PPARgamma coactivator 1beta/ERR ligand 1 is an ERR protein ligand, whose expression induces a high-energy expenditure and antagonizes obesity.
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.
Kamei
Yasutomi
Y
Department of Molecular Medical Science, Osaka Bioscience Institute, Osaka 565-0874, Japan.
Ohizumi
Hiroshi
H
Fujitani
Yasushi
Y
Nemoto
Tomoyuki
T
Tanaka
Toshiya
T
Takahashi
Nobuyuki
N
Kawada
Teruo
T
Miyoshi
Masamitsu
M
Ezaki
Osamu
O
Kakizuka
Akira
A
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D004247:DNA / Q000235:genetics; D004734:Energy Metabolism; D015870:Gene Expression; D008024:Ligands; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009765:Obesity / Q000235:genetics / Q000517:prevention & control; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000097983:ERRalpha Estrogen-Related Receptor
D004247:DNA; D008024:Ligands; D018160:Receptors, Cytoplasmic and Nuclear; D011960:Receptors, Estrogen; D011994:Recombinant Proteins; D014157:Transcription Factors; D000097983:ERRalpha Estrogen-Related Receptor; C111264:peroxisome-proliferator-activated receptor-gamma coactivator-1