Pharmacologic IRE1/XBP1s activation promotes systemic adaptive remodeling in obesity.
Animals
Fatty Liver
/ metabolism
Gene Expression Regulation
Glucose
/ metabolism
Homeostasis
Liver
/ metabolism
Membrane Proteins
/ genetics
Mice
Mice, Obese
Molecular Medicine
Obesity
/ genetics
Protein Serine-Threonine Kinases
/ genetics
Signal Transduction
Transcription Factors
/ metabolism
Unfolded Protein Response
X-Box Binding Protein 1
/ genetics
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
01 02 2022
01 02 2022
Historique:
received:
30
08
2021
accepted:
18
01
2022
entrez:
2
2
2022
pubmed:
3
2
2022
medline:
16
2
2022
Statut:
epublish
Résumé
In obesity, signaling through the IRE1 arm of the unfolded protein response exerts both protective and harmful effects. Overexpression of the IRE1-regulated transcription factor XBP1s in liver or fat protects against obesity-linked metabolic deterioration. However, hyperactivation of IRE1 engages regulated IRE1-dependent decay (RIDD) and TRAF2/JNK pro-inflammatory signaling, which accelerate metabolic dysfunction. These pathologic IRE1-regulated processes have hindered efforts to pharmacologically harness the protective benefits of IRE1/XBP1s signaling in obesity-linked conditions. Here, we report the effects of a XBP1s-selective pharmacological IRE1 activator, IXA4, in diet-induced obese (DIO) mice. IXA4 transiently activates protective IRE1/XBP1s signaling in liver without inducing RIDD or TRAF2/JNK signaling. IXA4 treatment improves systemic glucose metabolism and liver insulin action through IRE1-dependent remodeling of the hepatic transcriptome that reduces glucose production and steatosis. IXA4-stimulated IRE1 activation also enhances pancreatic function. Our findings indicate that systemic, transient activation of IRE1/XBP1s signaling engenders multi-tissue benefits that integrate to mitigate obesity-driven metabolic dysfunction.
Identifiants
pubmed: 35105890
doi: 10.1038/s41467-022-28271-2
pii: 10.1038/s41467-022-28271-2
pmc: PMC8807832
doi:
Substances chimiques
Membrane Proteins
0
Transcription Factors
0
X-Box Binding Protein 1
0
Xbp1 protein, mouse
0
Ern2 protein, mouse
EC 2.7.1.-
Protein Serine-Threonine Kinases
EC 2.7.11.1
Glucose
IY9XDZ35W2
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
608Subventions
Organisme : NIA NIH HHS
ID : R01 AG046495
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK123038
Pays : United States
Organisme : NIDDK NIH HHS
ID : RC2 DK114785
Pays : United States
Informations de copyright
© 2022. The Author(s).
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