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A novel pharmacogenetic strategy to study the regulation of glucose and energy homeostasis by distinct GPCR signaling pathways

Jurgen Wess

G protein-coupled receptors (GPCRs) play critical roles in maintaining proper glucose and energy homeostasis. During the past few years, clozapine-N-oxide (CNO)-sensitive designer GPCRs have emerged as valuable new tools to dissect the in vivo roles of distinct G protein signaling pathways in specific cell types or tissues. Structurally, these novel receptors (alternative name: designer receptors exclusively activated by designer drugs; DREADDs) are mutant muscarinic acetylcholine (ACh) receptors that are unable to bind the endogenous ligand, ACh. However, DREADDs can be activated by CNO with high potency and efficacy. Importantly, CNO is otherwise pharmacologically inert. 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: Gαs, Gαi, Gαq/11, and G12/13, 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.