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: 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.
Highlights
Type 2 diabetes (T2D) is a complex, heterogeneous disease afflicting an increasing proportion of the population
We focus on G protein-coupled receptors (GPCRs) that function in metabolic disorders, GPCR and b-Arrestin Signaling in Metabolism in type 2 diabetes (T2D) and obesity-related diseases
In contrast to b-arrestin1, mice lacking b-arrestin2 in adipocytes display improved metabolic phenotypes [118]. These findings convincingly identify that b-arrestin1 and 2 are required for the maintenance of glucose homeostasis in their own right and strongly suggest that strategies aiming to enhance b-arrestin activity in adipocytes may be beneficial for the treatment of T2D and obesity-related metabolic disorders
Summary
Type 2 diabetes (T2D) is a complex, heterogeneous disease afflicting an increasing proportion of the population. Eventually b-cell dysfunction emerges and is characterized by a decrease in b-cell mass, as well as poor ability of b-cells to correctly secrete insulin in response to glucose In this context, hyperinsulinemia is no longer able to compensate resulting in hyperglycemia and the development of T2D [2, 4, 5]. We focus on GPCRs that function in metabolic disorders, GPCR and b-Arrestin Signaling in Metabolism in T2D and obesity-related diseases. Several endogenous ligands such as free fatty acids and their receptors (e.g., GPR40, GPR41, GPR43, GPR84, GPR119, and GPR120) have been extensively studied in the regulation of insulin secretion, insulin sensitization, b-cell expansion, and glucose homeostasis (Figure 1 and Table 1). This review will discuss GPCRs and their signaling pathways (G protein-dependent and/or b-arrestin-dependent) that can be targeted pharmacologically to treat T2D by improving insulin sensitivity (Figures 1 and 2)
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