GPCRs involved in metabolic diseases: pharmacotherapeutic development updates

Abstract

G protein-coupled receptors (GPCRs) are expressed in a variety of cell types and tissues, and activation of GPCRs is involved in enormous metabolic pathways, including nutrient synthesis, transportation, storage or insulin sensitivity, etc. This review intends to summarize the regulation of metabolic homeostasis and mechanisms by a series of GPCRs, such as GPR91, GPR55, GPR119, GPR109a, GPR142, GPR40, GPR41, GPR43 and GPR120. With deep understanding of GPCR's structure and signaling pathways, it is attempting to uncover the role of GPCRs in major metabolic diseases, including metabolic syndrome, diabetes, dyslipidemia and nonalcoholic steatohepatitis, for which the global prevalence has risen during last two decades. An extensive list of agonists and antagonists with their chemical structures in a nature of small molecular compounds for above-mentioned GPCRs is provided as pharmacologic candidates, and their preliminary data of preclinical studies are discussed. Moreover, their beneficial effects in correcting abnormalities of metabolic syndrome, diabetes and dyslipidemia are summarized when clinical trials have been undertaken. Thus, accumulating data suggest that these agonists or antagonists might become as new pharmacotherapeutic candidates for the treatment of metabolic diseases.

Keywords: G protein-coupled receptor; agonist; antagonist; diabetes; metabolic syndrome; nonalcoholic steatohepatitis.

Fig. 1. Signaling pathways and metabolic effects GPCRs.

Different types of ligands bind to the binding pocket of quiescent GPCRs and the coupling of the ligands to the receptor activates GPCRs. The spatial conformation of activated GPCRs changes along with activation, resulting in the replacement of GDP bound to the G_α subunit on the G_αβγ/GDP complex by GTP, and the complex dissociates into G_α and G_βγ subunits, which are active and begin to exert modulating effects through the downstream signaling molecules. The effects of GPCRs are diverse and may be classified into two categories: (1) Physiological effects manifest as improvements in dyslipidemia and insulin resistance and diabetic status by promoting glucose-dependent insulin secretion; (2) Pathological effects arrange from enhanced inflammatory response and hepatocellular lipid accumulation, to deposition of lipid in vascular lining, in turn result in NAFLD and atherosclerosis in metabolic disorders. AC adenylate cyclase, DAG diacylglycerol, ECL extracellular loop, GRK G protein-coupled receptor kinases, GPCR G protein-coupled receptor, ICL intracellular loop, IP3 inositol triphosphates, LPC lysophosphatidylcholine, LPI L-α-lysophosphatidylinositol, NAFLD nonalcoholic fatty liver diseases, OEA oleoylethanolamide, 2-OG 2-oleoyl glycerol, PKA protein kinase A, PKC: protein kinase C, PLC phospholipase C, SCFAs short-chain fatty acids, TM transmembrane domains.

Fig. 2. Pharmacologic mechanisms of GPR55 antagonists in metabolic disorders.

GPR55 activated by specific ligands exerts pathophysiologic effects mainly through two subunits, (1) G_12/13 that upregulates SREBP-1c expression in hepatocytes through the PI3K/Akt pathway and promotes de novo lipid genesis, leading to lipid accumulation in hepatocytes and the development of cirrhosis; (2) G_αq/11 that promotes insulin secretion by increasing intracellular calcium levels through various pathways. On the other hand, elevated Ca²⁺ will also lead to elevated expression of MAC-1, which not only inhibits islet β-cell proliferation (causing diabetes), but also leads to inflammatory responses and atherosclerosis in human. Antagonists of GPR55 bind to specific sites on the receptor, causing conformational changes in GPR55, thereby blocking the action of the ligand, which mainly acting as anti-inflammatory and anti-atherosclerotic agents. Abbreviations in this illustration: MAC-1: macrophage-1 antigen; SREBP-1c: sterol regulatory element-binding protein-1c.

Fig. 3. Promotional role of GPR142 agonists for potential treatment of type 2 diabetes.

GPR142 elicits PLC-mediated generation of second messengers, DAG and IP3, via the G_αq/11 subunit, promotes ERK phosphorylation, which is a downstream response of the G_βγ subunit, thereby increasing the secretion of the incretins: GIP and GLP-1, ultimately inducing glucose-dependent insulin secretion. GPR142 agonists may enhance this process, and agonist LY3325656 has entered into phase I clinical trials for the treatment of T2D. In addition, GPR142 activation improves lipid metabolism via G_αi/o and G_αq/11 subunits. DAG diacylglycerol, ERK extracellular regulated protein kinases, GIP glucose-dependent insulinotropic polypeptide, GLP glucagon-like peptide, IP3 inositol triphosphates, PLC phospholipase C, T2D type 2 diabetes.