The mouse nuclear receptor ERRgamma (estrogen receptor-related receptor 7) is highly expressed in heart, skeletal muscle, kidney, and brain, as well as in the developing nervous system. We found that the expression of the coactivators PGC-1 (PGC-1alpha) and PERC (PGC-1beta) in mammalian cells augmented potently the transcriptional activation by ERRgamma. The constitutive activation function 2 (AF-2) of the orphan receptor was important for the synergistic enhancement. Functional receptor truncation analysis revealed an additional amino-terminal activation function, specific for the ERRgamma2 isoform and PGC-1. In vitro experiments showed a direct interaction of ERRgamma with both coactivators. Our findings suggest distinct regulatory functions for PGG-1 and PERC as tissue-specific coactivators for ERRgamma. (C) 2002 Elsevier Science (USA). All rights reserved.