PMID- 27080257 OWN - NLM STAT- MEDLINE DCOM- 20161213 LR - 20220318 IS - 1083-351X (Electronic) IS - 0021-9258 (Print) IS - 0021-9258 (Linking) VI - 291 IP - 23 DP - 2016 Jun 3 TI - Intermedin Restores Hyperhomocysteinemia-induced Macrophage Polarization and Improves Insulin Resistance in Mice. PG - 12336-45 LID - 10.1074/jbc.M115.702654 [doi] AB - Hyperhomocysteinemia (HHcy) is a condition characterized by an abnormally high level of homocysteine, an inflammatory factor. This condition has been suggested to promote insulin resistance. To date, the underlying molecular mechanism remains largely unknown, and identifying novel therapeutic targets for HHcy-induced insulin resistance is of high priority. It is well known that intermedin (IMD), a calcitonin family peptide, exerts potent anti-inflammatory effects. In this study, the effects of IMD on HHcy-induced insulin resistance were investigated. Glucose tolerance and insulin tolerance tests were performed on mice treated with IMD by minipump implantation (318 ng/kg/h for 4 weeks) or adipocyte-specific IMD overexpression mice (Adipo-IMD transgenic mice). The expression of genes and proteins related to M1/M2 macrophages and endoplasmic reticulum stress (ERS) was evaluated in adipose tissues or cells. The expression of IMD was identified to be lower in the plasma and adipose tissues of HHcy mice. In both IMD treatment by minipump implantation and Adipo-IMD transgenic mice, IMD reversed HHcy-induced insulin resistance, as revealed by glucose tolerance and insulin tolerance tests. Further mechanistic study revealed that IMD reversed the Hcy-elevated ratio of M1/M2 macrophages by inhibiting AMP-activated protein kinase activity. Adipo-IMD transgenic mice displayed reduced ERS and lower inflammation in adipose tissues with HHcy. Soluble factors from Hcy-treated macrophages induced adipocyte ERS, which was reversed by IMD treatment. These findings revealed that IMD treatment restores the M1/M2 balance, inhibits chronic inflammation in adipose tissues, and improves systemic insulin sensitivity of HHcy mice. CI - (c) 2016 by The American Society for Biochemistry and Molecular Biology, Inc. FAU - Pang, Yanli AU - Pang Y AD - From the Department of Physiology and Pathophysiology, Basic Medical College, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, and Center for Reproductive Medicine of Third Hospital, Peking University, Beijing 100191, China. FAU - Li, Yang AU - Li Y AD - From the Department of Physiology and Pathophysiology, Basic Medical College, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, and. FAU - Lv, Ying AU - Lv Y AD - From the Department of Physiology and Pathophysiology, Basic Medical College, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, and. FAU - Sun, Lulu AU - Sun L AD - From the Department of Physiology and Pathophysiology, Basic Medical College, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, and. FAU - Zhang, Songyang AU - Zhang S AD - From the Department of Physiology and Pathophysiology, Basic Medical College, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, and. FAU - Li, Yin AU - Li Y AD - From the Department of Physiology and Pathophysiology, Basic Medical College, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, and. FAU - Wang, Yuhui AU - Wang Y AD - From the Department of Physiology and Pathophysiology, Basic Medical College, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, and. FAU - Liu, George AU - Liu G AD - From the Department of Physiology and Pathophysiology, Basic Medical College, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, and. FAU - Xu, Ming-Jiang AU - Xu MJ AD - From the Department of Physiology and Pathophysiology, Basic Medical College, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, and. FAU - Wang, Xian AU - Wang X AD - From the Department of Physiology and Pathophysiology, Basic Medical College, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, and xwang@bjmu.edu.cn. FAU - Jiang, Changtao AU - Jiang C AD - From the Department of Physiology and Pathophysiology, Basic Medical College, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, and jiangchangtao@bjmu.edu.cn. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20160414 PL - United States TA - J Biol Chem JT - The Journal of biological chemistry JID - 2985121R RN - 0 (Neuropeptides) RN - 0 (intermedin protein, mouse) RN - EC 2.7.11.31 (AMP-Activated Protein Kinases) SB - IM MH - AMP-Activated Protein Kinases/antagonists & inhibitors/genetics/metabolism MH - Adipose Tissue/drug effects/metabolism/pathology MH - Animals MH - Blotting, Western MH - Cells, Cultured MH - Endoplasmic Reticulum Stress/drug effects/genetics MH - Hyperhomocysteinemia/*physiopathology MH - Inflammation/genetics/metabolism/prevention & control MH - Insulin Resistance/*physiology MH - Macrophage Activation/drug effects MH - Macrophages, Peritoneal/*drug effects/metabolism MH - Male MH - Mice, Inbred C57BL MH - Mice, Transgenic MH - Neuropeptides/genetics/metabolism/*pharmacology MH - RNA Interference MH - Reverse Transcriptase Polymerase Chain Reaction PMC - PMC4933280 OTO - NOTNLM OT - AMP-activated kinase (AMPK) OT - adipose tissue OT - homocysteine OT - insulin resistance OT - macrophage EDAT- 2016/04/16 06:00 MHDA- 2016/12/15 06:00 PMCR- 2017/06/03 CRDT- 2016/04/16 06:00 PHST- 2015/11/05 00:00 [received] PHST- 2016/04/16 06:00 [entrez] PHST- 2016/04/16 06:00 [pubmed] PHST- 2016/12/15 06:00 [medline] PHST- 2017/06/03 00:00 [pmc-release] AID - S0021-9258(20)35609-X [pii] AID - M115.702654 [pii] AID - 10.1074/jbc.M115.702654 [doi] PST - ppublish SO - J Biol Chem. 2016 Jun 3;291(23):12336-45. doi: 10.1074/jbc.M115.702654. Epub 2016 Apr 14.