Loss of atrial natriuretic peptide signaling causes insulin resistance, mitochondrial dysfunction, and low endurance capacity

Type 2 diabetes (T2D) and obesity are strongly associated with low natriuretic peptide (NP) plasma levels and a down-regulation of NP guanylyl cyclase receptor-A (GCA) in skeletal muscle and adipose tissue. However, no study has so far provided evidence for a causal link between atrial NP (ANP)/GCA deficiency and T2D pathogenesis. Here, we show that both systemic and skeletal muscle ANP/GCA deficiencies in mice promote metabolic disturbances and prediabetes. Skeletal muscle insulin resistance is further associated with altered mitochondrial function and impaired endurance running capacity. ANP/GCA-deficient mice exhibit increased proton leak and reduced content of mitochondrial oxidative phosphorylation proteins. We further show that GCA is related to several metabolic traits in T2D and positively correlates with markers of oxidative capacity in human skeletal muscle. Together, these results indicate that ANP/GCA signaling controls muscle mitochondrial integrity and oxidative capacity in vivo and plays a causal role in the development of prediabetes.

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Publication Details

Journal
Science Advances
Published
2024-10-09
DOI
https://doi.org/10.1126/sciadv.adl4374
Citations
10
Primary Topic
Cardiovascular Function and Risk Factors
Type
article
Field-Weighted Citation Impact
4.02

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Loss of atrial natriuretic peptide signaling causes insulin resistance, mitochondrial dysfunction, and low endurance capacity

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Loss of atrial natriuretic peptide signaling causes insulin resistance, mitochondrial dysfunction, and low endurance capacity

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article en
10 citations

Abstract

Type 2 diabetes (T2D) and obesity are strongly associated with low natriuretic peptide (NP) plasma levels and a down-regulation of NP guanylyl cyclase receptor-A (GCA) in skeletal muscle and adipose tissue. However, no study has so far provided evidence for a causal link between atrial NP (ANP)/GCA deficiency and T2D pathogenesis. Here, we show that both systemic and skeletal muscle ANP/GCA deficiencies in mice promote metabolic disturbances and prediabetes. Skeletal muscle insulin resistance is further associated with altered mitochondrial function and impaired endurance running capacity. ANP/GCA-deficient mice exhibit increased proton leak and reduced content of mitochondrial oxidative phosphorylation proteins. We further show that GCA is related to several metabolic traits in T2D and positively correlates with markers of oxidative capacity in human skeletal muscle. Together, these results indicate that ANP/GCA signaling controls muscle mitochondrial integrity and oxidative capacity in vivo and plays a causal role in the development of prediabetes.

Science AdvancesVol. 10(41)
Université Claude Bernard Lyon 1 (FR), Abu Dhabi University (AE), Scripps Research Institute (US), University of Copenhagen (DK), Physikalisch-Technische Bundesanstalt (DE), Centre National de la Recherche Scientifique (FR), Université Toulouse III - Paul Sabatier (FR), University of Ljubljana (SI), Inserm (FR), National University of Singapore (SG), University of Cologne (DE), Université de Montpellier (FR), University of Würzburg (DE), Novo Nordisk Foundation (DK), Deutsches Zentrum für Luft- und Raumfahrt e. V. (DLR) (DE), Helmholtz Zentrum München (DE), LMU Klinikum (DE), Medizinische Hochschule Hannover (DE), Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement (FR), Laboratoire Montpelliérain d’Economie Théorique et Appliquée (FR), Institut NeuroMyoGène (FR), Institut universitaire de cardiologie et de pneumologie de Québec (CA), Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (DE), Institut des Maladies Métaboliques et Cardiovasculaires (FR), Weill Cornell Medical College in Qatar (QA), University Hospital Cologne (DE), Nutrition, Diabète et Cerveau, Ludwig-Maximilians-Universität München (DE), University of California, Davis (US), Technische Universität Braunschweig (DE)
Institut National de la Santé et de la Recherche Médicale
Good health and well-being
Openalex Percentile: Top 5%
Cardiovascular Function and Risk Factors
4.02
DOIOpen Access PDFOpenAlex
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