br Methods br Results br Discussion Adiponectin

Methods
Results
Discussion Adiponectin is naturally expressed and secreted exclusively from adipocytes, and adiponectin levels and its isoforms in circulation have recently been reported to highly associate with human coronary artery disease (CAD) [46], [47], [48], [49], these studies clearly demonstrated that adiponectin plays an important role in human metabolic diseases. For adiponectin actions, adiponectin receptors play pivotal roles in many metabolic tissues [50]. Although adiponectin expression is undetectable in macrophages, adiponectin has been demonstrated to have effects on inhibiting both the inflammatory process and lipid accumulation in macrophages/foam YM 155 [15], [16], [51]; it is speculating that adiponectin receptors play key roles for adiponectin actions on macrophages. Although we recently engineered an adiponectin transgenic mouse model to directly express adiponectin in macrophages and observed a lean, insulin sensitive, diabetes-resistant, and atherosclerosis-resistant phenotype in those mice [39], [40], this model failed to exclusively point out the mechanisms for these anti-diabetic and anti-atherosclerotic phenotypes because these transgenic mice also exhibited increased circulating adiponectin concentrations. Therefore, higher adiponectin in these adiponectin transgenic mice could be influencing multiple tissues directly, not necessarily as a result of a specific interaction with macrophages. To investigate the mechanisms of adiponectin receptor-mediated alterations of whole body metabolism in vivo, we currently developed a mouse model in which the AdipoR1 gene was specifically overexpressed in macrophages using a human scavenger receptor A-I gene (SR-AI) enhancer/promoter. Our studies have shown that AdipoR1 overexpression in vivo by macrophages can significantly decrease cholesterol and triglyceride accumulation in the macrophages and also in mouse plasma despite no changes of the circulating adiponectin levels detected in these AdipoR1 transgenic mice when compared with those from control wild-type mice. Furthermore, the adiponectin receptor “modified macrophages” infiltrate or circulate into other metabolically active tissues such as adipose and skeletal muscle tissues, as well as liver, and there they can enhance local adiponectin actins on these metabolically active tissues and influence favorable changes to multiple metabolic pathways in these tissues. As demonstrated by our present data, macrophage overexpressing AdipoR1 can alter the expression of macrophage proinflammatory and anti-inflammatory molecules and lipid metabolic genes in metabolically active cells/tissues, such as macrophages, adipose tissue, skeletal muscle and liver. These macrophage AdipoR1 transgenic mice also showed increased glucose uptake in skeletal muscle, decreased glucose secretion in hepatocytes, probably contributing to increased glucose tolerance and improved insulin sensitivity in systemic metabolism in the whole body. Since macrophages in the arterial wall may be converted to the cholesterol-laden foam cells during atherogenesis, we crossed our macrophage AdipoR1 transgenic mouse with the low-density lipoprotein receptor (Ldlr) deficient mouse, a standard animal model for atherosclerosis. Our data also clearly showed that macrophage foam cell formation in atherosclerotic lesions was significantly reduced in this double crossed mouse model. These results suggest that AdipoR1 plays an important role in whole body metabolism by modulating inflammatory and metabolic signaling pathways, by improving glucose tolerance, insulin resistance, and by reducing atherogenesis which are typical characteristics of the Metabolic Syndrome. When generating the macrophage AdipoR1 transgenic mice, we also made macrophage AdipoR2 transgenic mice; and the macrophage AdipoR2 transgenic showed similar phenotypes as these from the macrophage AdipoR1 transgenic mice but with very weak phenotypes (data not shown). Although these two adiponectin receptors have been found to be expressed in human macrophages [26], [27], [28], AdipoR1 has predominating expression levels in these cells with almost 100-fold differences [27], [28]. Probably, due to the extremely different gene expression levels and differential signaling pathways of two adiponectin receptors in macrophages, we failed to detect a clear pattern of phenotypes from the macrophage adiponectin receptor 2 transgenic mice. In addition, although adiponectin has reported to interact with another putative receptor, T-cadherin, in pr-B-cells [23]; T-cadherin is almost undetectable in macrophage cells [28]. Moreover, since T-cadherin lacks the transmembrane and cytoplasmic domains, the biological significance of this non-transmembrane receptor is not clear yet in other cells [24].