Variable glucagon metabolic actions in diverse mouse models of obesity and type 2 diabetes.

Autor:	Wu Y; Nutrient Metabolism & Signalling Laboratory, Metabolism, Diabetes and Obesity Program, Biomedicine Discovery Institute, Monash University, Victoria 3800, Australia; Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Faculty of Medicine, Nursing & Health Sciences, Monash University, Victoria 3800, Australia., Chan AY; Nutrient Metabolism & Signalling Laboratory, Metabolism, Diabetes and Obesity Program, Biomedicine Discovery Institute, Monash University, Victoria 3800, Australia; Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Faculty of Medicine, Nursing & Health Sciences, Monash University, Victoria 3800, Australia., Hauke J; Division of Inherited Metabolic Diseases, University Children's Hospital, 69120 Heidelberg, Germany., Htin Aung O; Nutrient Metabolism & Signalling Laboratory, Metabolism, Diabetes and Obesity Program, Biomedicine Discovery Institute, Monash University, Victoria 3800, Australia; Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Faculty of Medicine, Nursing & Health Sciences, Monash University, Victoria 3800, Australia., Foollee A; Nutrient Metabolism & Signalling Laboratory, Metabolism, Diabetes and Obesity Program, Biomedicine Discovery Institute, Monash University, Victoria 3800, Australia; Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Faculty of Medicine, Nursing & Health Sciences, Monash University, Victoria 3800, Australia., Cleofe MAS; Nutrient Metabolism & Signalling Laboratory, Metabolism, Diabetes and Obesity Program, Biomedicine Discovery Institute, Monash University, Victoria 3800, Australia; Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Faculty of Medicine, Nursing & Health Sciences, Monash University, Victoria 3800, Australia., Stölting H; Nutrient Metabolism & Signalling Laboratory, Metabolism, Diabetes and Obesity Program, Biomedicine Discovery Institute, Monash University, Victoria 3800, Australia; Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Faculty of Medicine, Nursing & Health Sciences, Monash University, Victoria 3800, Australia., Han ML; Infection and Immunity Program, Department of Microbiology, Monash Biomedicine Discovery Institute, Monash University, Victoria 3800, Australia., Jeppe KJ; Monash Proteomics and Metabolomics Platform, Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Victoria 3800, Australia., Barlow CK; Monash Proteomics and Metabolomics Platform, Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Victoria 3800, Australia., Okun JG; Division of Inherited Metabolic Diseases, University Children's Hospital, 69120 Heidelberg, Germany., Rusu PM; Nutrient Metabolism & Signalling Laboratory, Metabolism, Diabetes and Obesity Program, Biomedicine Discovery Institute, Monash University, Victoria 3800, Australia; Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Faculty of Medicine, Nursing & Health Sciences, Monash University, Victoria 3800, Australia., Rose AJ; Nutrient Metabolism & Signalling Laboratory, Metabolism, Diabetes and Obesity Program, Biomedicine Discovery Institute, Monash University, Victoria 3800, Australia; Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Faculty of Medicine, Nursing & Health Sciences, Monash University, Victoria 3800, Australia. Electronic address: adam.rose@monash.edu.
Jazyk:	angličtina
Zdroj:	Molecular metabolism [Mol Metab] 2024 Dec; Vol. 90, pp. 102064. Date of Electronic Publication: 2024 Nov 12.
DOI:	10.1016/j.molmet.2024.102064
Abstrakt:	Objective: The study aimed to investigate the effects of glucagon on metabolic pathways in mouse models of obesity, fatty liver disease, and type 2 diabetes (T2D) to determine the extent and variability of hepatic glucagon resistance in these conditions. Methods: We investigated glucagon's effects in mouse models of fatty liver disease, obesity, and type 2 diabetes (T2D), including male BKS-db/db, high-fat diet-fed, and western diet-fed C57Bl/6 mice. Glucagon tolerance tests were performed using the selective glucagon receptor agonist acyl-glucagon (IUB288). Blood glucose, serum and liver metabolites include lipids and amino acids were measured. Additionally, liver protein expression related to glucagon signalling and a comprehensive liver metabolomics were performed. Results: Western diet-fed mice displayed impaired glucagon response, with reduced blood glucose and PKA activation. In contrast, high-fat diet-fed and db/db mice maintained normal glucagon sensitivity, showing significant elevations in blood glucose and phospho-PKA motif protein expression. Acyl-glucagon treatment also lowered liver alanine and histidine levels in high-fat diet-fed mice, but not in western diet-fed mice. Additionally, some amino acids, such as methionine, were increased by acyl-glucagon only in chow diet control mice. Despite normal glucagon sensitivity in PKA signalling, db/db mice had a distinct metabolomic response, with acyl-glucagon significantly altering 90 metabolites in db/+ mice but only 42 in db/db mice, and classic glucagon-regulated metabolites, such as cyclic adenosine monophosphate (cAMP), being less responsive in db/db mice. Conclusions: The study reveals that hepatic glucagon resistance in obesity and T2D is complex and not uniform across metabolic pathways, underscoring the complexity of glucagon action in these conditions. Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Adam Rose reports financial support was provided by Diabetes Australia. Adam Rose reports financial support was provided by National Health and Medical Research Council. Yuqin Wu reports financial support was provided by Australian Physiological Society. Adam Rose reports a relationship with Boehringer Ingelheim Pharma GmbH & Co KG that includes: funding grants. Patricia Rusu reports a relationship with Boehringer Ingelheim Pharma GmbH & Co KG that includes: funding grants. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. (Copyright © 2024 The Author(s). Published by Elsevier GmbH.. All rights reserved.)
Databáze:	MEDLINE
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