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PNAS 101 (24): 8912-8917

Copyright © 2004 by the National Academy of Sciences.

BIOCHEMISTRY

Regulation of PPAR{gamma} coactivator 1{alpha} (PGC-1{alpha}) signaling by an estrogen-related receptor {alpha} (ERR{alpha}) ligand

Patricia J. Willy *, {dagger}, Ian R. Murray *, Jing Qian *, Brett B. Busch {ddagger}, William C. Stevens, Jr. {ddagger}, Richard Martin {ddagger}, Raju Mohan {ddagger}, Sihong Zhou §, Peter Ordentlich §, Ping Wei §, Douglas W. Sapp §, Robert A. Horlick §, Richard A. Heyman *, and Ira G. Schulman *

Departments of *Biology, {ddagger}Chemistry, and §Lead Discovery, X-Ceptor Therapeutics, Inc., San Diego, CA 92121

Edited by Bruce M. Spiegelman, Harvard Medical School, Boston, MA, and approved May 10, 2004

Received for publication February 27, 2004.

Abstract: Peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) coactivator 1{alpha} (PGC-1{alpha}) is a transcriptional coactivator that is a key component in the regulation of energy production and utilization in metabolic tissues. Recent work has identified PGC-1{alpha} as a strong coactivator of the orphan nuclear receptor estrogen-related receptor {alpha} (ERR{alpha}), implicating ERR{alpha} as a potential mediator of PGC-1{alpha} action. To understand the role of ERR{alpha} in PGC-1{alpha} signaling, a parallel approach of high-throughput screening and gene-expression analysis was used to identify ERR{alpha} small-molecule regulators and target genes. We report here the identification of a potent and selective ERR{alpha} inverse agonist that interferes effectively with PGC-1{alpha}/ERR{alpha}-dependent signaling. This inverse agonist inhibits the constitutive activity of ERR{alpha} in both biochemical and cell-based assays. Also, we demonstrate that monoamine oxidase B is an ERR{alpha} target gene whose expression is regulated by PGC-1{alpha} and ERR{alpha} and inhibited by the ERR{alpha} inverse agonist. The discovery of potent and selective ERR{alpha} modulators and their effect on PGC-1{alpha} signaling provides mechanistic insight into gene regulation by PGC-1{alpha}. These findings validate ERR{alpha} as a promising therapeutic target in the treatment of metabolic disorders, including diabetes and obesity.

This paper was submitted directly (Track II) to the PNAS office.

Abbreviations: PPAR{gamma}, peroxisome proliferator-activated receptor {gamma}; AF2, activation function 2; DES, diethylstilbestrol; ER, estrogen receptor; ERR, estrogen-related receptor; FP, fluorescence polarization; MAOB, monoamine oxidase B; mSHP, mouse short heterodimer partner; OX/PHOS, oxidative phosphorylation; PGC-1{alpha}, PPAR{gamma} coactivator 1{alpha}; LBD, ligand-binding domain.

{dagger} To whom correspondence should be addressed at: Department of Biology, X-Ceptor Therapeutics, Inc., 4757 Nexus Center Drive, Suite 200, San Diego, CA 92121. E-mail: pwilly{at}x-ceptor.com.

© 2004 by The National Academy of Sciences of the USA

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