PPARγ Coactivator 1β/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: National Academy of Sciences 14.10.2003; National Acad Sciences
• Subjects: Amino acids; Biological Sciences; Body weight; High fat diet; Ligands; Messenger RNA; Mice; Nuclear receptors; Obesity; Receptors; Skeletal muscle
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2135217100

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) γ, 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 PPARγ coactivator 1 (PGC-1) β functions as ERRL1 (for ERR ligand 1), which can bind and activate orphan ERRs (estrogen receptor-related receptors) in vitro. Consistently, PGC-1β/ERRL1 transgenic mice exhibit increased expression of the medium-chain acyl CoA dehydrogenase, a known ERR target and a pivotal enzyme of mitochondrial β-oxidation in skeletal muscle. As a result, the PGC-1β/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-1β/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.