C/EBPα and the corepressors CtBP1 and CtBP2 regulate repression of select visceral white adipose genes during induction of the brown phenotype in white adipocytes by peroxisome proliferator-activated receptor γ agonists

White adipose tissue (WAT) stores energy in the form of triglycerides, whereas brown tissue (BAT) expends energy, primarily by oxidizing lipids. WAT also secretes many cytokines and acute-phase proteins that contribute to insulin resistance in obese subjects. In this study, we have investigated the mechanisms by which activation of peroxisome proliferator-activated receptor γ (PPARγ) with synthetic agonists induces a brown phenotype in white adipocytes in vivo and in vitro. We demonstrate that this phenotypic conversion is characterized by repression of a set of white fat genes ("visceral white"), including the resistin, angiotensinogen, and chemerin genes, in addition to induction of brown-specific genes, such as Ucp-1. Importantly, the level of expression of the "visceral white" genes is high in mesenteric and gonadal WAT depots but low in the subcutaneous WAT depot and in BAT. Mutation of critical amino acids within helix 7 of the ligand-binding domain of PPARγ prevents inhibition of visceral white gene expression by the synthetic agonists and therefore shows a direct role for PPARγ in the repression process. Inhibition of the white adipocyte genes also depends on the expression of C/EBPα and the corepressors, carboxy-terminal binding proteins 1 and 2 (CtBP1/2). The data further show that repression of resistin and angiotensinogen expression involves recruitment of CtBP1/2, directed by C/EBPα, to the minimal promoter of the corresponding genes in response to the PPARγ ligand. Developing strategies to enhance the brown phenotype in white adipocytes while reducing secretion of stressrelated cytokines from visceral WAT is a means to combat obesity-associated disorders.