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 ␥ (PPAR␥) 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 PPAR␥ prevents inhibition of visceral white gene expression by the synthetic agonists and therefore shows a direct role for PPAR␥ in the repression process. Inhibition of the white adipocyte genes also depends on the expression of C/EBP␣ 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/EBP␣, to the minimal promoter of the corresponding genes in response to the PPAR␥ 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.

SUMMARY Adipose tissue is an essential regulator of metabolic homeostasis. In contrast with white adipose tissue, which stores excess energy in the form of triglycerides, brown adipose tissue is thermogenic, dissipating energy as heat via the unique expression of the mitochondrial uncoupling protein UCP1. A subset of UCP1+ adipocytes develop within white adipose tissue in response to physiological stimuli, however, the developmental origin of these “brite” or “beige” adipocytes is unclear. Here, we report the identification of a BMP7-ROCK signaling axis regulating beige adipocyte formation via control of the G-actin-regulated transcriptional coactivator myocardin related transcription factor A, MRTFA. White adipose tissue from MRTFA–/– mice contains more multilocular adipocytes and expresses enhanced levels of brown-selective proteins, including UCP1. MRTFA–/– mice also show improved metabolic profiles and protection from diet-induced obesity and insulin resistance. Our study hence unravels a central pathway driving the development of physiologically functional beige adipocytes.

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Background: What are the mechanisms regulating compensatory responses to hypoxia in adipocytes? Results: Induction of hypoxia genes requires HIF-1␣ and PPAR␥ in white adipocytes and PGC-1 cofactors in brown adipocytes. Conclusion: Adipogenic factors and HIF-1␣ regulate hypoxia responses in adipocytes. Significance: Results suggest that obese adipose tissue is compromised due to defects in signaling pathways converging on HIF-1␣.