Metabolic Functions of G Protein-Coupled Receptors and β-Arrestin-Mediated Signaling Pathways in the Pathophysiology of Type 2 Diabetes and Obesity

Abstract

Seven transmembrane receptors (7TMRs), often termed G protein-coupled receptors (GPCRs), are the most common target of therapeutic drugs used today. Many studies suggest that distinct members of the GPCR superfamily represent potential targets for the treatment of various metabolic disorders including obesity and type 2 diabetes (T2D). GPCRs typically activate different classes of heterotrimeric G proteins, which can be subgrouped into four major functional types: G_αs, G_αi, G_αq/11, and G_12/13, in response to agonist binding. Accumulating evidence suggests that GPCRs can also initiate β-arrestin-dependent, G protein-independent signaling. Thus, the physiological outcome of activating a certain GPCR in a particular tissue may also be modulated by β-arrestin-dependent, but G protein-independent signaling pathways. In this review, we will focus on the role of G protein- and β-arrestin-dependent signaling pathways in the development of obesity and T2D-related metabolic disorders.

Keywords: GPCRs; biased signaling; obesity; type 2 diabetes; β-arrestins.

Figure 1

Expression and function of various GPCRs in metabolic tissues. Various GPCRs target insulin resistance, obesity, and T2D-related pathophysiology in the metabolic tissues. KA, kynurenic acid; LCFA, long-chain fatty acid; SCFA, short-chain fatty acid; OEA, oleylethanolamide; PUFA, polyunsaturated fatty acid; CCK, cholecystokinin; GLP-1, glucagon-like peptide 1; GIP, gastric inhibitory polypeptide.

Figure 2

The concept of GPCR signaling: biased signaling. (A) G protein-biased agonist. Biased agonists selectively activate the GPCR-dependent signaling pathway. Previous studies demonstrate that sustained G protein-mediated signaling can affect cellular response through second messenger activation. (B) β-Arrestin biased agonist. Biased agonists selectively activate the β-arrestin-dependent signaling pathway. The β-arrestin-mediated signaling leads to distinct physiological outcomes. (C) Balanced agonist. Balanced agonists activate both the G protein- and β-arrestin-dependent signaling pathway.