Lactate Inhibits Lipolysis in Fat Cells through Activation of an Orphan G-protein-coupled Receptor, GPR81

Abstract

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. GPR81(1) is an orphan G-protein-coupled receptor that is highly homologous to GPR109a and GPR109b. GPR109a and GPR109b were recently identified as receptors for niacin (also known as nicotinic acid) (2, 3) and subsequently characterized as receptors for the endogenous ketone body ␤-hydroxybutyrate (4). Niacin has been used clinically for a half-century as an effective treatment for dyslipidemia (5); however, its utility is somewhat hampered by a target-related effect on dendritic Langerhans cells, which release prostaglandin D2 in response to GPR109a stimulation, resulting in a cutaneous flushing response (6 -8). GPR81 is highly expressed in fat, similar to GPR109a, but is not expressed significantly in spleen; nor is it highly detected in any other tissue, and it has thus been hypothesized to be a potential target for the treatment of dyslipidemia that would be analogous to GPR109a/niacin but without the potential side effects (9).In this report, we demonstrate the initial identification of the ligand activity for GPR81 from the rat tissue extracts, the purification of L-lactate from porcine brain as the source of the ligand activity, and the pharmacological characterization of L-lactate as a ligand for GPR81. In addition, we show that in its physiological concentration range, L-lactate effectively inhibits lipolysis in adipocytes from humans, mice, and rats. Adipocytes from GPR81-deficient mice lack responses to L-lactate, indicating that the antilipolytic effect of L-lactate is mediated by GPR81. Despite a long history of being considered as waste or a by-product of metabolism, L-lactate has maintained some attention as a potential signaling molecule (10). As early as the 1960s, researchers have demonstrated significant effects of lactate on adipocytes (11); however, the mechanism by which this occurs has remained unknown. Our...

Assessment of Metabolic Flexibility by Means of Measuring Blood Lactate, Fat, and Carbohydrate Oxidation Responses to Exercise in Professional Endurance Athletes and Less-Fit Individuals

“…Accordingly, our data are in concordance with the scientific literature showing that endurance training increases the capacity to oxidize fatty acids [5,[51][52][53][54][55]. Not surprisingly, our data also show consistent and strong inverse correlations between [La -] and FATox in all three groups, as expected, as both are mitochondrial substrates and lactate inhibits lipolysis, as previously discussed [42]. Therefore, our correlations between fat and lactate oxidation implicate differences in mitochondrial function across the three categories of fitness level, PA [ MA [ MtS.…”

“…In this regard, it is noteworthy that lactate may inhibit lipolysis in fat cells through activation of an orphan G-proteincoupled receptor (GPR81) [41][42][43]. Furthermore, triglyceride metabolism can also be altered by lactate as it has been shown that exercise-induced lactate accumulation regulates intramuscular triglyceride metabolism via transforming growth factor (TGF)-b1-mediated pathways [44].…”

“…Far from being a 'dead end' metabolite produced as the result of oxygen insufficiency, we now know that lactate is a major energy source [4,[63][64][65], the major gluconeogenic precursor [6], and a signaling molecule, a 'lactormone' [66] responsible for diverse actions such as gene expression [67] and control of lactate-responsive genes such as GPR81 and TREK1 (vide infra) [41][42][43]68]. In the process of shuttling between sites of production and removal, lactate exerts profound effects on fat and CHO metabolism.…”

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“…In adipocytes, energy availability is communicated indirectly through insulin concentrations and sympathetic tone (4) but is also sensed directly through G protein-coupled receptors. In adipose tissue, G protein-coupled receptors respond to short chain fatty acids, lactate, ␤-hydroxybutyrate, ␤-hydroxyoctanoate, and succinate to mediate effects on lipolysis (5)(6)(7)(8)(9). A hypothesis explored in this study is whether nutritive signals regulating adipocyte differentiation and metabolism are also mediated in part by sweet taste receptors.…”

Triagem funcional de genes envolvidos no processo de manutenção da inativação do cromossomo X em humanos

“…Proteína está localizada na membrana plasmática. Lee et al, 2001;Cai et al, 2008;Liu et al, 2009;Kuei et al, 2011;Offermanns et al, 2011. Szenker et al, 2011).…”