PXD042277

PXD042277 is an original dataset announced via ProteomeXchange.

Title	Leveraging genetic diversity to identify small molecules that reverse mouse skeletal muscle insulin resistance
Description	Systems genetics has begun to tackle the complexity of insulin resistance by capitalising on computational advances to study high-diversity populations. “Diversity Outbred in Australia (DOz)” is a population of genetically unique mice with profound metabolic heterogeneity. We leveraged this variance to explore skeletal muscle’s contribution to whole-body insulin action through metabolic phenotyping and skeletal muscle proteomics of 215 DOz mice. Linear modelling identified 553 proteins that associated with whole-body insulin sensitivity (Matsuda Index) including regulators of endocytosis and muscle proteostasis. To enrich for causality, we refined this network by focussing on negatively associated, genetically regulated proteins, resulting in a 76-protein fingerprint of insulin resistance. We sought to perturb this network and restore insulin action with small molecules by integrating the Broad Institute Connectivity Map platform and in vitro assays of insulin action using the Prestwick chemical library. These complimentary approaches identified the antibiotic thiostrepton as an insulin resistance reversal agent. Subsequent validation in ex vivo insulin resistant mouse muscle, and palmitate induced insulin resistant myotubes demonstrated potent insulin action restoration, potentially via up-regulation of glycolysis. This work demonstrates the value of a drug-centric framework to validate systems level analysis by identifying potential therapeutics for insulin resistance.
HostingRepository	PRIDE
AnnounceDate	2023-11-14
AnnouncementXML	Submission_2023-11-14_09:04:22.399.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	David James
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2023-05-16 20:31:03	ID requested
1	2023-07-31 01:41:40	announced
⏵ 2	2023-11-14 09:04:31	announced	2023-11-14: Updated project metadata.

Masson SWC, Madsen S, Cooke KC, Potter M, Vegas AD, Carroll L, Thillainadesan S, Cutler HB, Walder KR, Cooney GJ, Morahan G, St, ö, ckli J, James DE, Leveraging genetic diversity to identify small molecules that reverse mouse skeletal muscle insulin resistance. Elife, 12():(2023) [pubmed]

submitter keyword: insulin resistance, skeletal muscle,diversty outbred, mouse

David Ernest James
contact affiliation	School of Life and Enviromental Sciences, Charles Perkins Centre, The University of Sydney
contact email	david.james@sydney.edu.au
lab head
David James
contact affiliation	The University of Sydney
contact email	david.james@sydney.edu.au
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2023/07/PXD042277

PRIDE project URI

• PRIDE
  1. PXD042277
     1. Label: PRIDE project
     2. Name: Leveraging genetic diversity to identify small molecules that reverse mouse skeletal muscle insulin resistance