AMPK is an essential player in adiponectin signaling pathway

AMPK is an essential player in adiponectin signaling pathway that regulates energy metabolism. The fact that suppression of AMPK activity by compound C largely diminished candesartan-mediated inhibition of NFκB via blocking AT1 also suggests that the AT1-mediated effect is at least partly resulted from direct inhibition of AdipoR1 and AdipoR2 via heterodimerization (Fig. 4). Thus, direct stimulation of AdipoR1 and AdipoR2 with adiponectin or their agonists may confer similar beneficial actions. In agreement with our findings and speculations, extensive evidence from the literature shows that adiponectin regulates glucose and lipid metabolism, improves insulin sensitivity, and exerts anti-atherosclerotic and anti-inflammatory effects [25], [26]. These effects depend on the interplay of its two receptor subtypes: AdipoR1 and AdipoR2 [27]. AdipoR1 is mainly expressed in skeletal muscle and AdipoR2 in the liver. As reported in one study [28], two types of islet β cells, macrophages, and endothelial cells contain cell surface AdipoR1 and R2 receptors. AdipoR1 and AdipoR2 have very similar structures containing seven transmembrane domains, both of which can activate peroxisome proliferator-activated receptor-α (PPARα), PPARγ, AMPK, p38 mitogen-activated protein kinase (p38MAPK) and other signaling pathways [11], [29], [30], [31], [32]. AdipoRs-induced activation of AMPK pathway was mainly involved in the fatty Concanamycin A australia oxidation improved by adiponectin, independent of glucose uptake. PPARα, p38MAPK signal pathway and adiponectin oxidation of fatty acids and glucose uptake were correlated. Adiponectin inhibits the high expression of MCP-1 mRNA in renal cortical tissues of diabetic mice, thus exerting a protective effect [33]. We have shown in this study that AT1 and AT2 also form heterodimer. Under HG condition, this heterodimerization showed a downward trend. Since AT2 antagonizes the function of AT1 in almost all AT1-mediated actions, such heterozimerization may be beneficial. At last, the counteractions mediated by candesartan and compound C in serum-free medium without AngII and adiponectin stimulation (Fig. 4) suggest that the heterodimerized AT1 is constitutively active and the heterodimerized adiponectin receptors are inactive. Since chronic kidney disease (CKD) including DKD is also an independent risk factor for atherogenic vascular diseases, alleviation of DKD with ARBs in diabetic patients even without hypertension can be largely beneficial [34]. Our result provides mechanistic support for this clinical practice.
Disclosure
Acknowledgments This work was supported by grants from the National Science Foundation of China (81170679 to X.W and 81400694 to D.Z).
Introduction The discovery of adipocyte-specific secreted molecules, termed adipokines, has dispelled the notion of adipose tissue as an inert storage depot for lipids, and highlighted its role as an active endocrine organ that monitors and alters whole-body metabolism and maintains energy homeostasis. Since its identification in the mid-90's [20], the adipokine adiponectin (also known as Acrp30, AdipoQ and GBP28) has become best known as a regulator of insulin sensitivity. The two adiponectin receptor isoforms, AdipoR1 and AdipoR2, previously have been shown to be associated with increases in activities of AMP-activated protein kinase (AMPK) and peroxisome-proliferator activated receptor (PPARα). Recently, our group has shown that adiponectin is capable of inducing ceramidase activity through its receptors, which results in the hydrolysis of ceramide to form sphingosine and free fatty acid. Sphingosine, produced in this reaction, can go on to be phosphorylated by sphingosine kinase to produce sphingosine 1-phosphate (S1P), which functions as an important signaling molecule in a number of different cellular processes. The ceramide lowering effect of the adiponectin receptors only marginally depends on the activity of AMP kinase (AMPK), but AMPK can be activated through increasing the local S1P pool. Thus, this process appears to be a proximal event in adiponectin signaling, since it is a necessary step in adiponectin's induction of AMPK activation. These data support a previous model based on data from a heterologous system that connected the family of Progesterone and AdipoQ receptors (PAQRs), which includes AdipoR1 and AdipoR2, with ceramidase activity [10,28] and suggested a revised view of adiponectin signaling with sphingolipid metabolism at its core.