PXD062962-1

PXD062962 is an original dataset announced via ProteomeXchange.

Title	Glucagon controls obesity-specific energy expenditure via persistent cAMP/PKA signaling
Description	Glucagon (GCG) analogues are gaining attention as promising components in incretin-based therapeutics for obesity and metabolic dysfunction-associated steatohepatitis. However, the biology of chronic glucagon treatment, in particular, the molecular underpinnings of GCG-induced energy expenditure and lipid metabolism, remain poorly defined. We utilized a long-acting GCG analogue (LA-GCG) in conjunction with hepatic and adipose glucagon receptor knockout mouse models. Through an integrative approach that combined metabolic, biochemical and omics techniques, we investigated the molecular mechanisms underlying GCG-induced energy expenditure and metabolic benefits. We demonstrate that the LA-GCG enhances energy expenditure in diet-induced obese mice with an essential role of hepatic, but not adipose, GCGR signaling. Intriguingly, the enhancement in energy expenditure is observed only in obese but not in lean mice. The preferential efficacy is plausibly found in a prolonged activation of cAMP/PKA signaling through PDE4B/4D downregulation by LA-GCG. Conversely, the cAMP/PKA signaling is promptly attenuated by the PDE4B/4D activity in lean mice. Interestingly, unlike the EE phenotype, the lipid-clearing capacity of LA-GCG is independent of the PDE4/cAMP/PKA axis. These findings provide the molecular basis for GCG-induced energy expenditure and metabolic benefits and suggest the phenotypic segregation of cAMP/PKA-dependent and independent effects.
HostingRepository	PRIDE
AnnounceDate	2025-06-24
AnnouncementXML	Submission_2025-06-24_03:45:00.997.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Fen Long
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	phosphorylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Exploris 480

Revision	Datetime	Status	ChangeLog Entry
0	2025-04-15 00:07:02	ID requested
⏵ 1	2025-06-24 03:45:01	announced

10.1016/J.JHEP.2025.06.011;

submitter keyword: Glucagon

liver

PDE4

cAMP

PKA

energy expenditure

lipid metabolism

obesity

phosphoproteomics

PTM, LC-MS/MS

Prof. Dr.
contact affiliation	Department of Health Sciences and Technology ETH Zurich, Switzerland
contact email	christian-wolfrum@ethz.ch
lab head
Fen Long
contact affiliation	ETH Zurich
contact email	fen.long@hest.ethz.ch
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD062962
     1. Label: PRIDE project
     2. Name: Glucagon controls obesity-specific energy expenditure via persistent cAMP/PKA signaling