| Lactate inhibits lipolysis in fat cells through activation of an orphan G-protein-coupled receptor, GPR81. | |
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MedLine Citation:
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PMID: 19047060 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Lactic acid is a well known metabolic by-product of intense exercise, particularly under anaerobic conditions. Lactate is also a key source of energy and an important metabolic substrate, and it has also been hypothesized to be a signaling molecule directing metabolic activity. Here we show that GPR81, an orphan G-protein-coupled receptor highly expressed in fat, is in fact a sensor for lactate. Lactate activates GPR81 in its physiological concentration range of 1-20 mM and suppresses lipolysis in mouse, rat, and human adipocytes as well as in differentiated 3T3-L1 cells. Adipocytes from GPR81-deficient mice lack an antilipolytic response to lactate but are responsive to other antilipolytic agents. Lactate specifically induces internalization of GPR81 after receptor activation. Site-directed mutagenesis of GPR81 coupled with homology modeling demonstrates that classically conserved key residues in the transmembrane binding domains are responsible for interacting with lactate. Our results indicate that lactate suppresses lipolysis in adipose tissue through a direct activation of GPR81. GPR81 may thus be an attractive target for the treatment of dyslipidemia and other metabolic disorders. |
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Authors:
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Changlu Liu; Jiejun Wu; Jessica Zhu; Chester Kuei; Jingxue Yu; Jonathan Shelton; Steven W Sutton; Xiaorong Li; Su Jin Yun; Taraneh Mirzadegan; Curt Mazur; Fredrik Kamme; Timothy W Lovenberg |
Publication Detail:
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Type: Journal Article Date: 2008-12-01 |
Journal Detail:
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Title: The Journal of biological chemistry Volume: 284 ISSN: 0021-9258 ISO Abbreviation: J. Biol. Chem. Publication Date: 2009 Jan |
Date Detail:
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Created Date: 2009-01-26 Completed Date: 2009-04-07 Revised Date: 2009-09-24 |
Medline Journal Info:
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Nlm Unique ID: 2985121R Medline TA: J Biol Chem Country: United States |
Other Details:
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Languages: eng Pagination: 2811-22 Citation Subset: IM |
Affiliation:
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Johnson & Johnson Pharmaceutical Research & Development LLC, San Diego, CA 92121, USA. cliu9@its.jnj.com |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Adipocytes
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drug effects*,
metabolism Amino Acid Sequence Animals Binding Sites Humans Lactic Acid / metabolism, pharmacology* Ligands Lipolysis / drug effects* Mice Models, Molecular Molecular Sequence Data Rats Receptors, G-Protein-Coupled / agonists*, chemistry, metabolism Species Specificity Swine |
| Chemical | |
Reg. No./Substance:
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0/G protein-coupled receptor 81, mouse; 0/GPR81 protein, human; 0/Ligands; 0/Receptors, G-Protein-Coupled; 50-21-5/Lactic Acid |
| Comments/Corrections | |
Comment In:
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J Biol Chem. 2009 Jul 31;284(31):le5; author reply le6
[PMID:
19632998
]
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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