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    • Two cell surface trans membrane receptors have been identifi

    2024-01-31

    Two cell-surface trans-membrane receptors have been identified for adiponectin, AdipoR1 and AdipoR2 [21], and adiponectin action is known to signal through these receptors and the docking protein APPL1 [22]. In muscle and liver cells, signal transduction involves the phosphorylation and activation of AMP-activated kinase (AMPK) [21], which plays a pivotal role in nutrient sensing and substrate metabolism. Adiponectin interacts with T-cadherin in pro-B-cells, however, the biological significance of this non-transmembrane receptor is not clear in other Propidium iodide since T-cadherin lacks the transmembrane and cytoplasmic domains [23], [24]. AdipoR1 is abundantly expressed in skeletal muscle and macrophages, whereas AdipoR2 is predominantly expressed in the liver [21]. Simultaneous disruption of both AdipoR1 and AdipoR2 abolished adiponectin binding and actions, resulting in increased liver triglyceride content, inflammation and oxidative stress in adipose tissue, and thus leading to insulin resistance and marked glucose intolerance [25]. Recently, these two receptors have also been found to be expressed in human macrophages [26], [27] with AdipoR1 predominating in these cells [27], [28]. Even so, the functions of AdipoR1/2 in macrophages remain poorly defined. Macrophages are a heterogenous and plastic population of phagocytic cells, which arise from circulating myeloid-derived blood monocytes, enter target tissues, and gain phenotypic and functional attributes partly determined by their tissue of residence [29]. Macrophages play a critical role in both metabolic and vascular components of cardiometabolic disease. In the vascular wall, macrophages accumulate lipid in the presence of excess oxidized and non-oxidized LDL, then transition to foam cells, and initiate the fatty streak which is the hallmark lesion of atherosclerosis [30]. Recent attention has also focused on the important role of macrophages in insulin resistance, the Metabolic Syndrome, and type II diabetes [31], [32]. In obesity and insulin resistance, adipose tissue contains an increased number of resident macrophages [33], [34], which secrete cytokines and other factors that cross-talk with adipocytes. This alters the systemic release of adipocytokines from adipose tissue, causing dysmetabolism in multiple organs. Thus, the proinflammatory state, established in adipose tissue as a consequence of the increase in resident activated macrophages (i.e., M1 macrophages), is believed to be instrumental in the development of systemic insulin resistance and other traits that characterize the Metabolic Syndrome [35]. There is also accumulating evidence that macrophages reside in skeletal muscle, and could contribute to insulin resistance by directly impairing insulin action in this key target tissue [36]. In support of the central role of the macrophages [37], mice fed a high-fat diet were protected against glucose intolerance and insulin resistance when inflammatory pathways in macrophages were genetically disrupted [38]. Recently, we engineered transgenic mice to synthesize and secrete adiponectin from macrophages in an attempt to augment adiponectin action in the microenvironment of the macrophage [39], [40]. This resulted in a lean, insulin sensitive, diabetes-resistant, and atherosclerosis-resistant phenotype, and gave us the idea that the adiponectin-macrophage axis could regulate multiple key components of the Metabolic Syndrome. However, this model failed to rigorously test this hypothesis since the transgenic mice also exhibited increased circulating adiponectin concentrations, and, therefore, higher adiponectin could be influencing multiple tissues directly, not necessarily as a result of a specific interaction with macrophages. The current studies have developed a novel approach to manipulate adiponectin action at the level of the macrophage in order to examine systemic effects related to metabolic diseases by genetic manipulation of the major receptor for adiponectin in macrophages, AdipoR1. Our data suggest that alterations in adiponectin effects, solely directed at the macrophage, can explain the co-occurrence of multiple components in the Metabolic Syndrome trait cluster and provide a novel unifying explanation for the pathophysiology of metabolic diseases. Our data, for the first time, suggest that overexpression of AdipoR1 can alter macrophage biology and impact systemic metabolism in vivo. These data point to the central role of macrophages, and the singular ability of adiponectin to regulate macrophage function, in metabolic diseases. Therefore, our studies provide new insights for investigating the mechanisms of metabolism and inflammatory response in vivo.