A Role for Estrogen-related Receptor α in the Control of Mitochondrial Fatty Acid β-Oxidation during Brown Adipocyte Differentiation*

Little is known about the factors involved in the brown adipocyte gene regulatory program. In contrast to the white adipocyte, the brown adipocyte is characterized by abundant mitochondria and high level expression of mitochondrial fatty acid β-oxidation enzymes. Previous studies in transgenic mice have shown that the brown adipose-enriched expression of a key β-oxidation enzyme, medium chain acyl-coenzyme A dehydrogenase (MCAD), requires cis-acting elements located within the proximal promoter region of the MCAD gene. The levels of mRNA encoding MCAD and several other β-oxidation cycle enzymes were coordinately induced during differentiation of brown adipocytes in culture. Expression of transgenes comprised of MCAD gene promoter fragments fused to chloramphenicol acetyltransferase reporters in differentiating brown adipocytes revealed that a known nuclear receptor response element (NRRE-1) was required for the transcriptional induction of the MCAD gene during brown adipocyte differentiation. Electrophoretic mobility shift assays and antibody recognition studies identified distinct brown adipocyte differentiation stage-specific, NRRE-1-protein complexes; the orphan nuclear receptors, chicken ovalbumin upstream promoter transcription factors I and II, were identified as major the NRRE-1 binding proteins in the pre-adipocyte, whereas the estrogen-related receptor α (ERRα) bound NRRE-1 in extracts prepared from differentiated brown adipocytes. DNA binding studies performed with a series of NRRE-1 mutant probes indicated that ERRα was capable of binding two distinct sites within NRRE-1, each of which conform to the known ERRα monomeric binding consensus. The expression of ERRα paralleled NRRE-1 binding activities and MCAD expression during brown adipocyte differentiation, cardiac development, and among a variety of adult mouse tissues. These results identify a new class of ERRα target genes and implicate ERRα and chicken ovalbumin upstream promoter transcription factor in the control of a pivotal metabolic pathway during brown adipocyte differentiation.

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