title: Adrenomedullin 2 Improves Early Obesity-Induced Adipose Insulin Resistance by Inhibiting the Class II MHC in Adipocytes.
abstract: MHC class II (MHCII) antigen presentation in adipocytes was reported to trigger early adipose inflammation and insulin resistance. However, the benefits of MHCII inhibition in adipocytes remain largely unknown. Here, we showed that human plasma polypeptide adrenomedullin 2 (ADM2) levels were negatively correlated with HOMA of insulin resistance in obese human. Adipose-specific human ADM2 transgenic (aADM2-tg) mice were generated. The aADM2-tg mice displayed improvements in high-fat diet-induced early adipose insulin resistance. This was associated with increased insulin signaling and decreased systemic inflammation. ADM2 dose-dependently inhibited CIITA-induced MHCII expression by increasing Blimp1 expression in a CRLR/RAMP1-cAMP-dependent manner in cultured adipocytes. Furthermore, ADM2 treatment restored the high-fat diet-induced early insulin resistance in adipose tissue, mainly via inhibition of adipocyte MHCII antigen presentation and CD4(+) T-cell activation. This study demonstrates that ADM2 is a promising candidate for the treatment of early obesity-induced insulin resistance.
authors.affiliation: Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education and Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, China.
authors.forename: Song-Yang
authors.initials: SY
authors.lastname: Zhang
authors.affiliation: Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education and Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Lv
authors.affiliation: Department of Endocrinology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China.
authors.forename: Heng
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of General Surgery, Peking University First Hospital, Peking University, Beijing, China.
authors.forename: Song
authors.initials: S
authors.lastname: Gao
authors.affiliation: Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education and Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Wang
authors.affiliation: Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education and Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Feng
authors.affiliation: Institute of Cardiovascular Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Beijing, China.
authors.forename: Yuhui
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Institute of Cardiovascular Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Beijing, China.
authors.forename: George
authors.initials: G
authors.lastname: Liu
authors.affiliation: Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education and Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, China.
authors.forename: Ming-Jiang
authors.initials: MJ
authors.lastname: Xu
authors.affiliation: Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education and Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, China jiangchangtao@bjmu.edu.cn xwang@bjmu.edu.cn.
authors.forename: Xian
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education and Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, China jiangchangtao@bjmu.edu.cn xwang@bjmu.edu.cn.
authors.forename: Changtao
authors.initials: C
authors.lastname: Jiang
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism*; D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D053607:Adrenomedullin / Q000494:pharmacology; D000818:Animals; D016026:Bone Marrow Transplantation; D002478:Cells, Cultured; D005802:Genes, MHC Class II / Q000235:genetics / Q000502:physiology; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological; D009765:Obesity / Q000378:metabolism* / Q000503:physiopathology; D036361:Peptide Hormones / Q000235:genetics / Q000378:metabolism*; D000074462:Positive Regulatory Domain I-Binding Factor 1; D058262:Receptor Activity-Modifying Protein 1 / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: C484330:ADM2 protein, human; D036361:Peptide Hormones; C513258:Prdm1 protein, mouse; C545505:Ramp1 protein, mouse; D058262:Receptor Activity-Modifying Protein 1; D014157:Transcription Factors; D053607:Adrenomedullin; D000074462:Positive Regulatory Domain I-Binding Factor 1