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  • AdipoRon acts on the anti diabetic effects


    AdipoRon acts on the anti-diabetic effects of adiponectin, exhibiting its effect through the activation of AMPK and PPARα pathways via AdipoR1 and AdipoR2, respectively [23]. AdipoR activation is a promising treatment for diabetes, nonalcoholic fatty liver disease, and cardiovascular disease, demonstrating anti-inflammatory action in macrophages and cytoprotective effects on pancreatic β-cells [51]. AdipoRon appears to be weight neutral and actually prolongs the life span in diabetic mice [23]. In the current study, AdipoRon-treated db/db mice exhibited improvements in albuminuria and renal pathologic phenotypes. They were associated with enhanced expression of AdipoR1 and AdipoR2 in the kidney. Furthermore, activated AdipoR1 and AdipoR2 induced increased expression of AMPK phosphorylation and PPARα, which resulted in suppressed lipogenic SREBP-1c and ACC and ultimately improved lipotoxicity in the kidney.
    Author Contributions
    Introduction An APPL (adaptor protein containing pleckstrin homology domain, phosphotyrosine binding domain and leucine zipper motif) was first identified as an AKT2-interacting protein using yeast two-hybrid screening in 1999 and was named after its unique structure [1]. As one of the APPL isoforms, APPL1 was first called DIP-13α (DCC-interacting protein 13α) due to its ability to interact with the tumor suppressor protein DCC (deleted in colorectal cancer), playing an important role in DCC-induced apoptosis [2]. DIP-13β, an isoform of DIP-13α, was accordingly named as APPL2 [3]. APPL1 is widely expressed in many cells and tissues. High APPL1 content was identified in differentiated C2C12 and L6 myoblast cells and in INS1 insulinoma cells [4]. Moderate expression levels of APPL1 were observed in HEK293 cells, hepatocytes and non-differentiated C2C12 myoblasts [4] as well as HeLa cells [4], MiaPaCa2 cells and Capan-1 pancreatic carcinoma cells [5]. In rodent tissues, high expression levels of APPL1 were reported in the mouse brain, skeletal muscle, fat, liver, heart, and spleen and, to a lesser extent, the pancreas and kidney [4]. In humans, high expression levels of APPL1 were detected in fat, the liver, muscle, brain, and, in particular, the pancreas [6], [7]. Similarly, moderate expression levels of APPL2 were observed in fat and the CC-223 [8], and high expression levels were observed in the kidney and pancreas tissues [8]. As an adaptor protein, APPL1 is essential for insulin signaling pathways and plays a vital role in the insulin-sensitizing effect of adiponectin [4]. APPL1 also regulates many biological activities and processes, including cell proliferation, chromatin remodeling [3], endosomal trafficking [9], cell survival [10], cell metabolism and apoptosis [2]. It interacts and synergizes with Dvl2 to regulate activating protein1 (AP-1)-dependent transcription in non-canonical Wnt signaling [11]. Apart from these signaling pathways, APPL1 also plays a role in animal development and acts on the reproductive system [12]. Dys-regulation of APPL1 is involved in the pathogenesis of some diseases, including familial diabetes, Down syndrome and Alzheimer's disease. Moreover, APPL1 may be involved in diabetic complications as patients with atherosclerotic plaques of type 2 diabetes (T2D) had lower APPL1 levels compared to non-diabetic patients [13]. Hence, it is important to explore the roles and the regulation of APPL1 for the development of new strategies against metabolic syndrome, T2D and related cardiovascular disease, Down syndrome and Alzheimer's disease. In this review, we summarize recent discoveries on the functions of APPLs, particularly APPL1, in adiponectin, insulin, endosomal trafficking and other signaling pathways.
    Structure of APPLs
    APPL1 and APPL2: friends or foes?
    APPLs in adiponectin signaling pathways As one of the most abundant adipokines secreted from adipocytes, adiponectin has numerous protective effects on metabolism. It is well documented that adiponectin possesses anti-obesity, anti-inflammatory, anti-proliferation and insulin-sensitizing effects [51], [52], which are mainly mediated by its seven transmembrane receptors, AdipoR1 and AdipoR2 [53], and by activating AMP-activated protein kinase (AMPK), MAPK, or peroxisome proliferator-activated receptor-α (PPARα) to stimulate or suppress the downstream signaling pathway cascades [54]. Although both are important for adiponectin action, AdipoR1 and AdipoR2 express and function differently. AdipoR1 is ubiquitously and highly expressed in the skeletal muscle, whereas AdipoR2 is expressed predominantly in the liver [53]. AdipoR1 is involved in activation of AMPK in skeletal muscle, while AdipoR2 is mainly concerned with the regulation and activation of PPARα in the liver, although both of them promote insulin sensitivity [55].