Abstract 14659: Novel Metabolic Regulations by Adrenomedullin-RAMP2 System
Various humoral factors are involved in the physiological and pathological conditions in both vascular and metabolic system. Adrenomedullin (AM), originally identified as a vasodilatory peptide, is now recognized as a multifunctional molecule, which possesses antioxidative, anti-inflammatory, and hormonal regulation functions. AM receptor, calcitonin receptor-like receptor (CLR), associates with one of the accessory proteins called receptor activity-modifying proteins (RAMPs). Through the studies of gene-targeted animal models, we have shown RAMP2 is the critical determinant of vascular functions of AM, including angiogenesis and vascular integrity (J Clin Invest. 2008).
Obesity is a risk factor for cardiovascular diseases. In this study, we analyzed the role of AM-RAMP2 system in metabolic regulations using a high-fat diet (HFD)-induced obesity model. As homozygote knockout mice are embryonic lethal, we used heterozygote knockout mice of RAMP2 (RAMP2+/−). 8 week-old RAMP2+/− male and their wild-type littermates were fed on HFD (32% fat) for 10 weeks. RAMP2+/− showed higher body weight compared with wild-type. Serum insulin and leptin were higher, whereas adiponectin was lower in RAMP2+/−. In OGTT and ITT analysis, RAMP2+/− showed higher glucose and insulin resistance. RAMP2+/− also showed higher white adipose tissue (WAT) weight with adipocyte hypertrophy and infiltration of macrophages. The expression of inflammatory cytokines, including IL-1β, IL-6, and TNF-α was enhanced in the WAT of RAMP2+/−. ERK signaling pathway was chronically upregulated in the WAT and liver of RAMP2+/−. Moreover, RAMP2+/− showed severe fatty liver changes and fibrosis. In MALDI-TOF Mass Spectrometry imaging, parenchymal hepatic cell specimen, which dose not contain vascular cell component, showed high accumulation of triglyceride, phosphatidylcholine, phosphatidylinositol, and sulfatide in RAMP2+/−.
These observations indicate that AM-RAMP2 system play critical roles in the regulation of glucose and lipid metabolism, and therefore in the pathophysiology of metabolic syndrome as well as the regulation of cardiovascular system.
- © 2011 by American Heart Association, Inc.