Peptide-YY 3-36 /glucagon-like peptide-1 combination treatment of obese diabetic mice improves insulin sensitivity associated with recovered pancreatic β-cell function and synergistic activation of discrete hypothalamic and brainstem neuronal circuitries.

Autor:	Boland BB; Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA; Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK; Gubra ApS, Horsholm, Denmark; PRECISIONscientia, Yardley, PA, USA., Laker RC; Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA; Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK., O'Brien S; Antibody and Protein Engineering, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA; Antibody and Protein Engineering, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK., Sitaula S; Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA; Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK., Sermadiras I; Antibody and Protein Engineering, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA; Antibody and Protein Engineering, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK., Nielsen JC; Gubra ApS, Horsholm, Denmark., Barkholt P; Gubra ApS, Horsholm, Denmark., Roostalu U; Gubra ApS, Horsholm, Denmark., Hecksher-Sørensen J; Gubra ApS, Horsholm, Denmark., Sejthen SR; Gubra ApS, Horsholm, Denmark., Thorbek DD; Gubra ApS, Horsholm, Denmark., Suckow A; Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA; Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK; DTX Pharma, San Diego, CA, USA., Burmeister N; Antibody and Protein Engineering, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA; Antibody and Protein Engineering, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK; Roche, Penzberg, Germany., Oldham S; Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA; Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK., Will S; Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA; Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK., Howard VG; Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA; Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK., Gill BM; Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA; Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK., Newton P; Antibody and Protein Engineering, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA; Antibody and Protein Engineering, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK., Naylor J; Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA; Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK., Hornigold DC; Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA; Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK., Austin J; University of Chicago Advanced Electron Microscopy Core Facility, Chicago, IL, USA., Lantier L; Vanderbilt University Mouse Metabolic Phenotyping Center, Nashville, TN, USA., McGuinness OP; Vanderbilt University Mouse Metabolic Phenotyping Center, Nashville, TN, USA., Trevaskis JL; Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA; Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK; Gilead Sciences, Foster City, CA, USA., Grimsby JS; Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA; Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK., Rhodes CJ; Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA; Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK. Electronic address: christopher.rhodes@astrazeneca.com.
Jazyk:	angličtina
Zdroj:	Molecular metabolism [Mol Metab] 2022 Jan; Vol. 55, pp. 101392. Date of Electronic Publication: 2021 Nov 12.
DOI:	10.1016/j.molmet.2021.101392
Abstrakt:	Objective: Obesity-linked type 2 diabetes (T2D) is a worldwide health concern and many novel approaches are being considered for its treatment and subsequent prevention of serious comorbidities. Co-administration of glucagon like peptide 1 (GLP-1) and peptide YY 3-36 (PYY 3-36 ) renders a synergistic decrease in energy intake in obese men. However, mechanistic details of the synergy between these peptide agonists and their effects on metabolic homeostasis remain relatively scarce. Methods: In this study, we utilized long-acting analogues of GLP-1 and PYY 3-36 (via Fc-peptide conjugation) to better characterize the synergistic pharmacological benefits of their co-administration on body weight and glycaemic regulation in obese and diabetic mouse models. Hyperinsulinemic-euglycemic clamps were used to measure weight-independent effects of Fc-PYY 3-36  + Fc-GLP-1 on insulin action. Fluorescent light sheet microscopy analysis of whole brain was performed to assess activation of brain regions. Results: Co-administration of long-acting Fc-IgG/peptide conjugates of Fc-GLP-1 and Fc-PYY 3-36 (specific for PYY receptor-2 (Y2R)) resulted in profound weight loss, restored glucose homeostasis, and recovered endogenous β-cell function in two mouse models of obese T2D. Hyperinsulinemic-euglycemic clamps in C57BLKS/J db/db and diet-induced obese Y2R-deficient (Y2RKO) mice indicated Y2R is required for a weight-independent improvement in peripheral insulin sensitivity and enhanced hepatic glycogenesis. Brain cFos staining demonstrated distinct temporal activation of regions of the hypothalamus and hindbrain following Fc-PYY 3-36  + Fc-GLP-1R agonist administration. Conclusions: These results reveal a therapeutic approach for obesity/T2D that improved insulin sensitivity and restored endogenous β-cell function. These data also highlight the potential association between the gut-brain axis in control of metabolic homeostasis. (Copyright © 2021 The Authors. Published by Elsevier GmbH.. All rights reserved.)
Databáze:	MEDLINE
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