PXD062990

PXD062990 is an original dataset announced via ProteomeXchange.

Title	An unimolecular GIPR:GLP-1R:PPAR𝛼,𝛾,𝛿 quintuple agonist eliminates obesity and insulin resistance in mice.
Description	Drugs to improve obesity-linked metabolic dysfunction are on the rise, with GLP-1:GIP co-agonism being effective in the management of obesity and type 2 diabetes, and with Lanifibranor (Lani), a nuclear acting small molecule triple agonist at the peroxisome proliferator-activated receptors alpha, gamma and delta (PPAR𝛼,𝛾,𝛿) being in phase 3 clinical trials for the treatment of metabolic dysfunction-associated steatohepatitis. Seeking to further improve the metabolic efficacy of GLP-1:GIP co-agonism, we here report the design and preclinical evaluation of an unimolecular quintuple agonist, which synergistically combines the body weight and blood glucose lowering effects of GLP-1:GIP co-agonism with the insulin sensitizing effects of Lani through its targeted delivery into only cells that express the receptor for either GIP or GLP-1. In vitro, GLP-1:GIP:Lani is indistinguishable from its GLP-1:GIP backbone in GIPR and GLP-1R signaling and equally stimulates insulin secretion in isolated murine islets. In vivo, however, GLP-1:GIP:Lani is much superior to GLP-1:GIP co-agonism, Semaglutide or Lani to decrease body weight, food intake, and hyperglycemia in obese and insulin resistant mice through synergistic incretin and PPAR action in key glucoregulatory tissues. The superior metabolic action of GLP-1:GIP:Lani is demonstrated in mice with genetic (db/db) and diet-induced obesity (DIO), is accelerated in DIO mice with adipose-specific overexpression of GIPR and is absent in DIO double-incretin receptor knock-out mice. Collectively, we show that GLP-1:GIP:Lani outperforms GLP-1:GIP co-agonism and Lani to further improve energy and glucose metabolism, suggesting that this novel quintuple polyagonist holds unprecedented therapeutic value to treat obesity and type 2 diabetes.
HostingRepository	PRIDE
AnnounceDate	2026-02-15
AnnouncementXML	Submission_2026-02-15_01:20:15.257.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Natalie Krahmer
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: NEWT:10090;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Exploris 480

Revision	Datetime	Status	ChangeLog Entry
0	2025-04-15 09:13:19	ID requested
⏵ 1	2026-02-15 01:20:15	announced

Dataset with its publication pending

submitter keyword: GIPR, GLP1R,obesity

Natalie Krahmer
contact affiliation	Helmholtz diabetes center
contact email	natalie.krahmer@helmholtz-munich.de
lab head
Natalie Krahmer
contact affiliation	Helmholtz Center Munich
contact email	natalie.krahmer@helmholtz-muenchen.de
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/2026/02/PXD062990

PRIDE project URI

• PRIDE
  1. PXD062990
     1. Label: PRIDE project
     2. Name: An unimolecular GIPR:GLP-1R:PPAR𝛼,𝛾,𝛿 quintuple agonist eliminates obesity and insulin resistance in mice.