Lactate inhibits lipolysis in fat cells through activation of an orphan G-protein-coupled receptor, GPR81.
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.
Liu
Changlu
C
Johnson & Johnson Pharmaceutical Research & Development, LLC, San Diego, California 92121. Electronic address: cliu9@its.jnj.com.
Wu
Jiejun
J
Johnson & Johnson Pharmaceutical Research & Development, LLC, San Diego, California 92121.
Zhu
Jessica
J
Johnson & Johnson Pharmaceutical Research & Development, LLC, San Diego, California 92121.
Kuei
Chester
C
Johnson & Johnson Pharmaceutical Research & Development, LLC, San Diego, California 92121.
Yu
Jingxue
J
Johnson & Johnson Pharmaceutical Research & Development, LLC, San Diego, California 92121.
Shelton
Jonathan
J
Johnson & Johnson Pharmaceutical Research & Development, LLC, San Diego, California 92121.
Sutton
Steven W
SW
Johnson & Johnson Pharmaceutical Research & Development, LLC, San Diego, California 92121.
Li
Xiaorong
X
Johnson & Johnson Pharmaceutical Research & Development, LLC, San Diego, California 92121.
Yun
Su Jin
SJ
Johnson & Johnson Pharmaceutical Research & Development, LLC, San Diego, California 92121.
Mirzadegan
Taraneh
T
Johnson & Johnson Pharmaceutical Research & Development, LLC, San Diego, California 92121.
Mazur
Curt
C
Johnson & Johnson Pharmaceutical Research & Development, LLC, San Diego, California 92121.
Kamme
Fredrik
F
Johnson & Johnson Pharmaceutical Research & Development, LLC, San Diego, California 92121.
Lovenberg
Timothy W
TW
Johnson & Johnson Pharmaceutical Research & Development, LLC, San Diego, California 92121.
D017667:Adipocytes / Q000187:drug effects* / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D006801:Humans; D019344:Lactic Acid / Q000378:metabolism / Q000494:pharmacology*; D008024:Ligands; D008066:Lipolysis / Q000187:drug effects*; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000737:chemistry / Q000378:metabolism; D013045:Species Specificity; D013552:Swine
C000603107:GPR81 protein, rat; C533610:HCAR1 protein, human; C529424:Hcar1 protein, mouse; D008024:Ligands; D043562:Receptors, G-Protein-Coupled; D019344:Lactic Acid