Metabolite-sensing GPCRs controlling interactions between adipose tissue and inflammation

Abstract

Metabolic disorders including obesity, diabetes and non-alcoholic steatohepatitis are a group of conditions characterised by chronic low-grade inflammation of metabolic tissues. There is now a growing appreciation that various metabolites released from adipose tissue serve as key signalling mediators, influencing this interaction with inflammation. G protein-coupled receptors (GPCRs) are the largest family of signal transduction proteins and most historically successful drug targets. The signalling pathways for several key adipose metabolites are mediated through GPCRs expressed both on the adipocytes themselves and on infiltrating macrophages. These include three main groups of GPCRs: the FFA4 receptor, which is activated by long chain free fatty acids; the HCA₂ and HCA₃ receptors, activated by hydroxy carboxylic acids; and the succinate receptor. Understanding the roles these metabolites and their receptors play in metabolic-immune interactions is critical to establishing how these GPCRs may be exploited for the treatment of metabolic disorders.

Keywords: G protein-coupled receptor; adipose; free fatty acid; hydroxy carboxylic acids; inflammation; metabolite signalling; succinate.

Figure 1

FFA4 signalling between adipocytes and macrophages. Saturated and unsaturated fatty acids are released from adipocytes by lipolysis, supplemented from the diet and may be produced through PLA₂-mediated hydrolysis of phospholipids. These fatty acids act as ligands of FFA4 in an autocrine manner to inhibit lipolysis via Gα_i signalling, stimulate glucose uptake via a Gα_q pathway and stimulate or enhance adipogenesis via Gα_s signalling. Fatty acids may also act in a paracrine manner to activate anti-inflammatory pathways in macrophages. Dashed lines represent interactions lacking direct mechanistic evidence, and thus further investigation is required. Created with BioRender.com.

Figure 2

HCA receptor signalling between adipocytes and macrophages. During periods of fasting or exercise, there is an increase in lipolysis and subsequently an increased release of fatty acids from adipocytes. These fatty acids are converted in the liver or muscle (purple box) to Acyl-CoA and then transported into mitochondria (red box). Beta-oxidation in the mitochondria produces acetyl-CoA, which undergoes ketogenesis, a four-step process that can produce beta-hydroxybutyrate (BHB). BHB binds to and activates the HCA₂ receptor and through Gα_i signalling, evokes antilipolytic effects in adipocytes and anti-inflammatory effects in macrophages. The anti-inflammatory effects include a reduction in cytokine production and suppression of chemokine signalling. Additionally, in macrophages the HCA₂ receptor signals via the Gβγ subunit and β-arrestin-1 to mediate the release of prostanoids. Similarly, beta-hydroxyoctanoate is produced via beta-oxidation of fatty acids. However, beta-hydroxyoctanoate is released as a result of incomplete beta-oxidation. Beta-hydroxyoctanoate binds to and activates the HCA₃ receptor on adipocytes and macrophages and through its Gα_i evokes anti-inflammatory and antilipolytic effects. Created with BioRender.com.

Figure 3

Succinate Receptor signalling between adipocytes and macrophages. Under conditions of hypoxic or metabolic stress succinate dehydrogenase reverses function, leading to a build-up of succinate in the mitochondria. When concentrations become elevated, succinate leaves the mitochondria through a dicarboxylate carrier, before exiting the cell through other solute carriers. Once outside the cell, succinate binds to and activates SUCNR1 on the surface of adipocytes and macrophages to inhibit lipolysis and control inflammation respectively. In macrophages, SUCNR1 has been reported to have both pro-inflammatory and anti-inflammatory effects. These include mediating chemotaxis towards hypoxic adipose, likely through Gα_i activation, as well as hyperpolarisation to the M2 macrophage phenotype through a Gα_q mediated pathway. Created with BioRender.com.