Apelin-transgenic mice exhibit a resistance against diet-induced obesity by increasing vascular mass and mitochondrial biogenesis in skeletal muscle

Background: Apelin is an endogenous ligand for the G-protein-coupled 7-transmembrane receptor, APJ. The administration of apelin-13, a truncated 13-amino acid apelin peptide, in diet-induced obese mice is reported to result in a decrease in adiposity due to the increase of energy expenditure with an increase in the expression of uncoupling proteins. Methods: We systematically compared the phenotype of human apelin-transgenic (apelin-Tg) mice fed standard or high-fat diets (HFD) with that of non-Tg control mice to clarify the effect of apelin on obesity. The beneficial effects of apelin were evaluated by multiple assay methods including indirect calorimetrical measurements, gene expression analysis, and immunohistochemical staining. Results: Apelin-Tg mice inhibited HFD-induced obesity without altering food intake and exhibited increased oxygen consumption and body temperature compared to non-Tg controls. Interestingly, the mRNA expressions of angiopoietin-1 (Ang1), a key molecule for vascular maturation, and its receptor, endothelium-specific receptor tyrosine kinase 2 (Tie2), were significantly upregulated in the skeletal muscle of HFD-fed apelin-Tg mice, and the areas of anti-CD31 antibody-positive endothelial cells also increased. Furthermore, both the aerobic type-I muscle fibre ratio and the DNA copy number of mitochondria! NADH dehydrogenase subunit 1 increased 2.0- and 1.4-fold in skeletal muscle, respectively. Conclusions: These findings suggest that apelin stimulates energy expenditure via increase vascular mass and mitochondrial biogenesis in skeletal muscle. General Significance: Apelin is a prerequisite factor for anti-obesity by stimulating energy expenditure via regulating homeostatic energy balance. (C) 2011 Elsevier B.V. All rights reserved.