PXD044020-2

PXD044020 is an original dataset announced via ProteomeXchange.

Title	Uncoupling Metabolic Health from Thermogenesis via BCAA Flux in Brown Fat
Description	Brown adipose tissue (BAT) is best known for thermogenesis. Whereas numerous studies in rodents found tight associations between the metabolic benefits of BAT and enhanced whole-body energy expenditure, emerging evidence in humans suggests that BAT is protective against Type 2 diabetes independent of body-weight. The underlying mechanism for this dissociation remained unclear. Here, we report that impaired mitochondrial flux of branched-chain amino acids (BCAA) in BAT, by deleting mitochondrial BCAA carrier (MBC, encoded by Slc25a44), was sufficient to cause systemic insulin resistance without affecting whole-body energy expenditure or body-weight. We found that brown adipocytes catabolized BCAAs in the mitochondria as essential nitrogen donors for the biosynthesis of glutamate, N-acetylated amino acids, and one of the products, glutathione. BAT-selective impairment in mitochondrial BCAA flux led to elevated oxidative stress and insulin resistance in the liver, accompanied by reduced levels of BCAA-nitrogen derived metabolites in the circulation. In turn, supplementation of glutathione restored insulin sensitivity of BAT-specific MBC knockout mice. Notably, a high-fat diet rapidly impaired BCAA catabolism and the synthesis of BCAA-nitrogen derived metabolites in the BAT, while cold-induced BAT activity is coupled with an active synthesis of these metabolites. Together, the present work uncovers a mechanism through which brown fat controls metabolic health independent of thermogenesis via BCAA-derived nitrogen carriers acting on the liver.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_06:30:05.414.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Anthony Verkerke
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	biotinylated residue
Instrument	Orbitrap Eclipse

Revision	Datetime	Status	ChangeLog Entry
0	2023-07-24 01:58:55	ID requested
1	2024-02-15 10:14:40	announced
⏵ 2	2024-10-22 06:30:05	announced	2024-10-22: Updated project metadata.

Dataset with its publication pending

submitter keyword: Brown adipose tissue (BAT), branched-chain amino acids (BCAA)

Shingo Kajimura
contact affiliation	Howard Hughes Medical Institute Beth Israel Deaconess Medical Center Harvard Medical School
contact email	skajimur@bidmc.harvard.edu
lab head
Anthony Verkerke
contact affiliation	Beth Israel Deaconess Medical Center
contact email	averkerk@bidmc.harvard.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/2024/02/PXD044020

PRIDE project URI

• PRIDE
  1. PXD044020
     1. Label: PRIDE project
     2. Name: Uncoupling Metabolic Health from Thermogenesis via BCAA Flux in Brown Fat