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

Overview

Journal Front Endocrinol (Lausanne)

Specialty Endocrinology

Date 2021 Sep 9

PMID 34497585

Citations 12

Authors

Camila Oliveira de Souza

Xuenan Sun

Dayoung Oh

Affiliations

Soon will be listed here.

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, G, G, and G, 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.

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References

Oh D, Olefsky J . G protein-coupled receptors as targets for anti-diabetic therapeutics. Nat Rev Drug Discov. 2016; 15(3):161-72. DOI: 10.1038/nrd.2015.4. View

Husted A, Trauelsen M, Rudenko O, Hjorth S, Schwartz T . GPCR-Mediated Signaling of Metabolites. Cell Metab. 2017; 25(4):777-796. DOI: 10.1016/j.cmet.2017.03.008. View

Lin D, Zhang J, Zhuang R, Li F, Nguyen K, Chen M . AMG 837: a novel GPR40/FFA1 agonist that enhances insulin secretion and lowers glucose levels in rodents. PLoS One. 2011; 6(11):e27270. PMC: 3210765. DOI: 10.1371/journal.pone.0027270. View

Hassing H, Fares S, Larsen O, Pad H, Hauge M, Jones R . Biased signaling of lipids and allosteric actions of synthetic molecules for GPR119. Biochem Pharmacol. 2016; 119:66-75. DOI: 10.1016/j.bcp.2016.08.018. View

McNelis J, Lee Y, Mayoral R, van der Kant R, Johnson A, Wollam J . GPR43 Potentiates β-Cell Function in Obesity. Diabetes. 2015; 64(9):3203-17. PMC: 4542437. DOI: 10.2337/db14-1938. View

Stone V, Dhayal S, Brocklehurst K, Lenaghan C, Winzell M, Hammar M . GPR120 (FFAR4) is preferentially expressed in pancreatic delta cells and regulates somatostatin secretion from murine islets of Langerhans. Diabetologia. 2014; 57(6):1182-91. PMC: 4018485. DOI: 10.1007/s00125-014-3213-0. View

Tan C, Feng Y, Zhou Y, Eiermann G, Petrov A, Zhou C . Selective small-molecule agonists of G protein-coupled receptor 40 promote glucose-dependent insulin secretion and reduce blood glucose in mice. Diabetes. 2008; 57(8):2211-9. PMC: 2494688. DOI: 10.2337/db08-0130. View

Senga T, Iwamoto S, Yoshida T, Yokota T, Adachi K, Azuma E . LSSIG is a novel murine leukocyte-specific GPCR that is induced by the activation of STAT3. Blood. 2002; 101(3):1185-7. DOI: 10.1182/blood-2002-06-1881. View

Ge H, Weiszmann J, Reagan J, Gupte J, Baribault H, Gyuris T . Elucidation of signaling and functional activities of an orphan GPCR, GPR81. J Lipid Res. 2008; 49(4):797-803. DOI: 10.1194/jlr.M700513-JLR200. View

10.

Cai T, Ren N, Jin L, Cheng K, Kash S, Chen R . Role of GPR81 in lactate-mediated reduction of adipose lipolysis. Biochem Biophys Res Commun. 2008; 377(3):987-91. DOI: 10.1016/j.bbrc.2008.10.088. View

11.

Paschoal V, Walenta E, Talukdar S, Pessentheiner A, Osborn O, Hah N . Positive Reinforcing Mechanisms between GPR120 and PPARγ Modulate Insulin Sensitivity. Cell Metab. 2020; 31(6):1173-1188.e5. PMC: 7337476. DOI: 10.1016/j.cmet.2020.04.020. View

12.

Pabreja K, Mohd M, Koole C, Wootten D, Furness S . Molecular mechanisms underlying physiological and receptor pleiotropic effects mediated by GLP-1R activation. Br J Pharmacol. 2013; 171(5):1114-28. PMC: 3952792. DOI: 10.1111/bph.12313. View

13.

Ge H, Li X, Weiszmann J, Wang P, Baribault H, Chen J . Activation of G protein-coupled receptor 43 in adipocytes leads to inhibition of lipolysis and suppression of plasma free fatty acids. Endocrinology. 2008; 149(9):4519-26. DOI: 10.1210/en.2008-0059. View

14.

Fletcher M, Halls M, Christopoulos A, Sexton P, Wootten D . The complexity of signalling mediated by the glucagon-like peptide-1 receptor. Biochem Soc Trans. 2016; 44(2):582-8. DOI: 10.1042/BST20150244. View

15.

Mancini A, Bertrand G, Vivot K, Carpentier E, Tremblay C, Ghislain J . β-Arrestin Recruitment and Biased Agonism at Free Fatty Acid Receptor 1. J Biol Chem. 2015; 290(34):21131-21140. PMC: 4543669. DOI: 10.1074/jbc.M115.644450. View

16.

Bjursell M, Admyre T, Goransson M, Marley A, Smith D, Oscarsson J . Improved glucose control and reduced body fat mass in free fatty acid receptor 2-deficient mice fed a high-fat diet. Am J Physiol Endocrinol Metab. 2010; 300(1):E211-20. DOI: 10.1152/ajpendo.00229.2010. View

17.

Yoshida S, Ohishi T, Matsui T, Tanaka H, Oshima H, Yonetoku Y . Novel GPR119 agonist AS1535907 contributes to first-phase insulin secretion in rat perfused pancreas and diabetic db/db mice. Biochem Biophys Res Commun. 2010; 402(2):280-5. DOI: 10.1016/j.bbrc.2010.10.015. View

18.

Park S, Lee S, Nam S, Im D . GPR35 mediates lodoxamide-induced migration inhibitory response but not CXCL17-induced migration stimulatory response in THP-1 cells; is GPR35 a receptor for CXCL17?. Br J Pharmacol. 2017; 175(1):154-161. PMC: 5740256. DOI: 10.1111/bph.14082. View

19.

Oakley R, Laporte S, Holt J, Barak L, Caron M . Association of beta-arrestin with G protein-coupled receptors during clathrin-mediated endocytosis dictates the profile of receptor resensitization. J Biol Chem. 1999; 274(45):32248-57. DOI: 10.1074/jbc.274.45.32248. View

20.

Boitsova E, Morgun A, Osipova E, Pozhilenkova E, Martinova G, Frolova O . The inhibitory effect of LPS on the expression of GPR81 lactate receptor in blood-brain barrier model in vitro. J Neuroinflammation. 2018; 15(1):196. PMC: 6030740. DOI: 10.1186/s12974-018-1233-2. View