Endotoxemia-mediated activation of acetyltransferase P300 impairs insulin signaling in obesity

Jia Cao, Jinghua Peng, Hongying An, Qiyi He, Tatiana Boronina, Shaodong Guo, Morris F. White, Philip A. Cole and Ling He ()
Additional contact information
Jia Cao: Johns Hopkins University School of Medicine
Jinghua Peng: Johns Hopkins University School of Medicine
Hongying An: Johns Hopkins University School of Medicine
Qiyi He: Brown University
Tatiana Boronina: Johns Hopkins University School of Medicine
Shaodong Guo: Texas A&M University
Morris F. White: Harvard University
Philip A. Cole: Johns Hopkins University School of Medicine
Ling He: Johns Hopkins University School of Medicine

Nature Communications, 2017, vol. 8, issue 1, 1-12

Abstract: Abstract Diabetes and obesity are characterized by insulin resistance and chronic low-grade inflammation. An elevated plasma concentration of lipopolysaccharide (LPS) caused by increased intestinal permeability during diet-induced obesity promotes insulin resistance in mice. Here, we show that LPS induces endoplasmic reticulum (ER) stress and protein levels of P300, an acetyltransferase involved in glucose production. In high-fat diet fed and genetically obese ob/ob mice, P300 translocates from the nucleus into the cytoplasm of hepatocytes. We also demonstrate that LPS activates the transcription factor XBP1 via the ER stress sensor IRE1, resulting in the induction of P300 which, in turn, acetylates IRS1/2, inhibits its association with the insulin receptor, and disrupts insulin signaling. Pharmacological inhibition of P300 acetyltransferase activity by a specific inhibitor improves insulin sensitivity and decreases hyperglycemia in obese mice. We suggest that P300 acetyltransferase activity may be a promising therapeutic target for the treatment of obese patients.

Date: 2017
References: Add references at CitEc
Citations: View citations in EconPapers (1)

Downloads: (external link)
https://www.nature.com/articles/s41467-017-00163-w Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-00163-w

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-017-00163-w

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().