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The adiponectin receptor (AdipoR) is a 7-pass transmembrane protein. AdipoR2 is mainly found in the liver and has moderate affinity for both full-length and globular adiponectin. AdipoR1 and AdipoR2 are transmembrane proteins with ceramidase activity.
Expression and Distribution of AdipoR2
AdipoR2 is mainly expressed in the liver and expressed in tumor tissues such as breast cancer, colon cancer, and prostate cancer. Studies have shown that AdipoR1 and AdipoR2 are present in macrophages of human atherosclerotic lesions, and AdipoR1 is more abundant in monocytes than in AdipoR2. When differentiated into macrophages, the AdipoR1 expression is decreased and AdipoR2 remains unchanged. Studies have shown that adiponectin and its receptor are expressed in osteoblasts (mainly human osteoblasts of the femur and tibia). Studies have confirmed that AdipoR1 and AdipoR2 genes are expressed in both adipocytes and mesenchymal cells, and AdipoR1 expression levels in human subcutaneous and peritoneal omentum are about 10 times higher than AdipoR2. The study found that AdipoR is also expressed in human placenta, but mainly AdipoR1. Studies have found that pig AdipoR1 is highly expressed in the heart and skeletal muscle, while AdipoR2 is highly expressed in the subcutaneous adipose tissue. Other studies have found that the expression of AdipoR1 and AdipoR2 interacts positively, and the expression of both is positively correlated in human skeletal muscle. This may be because the regulatory site of gene expression control is regulated by the same transcription factor.
Figure 1. AdipoR2 activation pathway. (Okada-Iwabu M, et al. 2015)
AdipoR2-mediated Signal Transduction Pathway
Adiponectin receptors are key proteins that mediate the biological effects of adiponectin. Scatchard plot analysis showed that the active fragment of adiponectin, globular adiponectin (gAd), had a higher affinity with C2C12 myopocytic AdipoR1 (Kd=1.14nmol/L) and moderate affinity with AdipoR2 (Kd=14.4nmol/L). The full length adiponectin has a lower affinity with AdipoR1 (Kd = 2415nmol/L) and a central affinity with AdipoR2 (Kd=49.1nmol/L). This suggests that AdipoR1 is a high-affinity receptor for globular adiponectin and a low-affinity receptor for full-length adiponectin, while AdipoR2 is a medium-affinity receptor for full-length adiponectin and globular adiponectin. AdipoR1-/- mice exhibited obesity and impaired glucose tolerance. Mice with down-regulated AdipoR2 expression are resistant to insulin resistance induced by a high-fat diet. In the long-term high-fat diet, AdipoR2 does not function, limiting islet β cell proliferation and eventually develops type 2 diabetes.
T-cadherin is a receptor for adiponectin hexamers and macromolecular complexes, but due to the lack of intracellular domains, further studies are needed on the biological functions of adiponectin. AdipoR1/2 double knockout mice have significantly impaired glucose tolerance and hyperinsulinemia marked insulin resistance, and are prone to inflammation and oxidative stress. Because of the absence of an effective adiponectin receptor, adiponectin cannot bind to hepatocytes, suggesting that the biological function of adiponectin is mainly mediated by AdipoR1/2 and T-cadherin is weak.
AdipoR2 and T-cadherin with Breast Cancer
T-cadherin is a glycosylphosphatidylinositol-anchored protein that is considered to be an atypical adiponectin "receptor". At the genetic level, adiponectin, AdipoR2 and T-cadherin are most closely linked. Studies have shown that after adiponectin treatment, intracellular signaling pathways are first and mainly achieved by AdipoR2 and T-cadherin. Among them, T-cadherin assists AdipoR2 in transmitting adiponectin signaling. T-cadherin, in addition to affecting the progression of breast cancer through the associated pathways involved in adiponectin, is also involved in cell adhesion, which promotes invasion and metastasis of tumor cells. The study found that hypermethylation of T-cadherin in breast cancer patients suggests that this change promotes the development of breast cancer.
Studies have shown that adipoin can inhibit cell growth via AdipoR1 and prevent the transformation of ductal carcinoma in situ (DCIS) into invasive breast cancer. The higher the AdipoR2 expression, the higher the risk of lymphatic and vascular metastasis in the patient. AdipoR2 achieves this by increasing cyclooxygenase 2 (COX-2) and activating the peroxisome proliferator activated receptor-γ (PPAR-γ) signaling pathway. The result of both is to attenuate the activation of T cells by dendritic cells, leading to immune escape of tumor cells.
AdipoR2 and Hepatitis
Studies have shown that in hepatocytes and muscle cells, insulin can reduce AdipoR2 expression via a phosphatidylinositol 3-kinase/cross-head (PI3K/FOXO)-dependent pathway. Therefore, when insulin resistance occurs, excessive insulin can cause a decrease in AdipoR2, which leads to a decrease in its mediated adiponectin action. The study found that with the development of nonalcoholic steatohepatitis (NASH), the expression of AdipoR2 in the liver is also gradually decreasing as with adiponectin. In the further development of liver fibrosis, the expression of AdipoR2 is also gradually decreasing, which may be related to the progressive increase in systemic and/or local insulin resistance during the onset of NASH.
Studies have shown that adiponectin is mainly located in the endothelial cells of the human portal vein and sinus, while AdipoR2 is mainly located in the cytoplasm of hepatocytes. The location of adiponectin and AdipoR2 is different, suggesting that a paracrine pathway may be present to function. When NASH occurs, this pathway may be destroyed, blocking the role of adiponectin and leading to the development of NASH. The location of the distribution may also be inferred that AdipoR2 may also have direct liver protection when mediating the action of adiponectin.