Lactate inhibits lipolysis in fat cells through activation of an orphan g-protein-coupled receptor, gpr81
Open accessAbstract
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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The lactate receptor G-protein-coupled receptor (GBR81) is expressed in adipose tissue, and this receptor mediates a marked anti-lipolytic action.
“the lactate receptor G-protein-coupled receptor (GBR81) is expressed in adipose tissue, and that this receptor mediates a marked anti-lipolytic action [154].”
From Regulation of Energy Substrate Metabolism in Endurance Exercise (2021) · cites this paper as [154]
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- Authors
- Liu, C., Wu, J., Zhu, J., Kuei, C., Yu, J., Shelton, J., Sutton, S. W., Li, X., Yun, S. J., Mirzadegan, T., Mazur, C., Kamme, F., & Lovenberg, T. W.
- Corresponding author
- Liu, Changlu
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2009-01
- Volume
- 284
- Issue
- 5
- Pages
- 2811-2822
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2086554547
- Cited by
- 606
- References
- 47
- Citations by year
- 2026: 65 · 2025: 62 · 2024: 57 · 2023: 53 · 2022: 70 · 2021: 32 · 2020: 48 · 2019: 24 · 2018: 26 · 2017: 31 · 2016: 27 · 2015: 27 · 2014: 19 · 2013: 13 · 2012: 14
- FWCI
- 8.58
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
- Keywords
- lactate, GPR81, orphan G protein-coupled receptor, lipolysis, adipocytes, adipose tissue, receptor internalization, dyslipidemia, metabolic signaling, 3T3-L1 cells
- MeSH terms
- Amino Acid Sequence, Animals, Binding Sites, Humans, Ligands, Lipolysis, Models, Molecular, Molecular Sequence Data, Species Specificity, Swine, Adipocytes, Lactic Acid, Receptors, G-Protein-Coupled, Mice, Rats
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