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Identification and characterization of a novel adiponectin receptor agonist adipo anti‐inflammation agonist and its anti‐inflammatory effects in vitro and in vivo
Author(s) -
Qiu Wei,
Wu Hongle,
Hu Zhekai,
Wu Xingwen,
Tu Maxwell,
Fang Fuchun,
Zhu Xiaofang,
Liu Yao,
Lian Junxiang,
Valverde Paloma,
Van Dyke Thomas,
Steffensen Bjorn,
Dong Lily Q.,
Tu Qisheng,
Zhou Xuedong,
Chen Jake
Publication year - 2021
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.15277
Subject(s) - inflammation , agonist , lipopolysaccharide , receptor , proinflammatory cytokine , adiponectin , mapk/erk pathway , signal transduction , biology , endocrinology , pharmacology , chemistry , medicine , immunology , microbiology and biotechnology , insulin resistance , insulin
Background and Purpose Adiponectin (APN) is an adipokine secreted from adipocytes that binds to APN receptors AdipoR1 and AdipoR2 and exerts an anti‐inflammatory response through mechanisms not fully understood. There is a need to develop small molecules that activate AdipoR1 and AdipoR2 and to be used to inhibit the inflammatory response in lipopolysaccharide (LPS)‐induced endotoxemia and other inflammatory disorders. Experimental Approach We designed 10 new structural analogues of an AdipoR agonist, AdipoRon (APR), and assessed their anti‐inflammatory properties. Bone marrow‐derived macrophages (BMMs) and peritoneal macrophages (PEMs) were isolated from mice. Levels of pro‐inflammatory cytokines were measured by reverse transcription and real‐time quantitative polymerase chain reaction (qRT‐PCR), enzyme‐linked immunosorbent assay (ELISA) and microarray in LPS‐induced endotoxemia mice and diet‐induced obesity (DIO) mice in which systemic inflammation prevails. Western blotting, immunohistochemistry (IHC), siRNA interference and immunoprecipitation were used to detect signalling pathways. Key Results A novel APN receptor agonist named adipo anti‐inflammation agonist (AdipoAI) strongly suppresses inflammation in DIO and endotoxemia mice, as well as in cultured macrophages. We also found that AdipoAI attenuated the association of AdipoR1 and APPL1 via myeloid differentiation marker 88 (MyD88) signalling, thus inhibiting activation of nuclear factor kappa B (NF‐κB), mitogen‐activated protein kinase (MAPK) and c‐Maf pathways and limiting the production of pro‐inflammatory cytokines in LPS‐induced macrophages. Conclusion and Implications AdipoAI is a promising alternative therapeutic approach to APN and APR to suppress inflammation in LPS‐induced endotoxemia and other inflammatory disorders via distinct signalling pathways.