Involvement of the metabolic sensor GPR81 in cardiovascular control

Wallenius, Kristina; Thalén, Pia; Björkman, Jan-Arne; Johannesson, Petra; Wiseman, John; Böttcher, Gerhard; Fjellström, Ola; Oakes, Nicholas D.

doi:10.1172/jci.insight.92564

Cited by 34 publications

(44 citation statements)

References 67 publications

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“…Involved in thermogenesis and antiinflammatory responses in adipose tissue [97] T1R2/T1R3 Glucose, sucrose, maltose Leptin downregulates T1R2 and T1R3 in hypothalamic neurons [168] Gpr81 Lactate Inhibits lipolysis in adipocytes [169]. Reduces FFAs in circulation [170].…”

Section: -Hydroxybutyrate Inhibits Adipocyte Lipolysis [164]mentioning

confidence: 99%

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The weight of nutrients: kynurenine metabolites in obesity and exercise

et al. 2018

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Obesity ultimately results from an imbalance between energy intake and expenditure. However, in addition to their bioenergetic value, nutrients and their metabolites can function as important signalling molecules in energy homeostasis. Indeed, macronutrients and their metabolites can be direct regulators of metabolism through their actions on different organs. In turn, target organs can decide to use, store or transform the incoming nutrients depending on their physiological context and in coordination with other cell types. Tryptophan-kynurenine metabolites are an example of a family of compounds that can serve as systemic integrators of energy metabolism by signalling to different cell types. These include adipocytes, immune cells and muscle fibres, in addition to the well-known effects of kynurenine metabolites on the central nervous system. In the context of energy metabolism, several of the effects elicited by kynurenic acid are mediated by the G-protein-coupled receptor, GPR35. As GPR35 is expressed in tissues such as the adipose tissue, immune cells and the gastrointestinal tract, this receptor could be a potential therapeutic target for the treatment of obesity, diabetes and other metabolic diseases. In addition, metabolic disorders often coincide with states of chronic inflammation, which further highlights GPR35 as an integration node in conditions where inflammation skews metabolism. Defining the molecular interplay between different tissues in the regulation of energy homeostasis can help us understand interindividual variability in the response to nutrient intake and develop safe and efficient therapies to fight obesity and metabolic disease.

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Section: -Hydroxybutyrate Inhibits Adipocyte Lipolysis [164]mentioning

confidence: 99%

“…Improves insulin sensitivity [170]. Increases blood pressure [170] Adenosine A2A Adenosine Stimulates noradrenaline-induced lipolysis in brown adipocytes [51].…”

Section: -Hydroxybutyrate Inhibits Adipocyte Lipolysis [164]mentioning

confidence: 99%

The weight of nutrients: kynurenine metabolites in obesity and exercise

et al. 2018

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“…Of the roughly 800 members of the GPCR family, GPR81, also known as hydroxycarboxylic acid receptor 1 (HCA 1 or HCAR1), is a selective lactate‐sensing receptor known to be expressed in several cell types including brain cells, adipocytes, various cancer cells, and retina, among others. Recently, agonism of GPR81 was found to affect blood pressure and vascular resistance by modulating the endothelin system . GPR81 has been shown to be highly expressed in bone marrow endothelial cells, and GPR81‐mediated lactate signaling is reported to modulate the inflammatory response .…”

Section: Introductionmentioning

confidence: 99%

Activation of GPR81 by lactate inhibits oscillatory shear stress‐induced endothelial inflammation by activating the expression of KLF2

et al. 2019

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Atherosclerosis is a common and deadly cardiovascular disease with extremely high prevalence. Areas of the vasculature exposed to oscillatory shear stress (OSS) or disturbed blood flow are particularly prone to the development of atherosclerotic lesions. In part, various mechanosensitive receptors on the surface of endothelial cells play a role in regulating the ability of the vasculature to cope with variations in blood flow patterns. However, the exact mechanisms behind flow-mediated endothelial responses remain poorly understood. Along with the development of highly specific receptor agonists, the class of G coupled-protein receptors has been receiving increasing attention as potential therapeutic targets. G coupled-protein receptor 81 (GPR81), also known as hydroxycarboxylic acid receptor 1 (HCA 1 ), is activated by lactate, its endogenous ligand. In the present study, we show for the first time that expression of GPR81 is significantly downregulated in response to OSS in endothelial cells and that activation of GPR81 using physiologically relevant doses of lactate can rescue OSS-induced reduced GPR81 expression. Importantly, our findings demonstrate that activation of GPR81 can exert valuable atheroprotective effects in endothelial cells exposed to OSS by reducing oxidative stress and significantly downregulating the expression of inflammatory cytokines including interleukin (IL)-6, IL-8, monocyte chemoattractant protein (MCP)-1, and high mobility group box 1 (HMGB1). We also show that activation of GPR81 can potentially prevent the attachment of monocytes to the endothelium by suppressing OSS-induced secretion of vascular cellular adhesion molecule (VCAM)-1 and endothelial-selectin (E-selectin). Finally, we show that activation of GPR81 can rescue OSS-induced reduced expression of the key atheroprotective transcription factor Kruppel-like factor 2 (KLF2), which is mediated through the extracellularregulated kinase 5 (ERK5) pathway. These findings demonstrate a potential Abbreviations: ECL, electrochemiluminescence; E-selectin, endothelial-selectin; ELISA, Enzyme-linked immunosorbent assay; ERK5, extracellularregulated kinase 5; FBS, fetal bovine serum; GPR81, G coupled-protein receptor 81; GPCRs, G protein-coupled receptors; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; HMGB1, high mobility group box 1; HSS, high shear stress; HUVECs, human umbilical vascular endothelial cells; HCA 1 , hydroxycarboxylic acid receptor 1; IL-6, interleukin; KLF2, Kruppel-like factor 2; MAPK, mitogen-activated protein kinase; MCP-1, monocyte chemoattractant protein; OSS, oscillatory shear stress; PAK1, p21-activated kinase 1; PVDF, polyvinylidene fluoride; ROS, reactive oxygen species; RT-PCR, reverse transcription PCR; SDS-PAGE, sodium dodecyl sulfate-polyacrylamide gel electrophoresis; VCAM-1, vascular cellular adhesion molecule.

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“…Indeed, a small molecule GPR81 agonist, AZ2 (aka AZ′5538), which suppressed in vivo free fatty acid levels, also increased blood pressure (BP) when infused intravenously. 9 Nonselective α-adrenoceptor antagonism and endothelin receptor blockade separately reduced this pressor effect. 9 The concept that lactate could influence blood pressure (BP) through activation of GPR81 is relevant to human health.…”

mentioning

confidence: 98%

“…9 Nonselective α-adrenoceptor antagonism and endothelin receptor blockade separately reduced this pressor effect. 9 The concept that lactate could influence blood pressure (BP) through activation of GPR81 is relevant to human health. In the current study, we used AZ′5538 and Gpr81 −/− mice to resolve the effects of GPR81 activation on BP and renal hemodynamics in mice and further demonstrated that genetic deletion of the receptor conferred protection against renal ischemia-reperfusion injury.…”

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confidence: 98%

Endothelin-1 Mediates the Systemic and Renal Hemodynamic Effects of GPR81 Activation

et al. 2020

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Endothelin-1 mediates the systemic and renal hemodynamic effects of GPR81 activation', Hypertension. G PR81 (G-protein-coupled receptor 81), GPR109a, and GPR109b form the hydroxycarboxylic acid receptor subfamily. 1 Encoded by the HCAR1 gene, GPR81 is predominantly expressed in brown and white adipose tissue. 2 L-lactate is the endogenous ligand with an EC 50 of ≈5 mmol/L. 3 Lactate, formed from pyruvate during anaerobic glycolysis, has a physiological plasma concentration of 0.5 to 2 mmol/L, rising from 10 to 30 mmol/L during intense exercise or prolonged hypoxia. 4,5 This suggests that GPR81 is either physiologically quiescent basally or that it is primarily responsive to the local, rather than circulating, concentration of lactate. In adipocytes, activation of GPR81 by L-lactate prevents lipid breakdown and promotes storage of energy-rich metabolites in adipocytes. 2,6 Synthetic GPR81 agonists 7-9 are potential therapies for dyslipidemia and inhibit lipolysis in cultured adipocytes and in vivo.

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Involvement of the metabolic sensor GPR81 in cardiovascular control

Cited by 34 publications

References 67 publications

The weight of nutrients: kynurenine metabolites in obesity and exercise

The weight of nutrients: kynurenine metabolites in obesity and exercise

Activation of GPR81 by lactate inhibits oscillatory shear stress‐induced endothelial inflammation by activating the expression of KLF2

Endothelin-1 Mediates the Systemic and Renal Hemodynamic Effects of GPR81 Activation

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