Regulatory roles of G-protein coupled receptors in adipose tissue metabolism and their therapeutic potential

AbstractThe high incidence of obesity has increased the need to discover new therapeutic targets to combat obesity and obesity-related metabolic diseases. Obesity is defined as an abnormal accumulation of adipose tissue, which is one of the major metabolic organs that regulate energy homeostasis. However, there are currently no approved anti-obesity therapeutics that directly target adipose tissue metabolism. With recent advances in the understanding of adipose tissue biology, molecular mechanisms involved in brown adipose tissue expansion and metabolic activation have been investigated as potential therapeutic targets to increase energy expenditure. This review focuses on G-protein coupled receptors (GPCRs) as they are the most successful class of druggable targets in human diseases and have an important role in regulating adipose tissue metabolism. We summarize recent findings on the major GPCR classes that regulate thermogenesis and mitochondrial metabolism in adipose tissue. Improved understanding of GPCR signaling pathways that regulate these processes could facilitate the development of novel pharmacological approaches to treat obesity and related metabolic disorders.

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Faculty Opinions recommendation of An Integrated Understanding of the Molecular Mechanisms How Adipose Tissue Metabolism Affects Long-Term Body Weight Maintenance.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.734356607.793555902 ◽

2019 ◽

Author(s):

Marleen van Baak

Keyword(s):

Body Weight ◽

Adipose Tissue ◽

Molecular Mechanisms ◽

Weight Maintenance ◽

Adipose Tissue Metabolism ◽

Tissue Metabolism

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G-protein-coupled receptors as therapeutic targets for glioblastoma

Drug Discovery Today ◽

10.1016/j.drudis.2021.07.008 ◽

2021 ◽

Author(s):

Kate F. Byrne ◽

Ajay Pal ◽

James F. Curtin ◽

John C. Stephens ◽

Gemma K. Kinsella

Keyword(s):

G Protein ◽

Therapeutic Targets ◽

G Protein Coupled Receptors ◽

G Protein Coupled

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G-protein-coupled receptors signalling at the cell nucleus: an emerging paradigmThis paper is one of a selection of papers published in this Special Issue, entitled The Nucleus: A Cell Within A Cell.

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y05-127 ◽

2006 ◽

Vol 84 (3-4) ◽

pp. 287-297 ◽

Cited By ~ 124

Author(s):

Fernand Gobeil ◽

Audrey Fortier ◽

Tang Zhu ◽

Michela Bossolasco ◽

Martin Leduc ◽

...

Keyword(s):

G Protein ◽

Cell Nucleus ◽

Intracellular Signaling ◽

Molecular Mechanisms ◽

Nuclear Translocation ◽

Cell Metabolism ◽

Hormone Secretion ◽

G Protein Coupled Receptors ◽

A Cell ◽

G Protein Coupled

G-protein-coupled receptors (GPCRs) comprise a wide family of monomeric heptahelical glycoproteins that recognize a broad array of extracellular mediators including cationic amines, lipids, peptides, proteins, and sensory agents. Thus far, much attention has been given towards the comprehension of intracellular signaling mechanisms activated by cell membrane GPCRs, which convert extracellular hormonal stimuli into acute, non-genomic (e.g., hormone secretion, muscle contraction, and cell metabolism) and delayed, genomic biological responses (e.g., cell division, proliferation, and apoptosis). However, with respect to the latter response, there is compelling evidence for a novel intracrine mode of genomic regulation by GPCRs that implies either the endocytosis and nuclear translocation of peripheral-liganded GPCR and (or) the activation of nuclearly located GPCR by endogenously produced, nonsecreted ligands. A noteworthy example of the last scenario is given by heptahelical receptors that are activated by bioactive lipoids (e.g., PGE2 and PAF), many of which may be formed from bilayer membranes including those of the nucleus. The experimental evidence for the nuclear localization and signalling of GPCRs will be reviewed. We will also discuss possible molecular mechanisms responsible for the atypical compartmentalization of GPCRs at the cell nucleus, along with their role in gene expression.

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Ionotropic and Metabotropic Proton-Sensing Receptors Involved in Airway Inflammation in Allergic Asthma

Mediators of Inflammation ◽

10.1155/2014/712962 ◽

2014 ◽

Vol 2014 ◽

pp. 1-8 ◽

Cited By ~ 23

Author(s):

Haruka Aoki ◽

Chihiro Mogi ◽

Fumikazu Okajima

Keyword(s):

Airway Inflammation ◽

Allergic Asthma ◽

G Protein ◽

Molecular Mechanisms ◽

G Protein Coupled Receptors ◽

Airway Smooth Muscle Cells ◽

Transient Receptor Potential Vanilloid ◽

Acidic Ph ◽

Airway Responses ◽

G Protein Coupled

An acidic microenvironment has been shown to evoke a variety of airway responses, including cough, bronchoconstriction, airway hyperresponsiveness (AHR), infiltration of inflammatory cells in the lung, and stimulation of mucus hyperproduction. Except for the participation of transient receptor potential vanilloid-1 (TRPV1) and acid-sensing ion channels (ASICs) in severe acidic pH (of less than 6.0)-induced cough and bronchoconstriction through sensory neurons, the molecular mechanisms underlying extracellular acidic pH-induced actions in the airways have not been fully understood. Recent studies have revealed that ovarian cancer G protein-coupled receptor 1 (OGR1)-family G protein-coupled receptors, which sense pH of more than 6.0, are expressed in structural cells, such as airway smooth muscle cells and epithelial cells, and in inflammatory and immune cells, such as eosinophils and dendritic cells. They function in a variety of airway responses related to the pathophysiology of inflammatory diseases, including allergic asthma. In the present review, we discuss the roles of ionotropic TRPV1 and ASICs and metabotropic OGR1-family G protein-coupled receptors in the airway inflammation and AHR in asthma and respiratory diseases.

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Hormonal Control of Brown-Adipose-Tissue Metabolism

Biochemical Society Transactions ◽

10.1042/bst0050908 ◽

1977 ◽

Vol 5 (4) ◽

pp. 908-911 ◽

Cited By ~ 9

Author(s):

DAVID G. NICHOLLS

Keyword(s):

Adipose Tissue ◽

Brown Adipose Tissue ◽

Hormonal Control ◽

Adipose Tissue Metabolism ◽

Tissue Metabolism ◽

Brown Adipose

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Misfolded G Protein-Coupled Receptors and Endocrine Disease. Molecular Mechanisms and Therapeutic Prospects

International Journal of Molecular Sciences ◽

10.3390/ijms222212329 ◽

2021 ◽

Vol 22 (22) ◽

pp. 12329

Author(s):

Alfredo Ulloa-Aguirre ◽

Teresa Zariñán ◽

Eduardo Jardón-Valadez

Keyword(s):

Plasma Membrane ◽

G Protein ◽

Intracellular Signaling ◽

Molecular Mechanisms ◽

G Protein Coupled Receptors ◽

Membrane Receptors ◽

Therapeutic Interventions ◽

Endocrine Function ◽

Receptor Protein ◽

G Protein Coupled

Misfolding of G protein-coupled receptors (GPCRs) caused by mutations frequently leads to disease due to intracellular trapping of the conformationally abnormal receptor. Several endocrine diseases due to inactivating mutations in GPCRs have been described, including X-linked nephrogenic diabetes insipidus, thyroid disorders, familial hypocalciuric hypercalcemia, obesity, familial glucocorticoid deficiency [melanocortin-2 receptor, MC2R (also known as adrenocorticotropin receptor, ACTHR), and reproductive disorders. In these mutant receptors, misfolding leads to endoplasmic reticulum retention, increased intracellular degradation, and deficient trafficking of the abnormal receptor to the cell surface plasma membrane, causing inability of the receptor to interact with agonists and trigger intracellular signaling. In this review, we discuss the mechanisms whereby mutations in GPCRs involved in endocrine function in humans lead to misfolding, decreased plasma membrane expression of the receptor protein, and loss-of-function diseases, and also describe several experimental approaches employed to rescue trafficking and function of the misfolded receptors. Special attention is given to misfolded GPCRs that regulate reproductive function, given the key role played by these particular membrane receptors in sexual development and fertility, and recent reports on promising therapeutic interventions targeting trafficking of these defective proteins to rescue completely or partially their normal function.

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