Cotadutide effect in liver and adipose tissue in obese mice

in Journal of Molecular Endocrinology
Authors:
Ilitch Aquino Marcondes-de-CastroLaboratory of Morphometry, Metabolism and Cardiovascular Diseases, Biomedical Center, Institute of Biology, The University of the State of Rio de Janeiro, Rio de Janeiro, Brazil

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Thamiris Ferreira OliveiraLaboratory of Morphometry, Metabolism and Cardiovascular Diseases, Biomedical Center, Institute of Biology, The University of the State of Rio de Janeiro, Rio de Janeiro, Brazil

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Renata SpezaniLaboratory of Morphometry, Metabolism and Cardiovascular Diseases, Biomedical Center, Institute of Biology, The University of the State of Rio de Janeiro, Rio de Janeiro, Brazil

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Thatiany Souza MarinhoLaboratory of Morphometry, Metabolism and Cardiovascular Diseases, Biomedical Center, Institute of Biology, The University of the State of Rio de Janeiro, Rio de Janeiro, Brazil

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Luiz Eduardo Macedo CardosoLaboratory of Morphometry, Metabolism and Cardiovascular Diseases, Biomedical Center, Institute of Biology, The University of the State of Rio de Janeiro, Rio de Janeiro, Brazil

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Marcia Barbosa AguilaLaboratory of Morphometry, Metabolism and Cardiovascular Diseases, Biomedical Center, Institute of Biology, The University of the State of Rio de Janeiro, Rio de Janeiro, Brazil

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Carlos Alberto Mandarim-de-LacerdaLaboratory of Morphometry, Metabolism and Cardiovascular Diseases, Biomedical Center, Institute of Biology, The University of the State of Rio de Janeiro, Rio de Janeiro, Brazil

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Correspondence should be addressed to C A Mandarim-de-Lacerda: mandarim@uerj.br
DOI:
https://doi.org/10.1530/JME-22-0168
Volume/Issue:
Volume 70: Issue 3
Article Type:
Research Article
Article ID:
e220168
Online Publication Date:
10 Mar 2023
Copyright:
© Society for Endocrinology 2023
Restricted access

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Obesity, adipose tissue inflammation, and nonalcoholic fatty liver disease (NAFLD) are associated with insulin resistance and type 2 diabetes (T2D). Cotadutide is a dual agonist GLP-1/glucagon, currently in a preclinical study phase 2 that presents an anti-obesity effect. Diet-induced obese (DIO) C57BL/6 mice were treated for 4 weeks with cotadutide (30 nm/kg once a day at 14:00 h). The study focused on epididymal white adipose tissue (eWAT), liver (NAFLD), inflammation, lipid metabolism, AMP-activated protein kinase (AMPK)/mechanistic target of rapamycin (mTOR) pathways, and the endoplasmic reticulum (ER) stress. As a result, cotadutide controlled weight gain, glucose intolerance, and insulin resistance and showed beneficial effects on plasma markers in DIO mice (triacylglycerol, total cholesterol, alanine aminotransferase, and aspartate aminotransferase, leptin, adiponectin, monocyte chemoattractant protein-1, resistin, interleukin-6, tumor necrosis factor-alpha). Also, cotadutide lessened liver fat accumulation, eWAT proinflammatory markers, and ER stress. In addition, cotadutide improved lipid metabolism genes in eWAT, fatty acid synthase, peroxisome proliferator-activated receptor gamma and mitigates adipocyte hypertrophy and apoptosis. Furthermore, the effects of cotadutide were related to liver AMPK/mTOR pathway and ER stress. In conclusion, cotadutide induces weight loss and treats glucose intolerance and insulin resistance in DIO mice. In addition, cotadutide shows beneficial effects on liver lipid metabolism, mitigating steatosis, inflammation, and ER stress. Besides, in adipocytes, cotadutide decreases hypertrophy and reduces apoptosis. These actions rescuing the AMPK and mTOR pathway, improving lipid metabolism, and lessening NAFLD, inflammation, and ER stress in both eWAT and liver of DIO mice indicate cotadutide as a potentially new pharmacological treatment for T2D and associated obesity.

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Print ISSN:
0952-5041
Online ISSN:
1479-6813
Copyright:
© Society for Endocrinology 2023
Article ID:
e220168
Article Type:
Research Article
Received Date:
26 Jan 2023
Accepted Date:
08 Feb 2023
Print Publication Date:
01 Apr 2023
Online Publication Date:
10 Mar 2023
Keywords:
inflammation; lipogenesis; ER stress; NAFLD; mice

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