Intermedin Restores Hyperhomocysteinemia-induced Macrophage Polarization and Improves Insulin Resistance in Mice

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.