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  • Review Article
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G protein-coupled receptors for energy metabolites as new therapeutic targets

Nature Reviews Drug Discovery volume 11, pages 603–619 (2012)Cite this article

Subjects

Key Points

  • In recent years, several G protein-coupled receptors (GPCRs) have been identified that are activated by energy substrates such as fatty acids and sucrose, or by metabolic intermediates such as acetate, lactate or ketone bodies.

  • These carbohydrate or lipid metabolites, by activating specific GPCRs, function in a hormone-like fashion in addition to their role as carriers of energy.

  • Metabolite receptors sense metabolic activity or levels of energy substrates and control the secretion of metabolic hormones or regulate the metabolic activity of particular cells.

  • Synthetic ligands of the heterodimeric sweet receptor taste receptor type 1 member 2 (TAS1R2)–TAS1R3, which is a receptor for mono- and disaccharides, are used as artificial sweeteners but may have additional metabolic functions, as TAS1R2–TAS1R3 appears to be also involved in non-gustatory metabolic functions.

  • The long-chain fatty acid receptors free fatty acid receptor 1 (FFA1; (also known as GPR40) and GPR120 (also known as omega-3 fatty acid receptor 1) mediate beneficial effects by promoting glucose-induced insulin secretion and by inhibiting inflammatory signalling in immune cells, respectively.

  • The short-chain fatty acid receptors FFA2 (also known as GPR43) and FFA3 (also known as GPR41) appear to link the gut microbiota to metabolic and immune functions. Whether these receptors can be exploited therapeutically is currently not clear.

  • Succinate receptor 1 (SUCNR1; also known as GPR91), which is activated by the citric acid cycle intermediate succinate (released by cells following cellular stress or hypoxia), is involved in the regulation of blood pressure, retinal angiogenesis and immune functions.

  • Of the hydroxycarboxylic acid receptors, which are activated by ketone bodies or lactate, hydroxycarboxylic acid receptor 2 (HCA2) — which is also activated by nicotinic acid — in particular is of pharmacological interest as it mediates some anti-dyslipidaemic effects as well as anti-inflammatory effects, which can be used to reduce the progression of atherosclerosis and potentially other diseases.

  • Several of these receptors have been tested as targets for drugs to treat particular metabolic diseases, and various synthetic ligands have been developed in recent years. Agonists of FFA1 and HCA2 are currently being tested in clinical trials.

Abstract

Several G protein-coupled receptors (GPCRs) that are activated by intermediates of energy metabolism — such as fatty acids, saccharides, lactate and ketone bodies — have recently been discovered. These receptors are able to sense metabolic activity or levels of energy substrates and use this information to control the secretion of metabolic hormones or to regulate the metabolic activity of particular cells. Moreover, most of these receptors appear to be involved in the pathophysiology of metabolic diseases such as diabetes, dyslipidaemia and obesity. This Review summarizes the functions of these metabolite-sensing GPCRs in physiology and disease, and discusses the emerging pharmacological agents that are being developed to target these GPCRs for the treatment of metabolic disorders.

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Figure 1: Basic catabolic pathways of carbohydrate and lipid energy metabolism.
Figure 2: Structures of synthetic ligands of the taste receptor TAS1R2–TAS1R3.
Figure 3: Simplified schematic diagram of the regulation of enteroendocrine cell function through GPCRs.
Figure 4: Simplified schematic diagram of the regulation of insulin secretion from pancreatic β-cells by metabolites and hormones acting through GPCRs.
Figure 5: Structures of synthetic ligands of long-chain fatty acid receptors.
Figure 6: Structures of synthetic ligands of the short-chain fatty acid receptor FFA2.
Figure 7: Model of the regulation of adipocyte function through GPCRs.
Figure 8: Structures of synthetic ligands of hydroxycarboxylic acid receptors and the succinate receptor.

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Acknowledgements

The authors wish to thank S. Hümmer for excellent secretarial help with the manuscript.

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Authors and Affiliations

  1. Department of Pharmacology, Max Planck Institute for Heart and Lung Research, Ludwigstrasse 43, Bad Nauheim, 61231, Germany

    Clara C. Blad, Cong Tang & Stefan Offermanns

  2. Medical Faculty, J.W. Goethe University Frankfurt, Theodor-Stern-Kai 7, Frankfurt, 60590, Germany

    Stefan Offermanns

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  1. Clara C. Blad
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  2. Cong Tang
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Correspondence to Stefan Offermanns.

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Glossary

Enteroendocrine cells

Specialized endocrine cells of the gastrointestinal tract that are in contact with the gut lumen and secrete various hormones such as the incretins glucagon-like peptide 1 and gastric inhibitory peptide.

Citric acid cycle

Also known as the Krebs cycle; the process by which organisms aerobically generate energy through the oxidation of acetate.

Protomers

Units of an oligomeric protein; a protein dimer consists of two protomers.

Orthosteric agonists

Ligands that bind to the receptor at the same site as the endogenous ligand of the receptor.

Allosteric agonists

Ligands that bind to the receptor at a site different to that of the endogenous ligand (or ligands).

Glucagon-like peptide 1

(GLP1). A peptide hormone produced by enteroendocrine cells that stimulates insulin secretion from pancreatic β-cells.

Post-prandial

After a meal.

Incretins

A group of gastrointestinal hormones, including glucagon-like peptide 1 and gastric inhibitory peptide, that regulate insulin secretion.

L-cells

A subgroup of enteroendocrine cells that produce glucagon-like peptide 1 and peptide YY with an amino-terminal tyrosine amide.

Ketogenesis

The process by which fatty acids, which are degraded in the liver, are further metabolized into ketone bodies.

Prostaglandin D2 receptor

A G protein-coupled receptor that is activated by prostaglandin D2.

Apolipoprotein E

A particular apolipoprotein that is found on chylomicrons and intermediate-density lipoproteins. Mice lacking the gene encoding apolipoprotein E are prone to developing atherosclerosis.

β-oxidation

A process (occurring in mitochondria) by which fatty acids are broken down to acetyl-CoA.

Macula densa cells

Specialized cells lining the wall of the distal tubulus of the kidney at the point where the distal tubulus comes into contact with its parent glomerulus.

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Blad, C., Tang, C. & Offermanns, S. G protein-coupled receptors for energy metabolites as new therapeutic targets. Nat Rev Drug Discov 11, 603–619 (2012). https://doi.org/10.1038/nrd3777

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