The genetic and dietary landscape of the muscle insulin signalling network
Author:
van Gerwen JulianORCID, Masson Stewart W. C., Cutler Harry B., Díaz-Vegas Alexis, Potter Meg, Stöckli Jacqueline, Madsen Søren, Nelson Marin E., Humphrey Sean J., James David E.
Abstract
AbstractMetabolic disease is caused by a combination of genetic and environmental factors, yet few studies have examined how these factors influence signal transduction, a key mediator of metabolism. Using mass spectrometry-based phosphoproteomics, we quantified 23,126 phosphosites in skeletal muscle of five genetically distinct mouse strains in two dietary environments, with and without acutein vivoinsulin stimulation. Almost half of the insulin-regulated phosphoproteome was modified by genetic background on an ordinary diet, and high-fat high-sugar feeding affected insulin signalling in a strain-dependent manner. Our data revealed coregulated subnetworks within the insulin signalling pathway, expanding our understanding of the pathway’s organisation. Furthermore, associating diverse signalling responses with insulin-stimulated glucose uptake uncovered regulators of muscle insulin responsiveness, including the regulatory phosphosite S469 on Pfkfb2, a key activator of glycolysis. Finally, we confirmed the role of glycolysis in modulating insulin action in insulin resistance. Our results underscore the significance of genetics in shaping global signalling responses and their adaptability to environmental changes, emphasizing the utility of studying biological diversity with phosphoproteomics to discover key regulatory mechanisms of complex traits.
Publisher
Cold Spring Harbor Laboratory
Reference89 articles.
1. Protein Phosphorylation: A Major Switch Mechanism for Metabolic Regulation 2. Illuminating the dark phosphoproteome 3. Global, In Vivo, and Site-Specific Phosphorylation Dynamics in Signaling Networks 4. Bodenmiller, B. , Wanka, S. , Kraft, C. , Urban, J. , Campbell, D. , Pedrioli, P.G. , Gerrits, B. , Picotti, P. , Lam, H. , Vitek, O. , Brusniak, M.-Y. , Roschitzki, B. , Zhang, C. , Shokat, K.M. , Schlapbach, R. , Colman-Lerner, A. , Nolan, G.P. , Nesvizhskii, A.I. , Peter, M. , Loewith, R. , von Mering, C. , and Aebersold, R . (2010). Phosphoproteomic analysis reveals interconnected system-wide responses to perturbations of kinases and phosphatases in yeast. Sci. Signal. 3, rs4. 5. Phosphoproteomics of Acute Cell Stressors Targeting Exercise Signaling Networks Reveal Drug Interactions Regulating Protein Secretion;Cell Rep,2019
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