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Immunotherapy against angiotensin II receptor ameliorated insulin resistance in a leptin receptor-dependent manner.

Immunotherapy against angiotensin II receptor ameliorated insulin resistance in a leptin receptor-dependent manner.

Authors :
Zheng J
Ding J
Liao M
Qiu Z
Yuan Q
Mai W
Dai Y
Zhang H
Wu H
Wang Y
Liao Y
Chen X
Cheng X
Source :
FASEB journal : official publication of the Federation of American Societies for Experimental Biology [FASEB J] 2021 Jan; Vol. 35 (1), pp. e21157. Date of Electronic Publication: 2020 Nov 06.
Publication Year :
2021

Abstract

The angiotensin II type 1 receptor (AT1R) signaling pathway is reported to modulate glucose metabolism. Targeting AT1R, our group invented ATRQβ-001 vaccine, a novel immunotherapeutic strategy to block the activation of AT1R. Here, we evaluated the therapeutic efficacy of ATRQβ-001 vaccine in insulin resistance, and investigated the mechanism. Our results showed that ATRQβ-001 vaccine and specific monoclonal antibody against epitope ATR-001 (McAb-ATR) decreased fasting serum insulin concentration and improved glucose and insulin tolerance in ob/ob mice. These beneficial effects were verified in high-fat diet-induced obese mice. McAb-ATR activated insulin signaling in skeletal muscle and insulin-resistant C2C12 myotubes without affecting liver or white adipose tissue of ob/ob mice. Mechanistically, the favorable impact of McAb-ATR on insulin resistance was abolished in db/db mice and in C2C12 myotubes with leptin receptor knockdown. AT1R knockdown also eradicated the effects of McAb-ATR in C2C12 myotubes. Furthermore, McAb-ATR treatment was able to activate the leptin receptor-mediated JAK2/STAT3 signaling in skeletal muscle of ob/ob mice and C2C12 myotubes. Additionally, angiotensin II downregulated the leptin signaling in skeletal muscle of ob/ob and diet-induced obese mice. We demonstrated that ATRQβ-001 vaccine and McAb-ATR improved whole-body insulin resistance and regulated glucose metabolism in skeletal muscle in a leptin receptor-dependent manner. Our data suggest that immunotherapy targeting AT1R is a novel strategy for treating insulin resistance.<br /> (© 2020 Federation of American Societies for Experimental Biology.)

Details

Language :
English
ISSN :
1530-6860
Volume :
35
Issue :
1
Database :
MEDLINE
Journal :
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Publication Type :
Academic Journal
Accession number :
33155736
Full Text :
https://doi.org/10.1096/fj.202000300R