Uncoupling Protein-2 Controls Adiponectin Gene Expression in Adipose Tissue Through the Modulation of Reactive Oxygen Species Production

Uncoupling Protein-2 Controls Adiponectin Gene Expression in Adipose Tissue Through the Modulation of Reactive Oxygen Species Production Emmanuel Chevillotte 1 , Marta Giralt 1 , Bruno Miroux 2 , Daniel Ricquier 2 and Francesc Villarroya 1 1 Department of Biochemistry and Molecular Biology and Institut de Biomedicina (IBUB), University of Barcelona, and Centro de Investigación Biomédica en Red Fisiopatologia de la Obesidad y Nutricion, Instituto de Salad Carlos III, Barcelona, Spain 2 Transporteurs Mitochondriaux et Métabolisme (BIOTRAM), Centre National de la Recerche Scientifique Faculté Necker-Enfants Malades, Paris, France Address correspondence and reprint requests to Francesc Villarroya, Departament de Bioquímica i Biologia Molecular. Facultat de Biologia, Universitat de Barcelona, Avda Diagonal 645, 08028 Barcelona, Spain. E-mail: fvillarroya{at}ub.edu Abstract Uncoupling protein-2 (UCP2) is a mitochondrial membrane transporter expressed in white adipose tissue. We observed that circulating adiponectin levels and adiponectin gene expression in adipose tissue are reduced in UCP2-null mice. We studied whether mitochondrial activity and its control by UCP2 may regulate adiponectin gene expression. In 3T3-L1 cells, increasing UCP2 mitochondrial levels by adenoviral-mediated gene transfer induced adiponectin gene expression, whereas oligomycin and antimycin A, inhibitors of ATP synthesis and mitochondrial respiration, led to a downregulation. Reactive oxygen species (ROS) scavengers alleviated the repression of adiponectin gene expression caused by oligomycin or antimycin A. The action of ROS involves the transcription factor CHOP-10, the abundance of which was reduced in response to UCP2 and was induced by oligomycin. CHOP-10 inhibited adiponectin gene expression by interfering with the −117/−73 CCAAT/enhancer binding protein–binding region in the adiponectin gene promoter. Moreover, CHOP-10 levels were increased in adipose tissue from UCP2-null mice. Results indicate that the modulation of ROS levels by mitochondrial activity, and specifically as a consequence of the action of UCP2, controls adiponectin gene expression. This provides a physiological mechanism by which the adipose tissue energetic status may determine the extent of adiponectin release and influence systemic insulin sensitivity. C/EBP, CCAAT/enhancer binding protein DMEM, Dulbecco's modified Eagle's medium H2-DCFDA, 6-carboxy-2′,7′-dichlorodihydrofluorescein diacetate, diacetoxymethyl-es