Macrophage Adiponectin Expression Improves Insulin Sensitivity and Protects Against Inflammation and Atherosclerosis

Nanlan Luo Jian Liu B. Hong Chung Qinglin Yang Richard L. Klein W. Timothy Garvey Yuchang Fu OBJECTIVE-Adiponectin is one of several important metabolically active cytokines secreted from adipose tissue. Epidemiologic studies have associated low-circulating levels of this adipokine with multiple metabolic disorders including obesity, insulin resistance, type 2 diabetes, and cardiovascular disease. To investigate adiponectin-mediated changes in metabolism in vivo, we generated transgenic mice that specifically express the gene coding for human adiponectin in mouse macrophages using the human scavenger receptor A-I gene enhancer/promoter. METHODS AND RESULTS-Using this transgenic mouse model, we found that adiponectin expression was associated with reduced whole-animal body and fat-pad weight and an improved lipid accumulation in macrophages when these transgenic mice were fed with a high-fat diet. Moreover, these macrophage Ad-TG mice exhibit enhanced whole-body glucose tolerance and insulin sensitivity with reduced proinflammatory cytokines, MCP-1 and TNF-a (both in the serum and in the metabolic active macrophage), adipose tissue, and skeletal muscle under the high-fat diet condition. Additional studies demonstrated that these macrophage adiponectin transgenic animals exhibit reduced macrophage foam cell formation in the arterial wall when these transgenic mice were crossed with an LDL receptor- deficient mouse model and were fed a high-fat diet. CONCLUSIONS-These results suggest that adiponectin expressed in macrophages can physiologically modulate metabolic activities in vivo by improving metabolism in distal tissues. The use of macrophages as carriers for adiponectin, a molecule with antidiabetes, anti-inflammatory, and antiatherogenic properties, provides a novel and unique strategy for studying the mechanisms of adiponectin-mediated alterations in body metabolism in vivo. Diabetes 59:791-799, 2010 - causes of mortality in the U.S. and in developing countries (13). Insulin resistance and hyperlipidemia have been linked to each of the traits, suggesting that these metabolic disorders and insulin resistance as well as hyperlipidemia are intimately related to one another. The diagnosis of the metabolic syndrome is a powerful risk factor for future development of type 2 diabetes and accelerated atherosclerosis resulting in heart attacks, stroke, and peripheral vascular disease. Atherosclerosis is considered a chronic inflammatory disease and a disorder of lipid metabolism (4). The complex physiopathologic process is initiated by the formation of cholesterol-rich lesions in the arterial wall. The accumulation of cholesterol-rich lipoproteins in the artery wall results in the recruitment of circulating monocytes, their adhesion to the endothelium, and their differentiation into tissue macrophages. Macrophages play a crucial role in this process because they accumulate large amounts of lipid to form the foam cells that initiate the formation of the lesion and participate actively in the development of the atherosclerotic lesion. Because the transformation of macrophages into foam cells is a critical component of atherosclerotic lesion formation (5), the prevention or reversal of cholesterol accumulation or the production of inflammatory mediators in macrophage foam cells could result in protection from multiple pathological effects of atherosclerosis and other abnormal metabolic disorders. Macrophages are a heterogeneous population of phagocytic cells found throughout the body that originate from the mononuclear phagocytic system (6). These are highly plastic cells that arise from circulating myeloid-derived blood monocytes that have entered target tissues and gained the phenotypic and functional attributes of their tissue of residence. Recent attention has focused on the potential role of macrophages in the process of metabolic diseases (7,8). It has been shown that in obesity, adipose tissue contains an increased number of resident macrophages and that, in some circumstances, macrophages can constitute up to 40% of the cell population within an adipose tissue depot (9,10); and macrophages are obviously a potential source of secreted proinflammatory factors to other tissues for insulin resistance. This correlative evidence has led to the concept that macrophages can directly influence other insulin target tissues and systemic insulin resistance. Furthermore, animal models have also been reported to evidence the causal role of the macrophage in leading to insulin resistance (11). When these animals were fed with a high-fat diet, the macrophage-specific inflammatory pathway knockout mice were relatively protected from glucose intolerance and hyperinsulinemia, and these results showed a global improvement in insulin sensitivity in all insulin-target tissues. These studies are consistent with the interpretation that the macrophage is an important, and potentially initiating, cell type in the process of inflammationinduced insulin resistance (12). To prevent macrophage infiltration into these insulin-target tissues will have beneficial effects on the inflammatory response and the abnormal metabolic state. Adiponectin (also known as apM1, AdipoQ, Gbp28, and Acrp30) is an adipocytokine identified by screening adipose-specific genes in the human cDNA projects (13). Epidemiological evidence has indicated that circulating adiponectin levels are reduced in patients with insulin resistance, type 2 diabetes, obesity, or cardiovascular disease (14 16). When examined, low plasma adiponectin levels in these disease states are accompanied by reduced adiponectin gene expression in adipose tissue (17,18). There is also evidence that adiponectin gene polymorphisms may be associated with hypoadiponectinemia together with insulin resistance and type 2 diabetes (19). Therefore, low levels of adiponectin and adiponectin gene variation have been associated with obesity and insulin resistance. The metabolic effects and action mechanisms for adiponectin are less clear. Adiponectin has been also shown to inhibit macrophage foam cell formation by downregulating scavenger receptor A (SR-A) expression and acyl-CoA: cholesterol-acyltransferase one (ACAT1) expression (20,21). It has been also reported that adiponectin may inhibit both the inflammatory process and atherogenesis by suppressing the migration of monocytes/macrophages and their transformation into macrophage foam cells in the vascular wall (20,22). These results suggest adiponectins inhibitory role in macrophage foam cell formation from human monocyte-derived macrophages. Our recently published data have demonstrated that expression of adiponectin in human THP-1 macrophage cells can modulate multiple pathways of lipid metabolism and reduce macrophage foam cell formation (23). All of these data point to the anti-inflammatory and antiatherogenic role of adiponectin during atherosclerosis. In current studies, we have generated an adip (...truncated)