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Atanes Et Al, Accepted Manuscript King’s Research Portal DOI: 10.1016/j.pharmthera.2021.107928 Document Version Peer reviewed version Link to publication record in King's Research Portal Citation for published version (APA): Atanes Juiz, P., Ashik, T., & Persaud, S. (2021). Obesity-induced changes in human islet G protein-coupled receptor expression: Implications for metabolic regulation. Pharmacology and Therapeutics, 228, [107928]. https://doi.org/10.1016/j.pharmthera.2021.107928 Citing this paper Please note that where the full-text provided on King's Research Portal is the Author Accepted Manuscript or Post-Print version this may differ from the final Published version. If citing, it is advised that you check and use the publisher's definitive version for pagination, volume/issue, and date of publication details. And where the final published version is provided on the Research Portal, if citing you are again advised to check the publisher's website for any subsequent corrections. 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Oct. 2021 Pharmacology & Therapeutics Obesity-induced changes in human islet G protein-coupled receptor expression: implications for metabolic regulation --Manuscript Draft-- Manuscript Number: PANDT-D-21-00134R1 Full Title: Obesity-induced changes in human islet G protein-coupled receptor expression: implications for metabolic regulation Article Type: Invited Article Section/Category: Keywords: obesity; Diabetes; GPCRs; adipose; human islets; insulin secretion Corresponding Author: Patricio Atanes King's College London London, UNITED KINGDOM Corresponding Author Secondary Information: Corresponding Author's Institution: King's College London Corresponding Author's Secondary Institution: First Author: Patricio Atanes, Ph.D. First Author Secondary Information: Order of Authors: Patricio Atanes, Ph.D. Tanyel Ashik, MRes Shanta J Persaud, Ph.D. Order of Authors Secondary Information: Abstract: G protein-coupled receptors (GPCRs) are a large family of cell surface receptors that are the targets for many different classes of pharmacotherapy. The islets of Langerhans are central to appropriate glucose homeostasis through their secretion of insulin, and islet function can be modified by ligands acting at the large number of GPCRs that islets express. The human islet GPCRome is not a static entity, but one that is altered under pathophysiological conditions and, in this review, we have compared expression of GPCR mRNAs in human islets obtained from normal weight range donors, and those with a weight range classified as obese. We have also considered the likely outcomes on islet function that the altered GPCR expression status confers and the possible impact that adipokines, secreted from expanded fat depots, could have at those GPCRs showing altered expression in obesity. Response to Reviewers: Additional Information: Question Response Powered by Editorial Manager® and ProduXion Manager® from Aries Systems Corporation Manuscript Click here to view linked References Obesity-induced changes in human islet G protein-coupled receptor expression: implications for 1 2 metabolic regulation 3 4 5 6 7 Patricio Atanes1, Tanyel Ashik and Shanta J Persaud1 8 9 10 11 12 Department of Diabetes, King’s College London, Guy’s Campus, London SE1 1UL, UK 13 14 15 16 17 18 1To whom correspondence should be addressed: Patricio Atanes and Shanta J. Persaud, Department 19 20 of Diabetes, King's College London, Guy’s Campus, London SE1 1UL, Email: 21 22 23 [email protected] ; [email protected] 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 Keywords: obesity, diabetes, GPCRs, adipose, human islets, insulin secretion 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 ABSTRACT 1 2 G protein-coupled receptors (GPCRs) are a large family of cell surface receptors that are the targets 3 4 5 for many different classes of pharmacotherapy. The islets of Langerhans are central to appropriate 6 7 glucose homeostasis through their secretion of insulin, and islet function can be modified by ligands 8 9 acting at the large number of GPCRs that islets express. The human islet GPCRome is not a static entity, 10 11 12 but one that is altered under pathophysiological conditions and, in this review, we have compared 13 14 expression of GPCR mRNAs in human islets obtained from normal weight range donors, and those 15 16 with a weight range classified as obese. We have also considered the likely outcomes on islet function 17 18 19 that the altered GPCR expression status confers and the possible impact that adipokines, secreted 20 21 from expanded fat depots, could have at those GPCRs showing altered expression in obesity. 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 ABBREVIATIONS 1 2 3 o ACTB: beta-actin. 4 5 o ACTH: adrenocorticotropic hormone. 6 7 8 o ADGRs: adhesion receptors. 9 10 o ADORAs: adenosine receptors. 11 12 o ADRs: adrenergic receptors. 13 14 15 o AVP: vasopressin. 16 17 o AVPRs: vasopressin receptors. 18 19 o 20 BAT: brown adipose tissue. 21 22 o BMI: body mass index. 23 24 o C3a: complement component 3a. 25 26 27 o C3AR: complement component 3a receptor. 28 29 o cAMP: cyclic adenosine monophosphate. 30 31 o CCLs: C-C chemokine ligands. 32 33 34 o CCRs: C-C chemokine receptors. 35 36 o CCRLs: C-C chemokine receptors-like. 37 38 o CELSRs: cadherin EGF LAG seven-pass g-type receptors. 39 40 41 o CNRs: cannabinoid receptors. 42 43 o CXCLs: CXC chemokine ligands. 44 45 46 o CXCRs: CXC chemokine receptors. 47 48 o DDRs: dopamine receptors. 49 50 o EST: expressed sequence tag. 51 52 53 o F2RLs: F2R like trypsin receptors. 54 55 o FFA: free fatty acids. 56 57 o FFARs: free fatty acid receptors. 58 59 60 o FZDs: frizzled receptors. 61 62 63 64 65 o GAPDH: glyceraldehyde 3-phosphate dehydrogenase. 1 2 o GLP-1: glucagon-like peptide-1. 3 4 5 o GLP-1RAs: glucagon-like peptide-1 receptor agonists. 6 7 o GPCR5B: G protein-coupled receptor family C group 5 member B. 8 9 o GPCRs: G protein-coupled receptors. 10 11 12 o GPRs: G protein-coupled receptors 13 14 o GRAFS system: G (Glutamate); R (Rhodopsin); A (Adhesion); F (Frizzled); S (Secretin) system. 15 16 o GSHR: Growth hormone secretagogue receptor. 17 18 19 o HbA1c: glycated haemoglobin. 20 21 o HCA: hydroxycarboxylic acid. 22 23 24 o HCAR: hydroxycarboxylic acid receptors. 25 26 o HFD: high-fat diet. 27 28 o HTRs: serotonin receptors. 29 30 31 o LPA: lysophosphatidic acid. 32 33 o LPARs: lysophosphatidic acid receptors. 34 35 o LTB4: leukotriene B4. 36 37 38 o MC2R: melanocortin 2 receptor. 39 40 o MRGPRXs: Mas-related G-protein coupled receptors. 41 42 o 43 mRNA: messenger ribonucleic acid. 44 45 o NMUR1: neuromedin U receptor 1. 46 47 o NPY: neuropeptide Y. 48 49 50 o NPY1R: neuropeptide Y receptor type 1. 51 52 o OXT: oxytocin. 53 54 o OXTR: oxytocin receptor. 55 56 57 o P2RYs: purinergic receptors. 58 59 o PGs: prostanoid ligands. 60 61 62 63 64 65 o PNX: phoenixin. 1 2 o PPIA: peptidylprolyl isomerase A. 3 4 5 o PRLHR: Prolactin-releasing peptide receptor. 6 7 o PrRP: prolactin-releasing peptide. 8 9 o PTGERs: prostaglandin receptors. 10 11 12 o PTH: parathyroid hormone. 13 14 o PTH2R: parathyroid hormone 2 receptor. 15 16 o qPCR: quantitative polymerase chain reaction. 17 18 19 o QRFPR: pyroglutamylated RFamide peptide receptor. 20 21 o RXFPs: relaxin receptors. 22 23 24 o S1P: sphingosine 1-phosphate. 25 26 o S1PRs: sphingosine 1-phosphate receptors. 27 28 o Shh: Sonic hedgehog. 29 30 31 o SNP: single-nucleotide polymorphism. 32 33 o SST: somatostatin. 34 35 o SSTR: somatostatin receptors. 36 37 38 o TAS2Rs: bitter-taste receptors. 39 40 o T2D: type 2 diabetes. 41 42 o 43 TBP: TATA-binding protein. 44 45 o TFRC: transferrin receptor. 46 47 o TSH: thyroid stimulating hormone. 48 49 50 o TSHR: thyroid stimulating hormone receptor. 51 52 o TUDCA: tauroursodeoxycholic acid. 53 54 o WAT: white adipose tissue. 55 56 57 58 59 60 61 62 63 64 65 TABLE OF CONTENTS 1 2 1. Introduction 3 4 5 1.1. Cross-talk between adipocytes and islets 6 7 1.2. Overview of islet GPCR expression 8 9 1.3. Targeting islet GPCRs to treat type 2 diabetes 10 11 12 2. Obesity-induced changes in human islet GPCR mRNA expression 13 14 2.1. Quantification of GPCR mRNA expression in islets from lean and obese donors 15 16 2.2. Summary of human islet GPCR mRNA expression in lean and obese donors 17 18 19 2.3. GRAFS stratification of human islet GPCR mRNA expression in lean and obese donors 20 21 2.3.1 Glutamate receptors 22 23 24 2.3.2 Rhodopsin receptors 25 26 2.3.2.1.
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