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

Abstract

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.Intermedin (IMD), 3 also known as adrenomedullin 2 (AM2), is a 53-amino acid peptide belonging to the calcitonin generelated peptide/calcitonin family (1, 2). IMD shares a common family of G-protein-coupled receptors with another calcitonin gene-related peptide/calcitonin family member, adrenomedullin (AM), which is involved in obesity and its related metabolic disorders (3-5). IMD regulates the central and peripheral circulation and water-electrolyte homeostasis and protects the myocardium from ischemia-reperfusion injury by inhibiting oxidative stress in both the heart and kidney (6 -9). The observation of decreased IMD in the plasma of diabetic rats linked IMD with diabetes (8). Previous studies from our group demonstrated that IMD inhibits scavenger receptors and foam cell formation of macrophages and, consequently, protects mice from atherosclerosis (10, 11). Recently published data from our group showed that IMD reduced insulin resistance in high-fat diet-induced obese mice through elevating thermogenesis in brown adipose tissue (12).Chronic inflammation is considered a pathological issue for aggravating insulin resistance (13,14). However, the effect of IMD on inflammation aggravated insulin resistance remains largely unknown. In a bacterial LPS-induced atypical orchitis rat model, IMD attenuated the expres...

Adrenomedullin 2/intermedin: a putative drug candidate for treatment of cardiometabolic diseases

“…ADM2/IMD 1–53 reverses the M1/M2 imbalance in adipose tissue in an AMPK‐dependent manner. The ADM2/IMD 1–53 ‐induced activation of adipose M2 macrophages induces beiging indirectly and ameliorates adipose inflammation (Lv et al , ; Pang et al , ). Noradrenaline released by M2 macrophages has an anti‐inflammatory effect on adipose macrophages through a β 2 ‐adrenoceptor‐cAMP‐HDAC4‐dependent pathway (Luan et al , ), which may be involved in the improvement of adipose inflammation.…”

Homocysteine regulates fatty acid and lipid metabolism in yeast

“…A pathological condition in humans termed hyperhomocysteinemia (HHcy) is characterized by elevated levels of Hcy in the serum ( 6 ). HHcy is linked to a number of disorders of modern society, including cardiovascular and neurological diseases, fatty liver, insulin resistance, and cancer ( 6 – 9 ). Notably, HHcy is present in 5–10% of the general population ( 10 ) and up to 30% of the elderly (>65 years) ( 11 ); however, mechanisms linking Hcy accumulation to disease phenotypes are unclear.…”

Adrenomedullin 2 Enhances Beiging in White Adipose Tissue Directly in an Adipocyte-autonomous Manner and Indirectly through Activation of M2 Macrophages

“…ADM2 can be synthesized and secreted from adipocytes, and its expression is down-regulated in adipose tissues of db/db mice and high-fat diet (HFD)-induced obese mice (29). Subcutaneous ADM2 dosing by minipump implantation could improve hyperhomocysteinemia or HFD-induced insulin resistance in mice (29,30). ADM2 was also reported to substantially inhibit adipocyte MHC II expression and thus ameliorate insulin resistance in adipose tissue (31).…”