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. 2003 Oct 14;100(21):12378-83.
doi: 10.1073/pnas.2135217100. Epub 2003 Oct 6.

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

Yasutomi Kamei  1 , Hiroshi Ohizumi, Yasushi Fujitani, Tomoyuki Nemoto, Toshiya Tanaka, Nobuyuki Takahashi, Teruo Kawada, Masamitsu Miyoshi, Osamu Ezaki, Akira Kakizuka
Affiliations

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

Yasutomi Kamei et al. Proc Natl Acad Sci U S A. .

Abstract

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.

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Figures

Fig. 1.
Fig. 1.
Amino acid sequence and the expression profile of ERRL1/PGC-1β.(A) LXXLL motifs are shown in bold. Glutamic acid (E) repeats and serine/arginine (SR)-rich regions are underlined. A putative RNA-binding motif is boxed. Vertical lines show tentative domain borders. A splice variant of ERRL1/PGC-1β was identified, which lacks 39 aa (from the 156th leucine to the 194th lysine). The 260th leucine is a proline in reported PGC-1β (17). (B) 3T3-L1 cells were induced to differentiate into adipocytes by treatment with dexamethasone, 1-methyl-3-isobutylxanthine, and insulin (day 0). RNAs were isolated on the days indicated, and Northern blot analysis was performed. The membrane was sequentially hybridized with the probes indicated. (C) Expression of PGC-1β, ERR1, MCAD, and a control GAPDH mRNA in 3T3-L1 and 10T1/2 cells. -, preadipocytes; +, mature adipocytes.
Fig. 2.
Fig. 2.
Profiles of PGC-1α and PGC-1β as protein ligands on specific nuclear receptors. (A–C) Transcriptional activation of various GAL4-fused nuclear receptors was examined in a transient transfection assay in the absence (A) or presence of PGC-1α (B) and PGC-1β (C). Mean values of triplicate experiments are shown as fold induction, where the Luc activity of nonfused GAL4 protein (GAL) as reference value (A), or where the Luc activity of GAL4-fused nuclear receptor in the absence of PGC-1α or PGC-1β serves as the reference values, which were obtained in the experiment shown in A (B and C). (Error bars, standard deviation.) (D) Dose-dependent activation of full-length ERR-mediated transcription via ERRE by PGC-1β. Mean values from triplicate experiments are shown as fold induction, where the Luc activity of TK-Luc in the absence of PGC-1β serves as the reference value. (Error bars, standard deviation.) (E) In vitro synthesized 35S-labeled PGC-1β shows strong interaction with GST-ERR1 and -ERR3. (F) Immunoprecipitation of PGC-1β with ERR1. HEK293T cells were transfected with pEGFP-PGC-1β with or without pCMX-FLAG-ERR1, cell lysates were immunoprecipitated with an anti-FLAG antibody, and immunoprecipitates were analyzed by Western blotting with anti-PGC-1β and anti-FLAG antibodies. (G) Chromatin immunoprecipitation assay on the MCAD promoter in 3T3-L1 cells using an anti-PGC-1β antibody. The chromatin from 3T3-L1 cells was cross-linked with formaldehyde and was immunoprecipitated with an anti-PGC-1β antibody. IgG was used as a nonrelated antibody for a negative control. The precipitated DNA was amplified by PCR by using the primers that cover the promoter region of the MCAD gene containing an ERR-responsive element.
Fig. 3.
Fig. 3.
Creation of PGC-1β mice. (A) A schematic drawing of the PGC-1β transgene and the positions of probes used for Southern (probe 1) and Northern (probe 1 and 2) blots are shown. (B) Two transgenic lines (A1 and A2) were established, containing 10 and 12 copies of the transgene, respectively. (C) Northern blot analysis on the skeletal muscle, WAT, and liver from 8-week-old PGC-1β (line A1) and control mice. Each lane contained 20μg of total RNA. mRNA expression of PGC-1β, MCAD, ACC2, UCP-3, and control GAPDH were examined. Three age-matched male mice in each group were used. Quantification of Northern signals (control as 100%) is shown under the panels. Data are represented as the mean ± SEM (*, P < 0.05). C, control mice; P, PGC-1β mice.
Fig. 4.
Fig. 4.
Phenotypes of PGC-1β mice. (A) Increased β-oxidation in the skeletal muscle of PGC-1β mice. No increase of β-oxidation was observed in the liver of PGC-1β mice (data not shown). (B) Food intake was measured every week and expressed as cumulative food intake per mouse during the indicated period. Data are means ± SEM (n = 6 per animal group; error bars are smaller than the symbols; *, P < 0.05; **, P < 0.01). (C) PGC-1β mice (•) weighed significantly less than their wild-type controls (○). Values represent mean body weight ± SEM (n = 6 per animal group; *, P < 0.05; **, P < 0.01). For some data points, the error bars are smaller than the symbols. (D) Comparison of epididymal WAT weight between PGC-1β mice and wild-type control mice. Columns represent mean values of WAT weight ± SEM (n = 6 per animal group; *, P < 0.05). (E) Comparison of the morphology of WAT between PGC-1β mice and littermate wild-type control mice. (Scale bar = 50 μm.) (F) Average diameter of adipose cells. The diameters of the cells were measured from the sections shown in E (n = 20, **, P < 0.01). (G–I) Resting (G) and total (H and I) energy expenditures were significantly higher in PGC-1β mice than in control mice at 12 weeks of age. Columns represent mean values of energy expenditure ± SEM (n = 6 per animal group; *, P < 0.05; **, P < 0.01).
Fig. 5.
Fig. 5.
Breeding of PGC-1β mice and genetically obese KKAy mice. Body weights of KKAy (+) PGC-1β (-)(□; n = 8), KKAy (-) PGC-1β (-)(○; n = 5), KKAy (+) PGC-1β (+) (▪; n = 5), and KKAy (-) PGC-1β (+) (•; n = 5) male mice were measured weekly. Values represent mean body weight ± SEM. For some data points, the error bars are smaller than the symbols. Body weight curves of each group were compared by one-way repeated-measures ANOVA. *, P < 0.05; **, P < 0.01.
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References

    1. Mangelsdorf, D. J., Thummel, C., Beato, M., Herrlich, P., Schutz, G., Umesono, K., Blumberg, B., Kastner, P., Mark, M., Chambon, P. & Evans, R. M. (1995) Cell 83, 835-839. - PMC - PubMed
    1. Giguere, V., Yang, N., Segui, P. & Evans, R. M. (1988) Nature 331, 91-94. - PubMed
    1. Shigeta, H., Zuo, W., Yang, N., DiAugustine, R. & Teng, C. T. (1997) J. Mol. Endocrinol. 19, 299-309. - PubMed
    1. Eudy, J. D., Yao, S., Weston, M. D., Ma-Edmonds, M., Talmadge, C. B., Cheng, J. J., Kimberling, W. J. & Sumegi, J. (1998) Genomics 50, 382-384. - PubMed
    1. Hong, H., Yang, L. & Stallcup, M. R. (1999) J. Biol. Chem. 274, 22618-22626. - PubMed