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Immunotherapy against angiotensin II receptor ameliorated insulin resistance in a leptin receptor‐dependent manner
Author(s) -
Zheng Jiayu,
Ding Jiaxing,
Liao Mengyang,
Qiu Zhihua,
Yuan Qingchen,
Mai Wuqian,
Dai Yong,
Zhang Hongrong,
Wu Hailang,
Wang Yingxuan,
Liao Yuhua,
Chen Xiao,
Cheng Xiang
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.202000300r
Subject(s) - insulin resistance , endocrinology , leptin , medicine , glucagon like peptide 1 receptor , receptor , immunotherapy , angiotensin ii , insulin receptor , insulin , obesity , agonist , cancer
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.