Loss of atrial natriuretic peptide signaling causes insulin resistance, mitochondrial dysfunction, and low endurance capacity
Deborah Carper, Marlène Lac, Marine Coué, Axel Labour, André Märtens, Jorge Alberto Ayala Banda, Laurène Mazeyrie, Mie Mechta, Lars R. Ingerslev, Mohamed A. Elhadad, Justine Vily‐Petit, Claire Maslo, Laurent Monbrun, Peggy del Carmine, Yannis Sainte–Marie, Virginie Bourlier, Claire Laurens, Gilles Mithieux, Denis R. Joanisse, Charles Coudray, Christine Feillet-Coudray, Émilie Montastier, Nathalie Viguerie, Geneviève Tavernier, Mélanie Waldenberger, Annette Peters, Rui Wang‐Sattler, Jerzy Adamski, Karsten Suhre, Christian Gieger, Gabi Kastenmüller, Thomas Illig, Ralf Lichtinghagen, Jochen Seißler, Remy Mounier, Karsten Hiller, Jens Jordan, Romain Barrès, Michaela Kühn, Dominik Pesta, Cédric Moro
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.