PXD027981

PXD027981 is an original dataset announced via ProteomeXchange.

Title	The cyclin dependent kinase inhibitor Roscovitine reverses diet-induced metabolic disruption in obese mice
Description	We show that roscovitine; a cyclin-dependent kinases inhibitor; given to mice during the last six weeks of a 19-week high fat diet, reduced weight gain and prevented accompanying insulin resistance, hepatic steatosis, visceral adipose tissue (eWAT) inflammation and fibrosis. It also restored insulin secretion and enhanced whole body energy expenditure. Proteomics and phosphoproteomics analysis of eWAT demonstrated that Roscovitine induced a limited set of proteins associated with lipid metabolism, fatty acid oxidation metabolism and adipose tissue remodeling but suppressed expression of a larger array of peptides and phosphopeptides linked to inflammation and extracellular matrix proteins. Furthermore, the phosphoproteome analysis identified 17 putative protein kinases perturbed by roscovitine, including CMGC kinases [e.g., CDKs and MAPKs], AGC kinases [e.g., S6K and PKC isoforms], and CAMK kinases [e.g., SIK1 and SIK2]). Pathway enrichment analysis of annotated kinase-substrate pairs showed that lipid metabolism, TCA cycle, fatty acid beta oxidation and phosphatidylcholine and creatine biosynthesis are enriched following roscovitine treatment. The increased creatine pathways combined with more active mitochondria in eWAT may contribute to roscovitine-induced weight loss. Surprisingly, we found that unlike for eWAT, roscovitine led to up regulation of large sets of proteins and phosphosites in brown adipose tissue (BAT). Analysis of upstream kinases controlling the phosphoproteome revealed two major kinase groups (AGC kinases [e.g., PKD1 and PKA] and CMGC kinases [e.g., CDKs and MAPKs]. Among the top enriched pathways of kinase-substrate pairs were insulin signaling, regulation of lipolysis in adipocytes, thyroid hormone signaling, thermogenesis and cAMP-PKG signaling, suggesting that roscovitine led to a metabolically more active BAT. Overall, roscovitine treatment led to restoration of mitochondrial activity in BAT and eWAT suppressed by HFD, likely accounting for enhanced energy expenditure and weight loss.
HostingRepository	PRIDE
AnnounceDate	2021-11-03
AnnouncementXML	Submission_2021-11-03_06:13:43.858.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Ryan Hekman
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	phosphorylated residue; acetylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2021-08-17 08:34:25	ID requested
⏵ 1	2021-11-03 06:13:44	announced

Rabhi N, Desevin K, Cortez BN, Hekman R, Lin JZ, Emili A, Farmer SR, The cyclin dependent kinase inhibitor Roscovitine prevents diet-induced metabolic disruption in obese mice. Sci Rep, 11(1):20365(2021) [pubmed]

submitter keyword: roscovitine, therapy, obesity, proteomics, adipose mitochondria

Nabil Rabhi
contact affiliation	Boston University School of Medicine
contact email	rabhi@bu.edu
lab head
Ryan Hekman
contact affiliation	Boston University
contact email	rhekman@bu.edu
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/2021/11/PXD027981

PRIDE project URI

• PRIDE
  1. PXD027981
     1. Label: PRIDE project
     2. Name: The cyclin dependent kinase inhibitor Roscovitine reverses diet-induced metabolic disruption in obese mice