher insulin sensitivity. The goal of our project is to identify molecular targets that can be used as diagnostics, prognostics, or for reprogramming adipose tissue to a healthier phenotype (e.g. reprogramming VAT to SAT or WAT to BAT). To this end, we used three approaches. First, we used metabolic modeling to compare brown and white adipocyte metabolic profiles to predict and experimentally validate flux differences in the metabolic networks. Through this, we predicted and discovered a difference in urea secretion between these two classes of adipocytes. Second, we conducted transcriptome analysis of preadipocytes derived from SAT and VAT to identify several differentially expressed genes. Among them, we focused on Membrane Metallo-Endopeptidase (MME/Neprilysin) and showed experimentally that MME regulated the inflammatory response and insulin signaling in white preadipocytes by differentially affecting the insulin receptor (IR) subunits by increasing IRα but not IRβ. Finally, we used single-cell transcriptomics in differentiating human white preadipocytes derived from a single adipose depot to identify two subpopulations populations and a novel gene cluster of zinc finger proteins involved in white preadipocyte differentiation. The results presented here identify several key targets underlying the molecular and metabolic heterogeneity of adipose tissue.