PPARgamma coactivator 1beta/ERR ligand 1 is an ERR protein ligand, whose expression induces a high-energy expenditure and antagonizes obesity

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 100; no. 21; pp. 12378 - 12383
• Main Authors: Kamei, Yasutomi, Ohizumi, Hiroshi, Fujitani, Yasushi, Nemoto, Tomoyuki, Tanaka, Toshiya, Takahashi, Nobuyuki, Kawada, Teruo, Miyoshi, Masamitsu, Ezaki, Osamu, Kakizuka, Akira
• Format: Journal Article
• Language: English
• Published: United States 14.10.2003
• Subjects: Amino Acid Sequence; Animals; Base Sequence; DNA - genetics; Energy Metabolism; ERRalpha Estrogen-Related Receptor; Gene Expression; Ligands; Mice; Mice, Transgenic; Molecular Sequence Data; Obesity - genetics; Obesity - prevention & control; Receptors, Cytoplasmic and Nuclear - metabolism; Receptors, Estrogen - metabolism; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; Transcription Factors - genetics; Transcription Factors - metabolism
• ISSN: 0027-8424; 1091-6490

A well balanced body energy budget controlled by limitation of calorie uptake and/or increment of energy expenditure, which is typically achieved by proper physical exercise, is most effective against obesity and diabetes mellitus. Recently, peroxisome proliferator-activated receptor (PPAR) gamma, a member of the nuclear receptor, and its cofactors have been shown to be involved in lipid metabolism and in the control of energy expenditure. Here we show that PPARgamma coactivator 1 (PGC-1) beta functions as ERRL1 (for ERR ligand 1), which can bind and activate orphan ERRs (estrogen receptor-related receptors) in vitro. Consistently, PGC-1beta/ERRL1 transgenic mice exhibit increased expression of the medium-chain acyl CoA dehydrogenase, a known ERR target and a pivotal enzyme of mitochondrial beta-oxidation in skeletal muscle. As a result, the PGC-1beta/ERRL1 mice show a state similar to an athlete; namely, the mice are hyperphagic and of elevated energy expenditure and are resistant to obesity induced by a high-fat diet or by a genetic abnormality. These results demonstrate that PGC-1beta/ERRL1 can function as a protein ligand of ERR, and that its level contributes to the control of energy balance in vivo, and provide a strategy for developing novel antiobesity drugs.