Intermedin/adrenomedullin 2 polypeptide promotes adipose tissue browning and reduces high-fat diet-induced obesity and insulin resistance in mice.

OBJECTIVES: There is an urgent need to develop interventions and policies to mitigate the health effects of obesity by targeting its metabolic mediators. Adrenomedullin 2 (AM2)/intermedin (IMD) is a secreted peptide that has an important role in protecting the cardiovascular system. However, the role of AM2 in type 2 diabetes is unknown.

METHODS: Wild-type (WT) and aP2/AM2 transgenic (aAM2-tg) mice were fed a high-fat diet (HFD) for 8 weeks, and WT mice were treated with AM2 through mini-osmotic pumps. Indirect calorimetry, ambulatory activity and food intake, hyperinsulinemic-euglycemic clamp test, glucose and insulin tolerance tests were used for assessing insulin resistance. Rat primary adipocytes and pre-adipocyte-derived adipocytes were used for in vitro experiments. Real-time PCR and western blot were used for analyses of gene expression and protein level.

RESULTS: AM2 and receptor activity-modifying proteins expressions were significantly decreased in the adipose tissue of obese mice. AM2 treatment significantly reduced blood glucose, fasting serum insulin and free fatty acid levels, improved glucose tolerance and insulin sensitivity, and increased the glucose infusion rate during a hyperinsulinemic-euglycemic clamp test, indicating ameliorated HFD-induced insulin resistance. These effects were consistently observed in aAM2-tg mice under HFD conditions, whereas the aAM2-tg mice showed less weight gain and improved glucose tolerance and insulin sensitivity. More importantly, the aAM2-tg mice had increased oxygen consumption and CO2 production, reflecting more energy expenditure. These effects may be due to increased AMP-activated protein kinase phosphorylation and reduced peroxisome proliferator-activated receptor gamma co-activator 1α (PGC1α) acetylation, which result in interactions between PGC1α and PR domain containing 16 and then promote uncoupling protein 1 (UCP1) expression in adipocytes.

CONCLUSIONS: These results indicate that endogenous AM2 might be involved in energy metabolism in adipocytes through the upregulation of UCP1 expression.