232-LB: Transcriptional Regulation of Adipocyte Insulin and Inflammatory Signaling by Early B-Cell Factor-1 (Ebf1)

Overnutrition is causally associated with many chronic diseases, including insulin resistance and diabetes, heart disease, hypertension, and cancer. Chronic activation of the innate immune system may lie at the heart of a majority of T2DM cases; the bulk of the evidence suggests that a litany of inflammatory cytokines and toxic lipid species released from irritated adipocytes contribute significantly to disrupted insulin signaling in metabolic tissues and may eventually lead to frank type 2 diabetes. However, the molecular mechanisms that initiate these inflammatory events in adipocytes remain unknown, particularly at the transcriptional level. Our previous work showed that the transcription factor Ebf1 regulates insulin signaling and promotes inflammation in adipocytes; however, the precise molecular mechanisms through which Ebf1 regulates the expression of inflammatory loci remain unknown (as evidence had suggested Ebf1 regulates these genes indirectly). We have recently discovered that Ebf1 can physically interact with multiple subunits of the well-known inflammatory transcription factor NF-κB, and many of the critical inflammatory loci showing impaired expression in Ebf1-deficient 3T3-L1 adipocytes also happen to be well-established NF-κB target genes. This striking result likely explains our paradoxical observations that EBF1 directly (and positively) regulates several core insulin signaling genes (Pik3r1, Akt, etc.) but also promotes insulin resistance in adipocytes—apparently without directly occupying inflammatory loci. We are currently working on physically and functionally characterizing these interactions and propose a model to explain the previously-mentioned paradox. If our hypothesis is correct, we anticipate that the eventual development of pharmaceutical agents designed to interfere with EBF1-NF-κB protein-protein interactions may represent a viable treatment for overnutrition-associated diabetes.