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    • Based on currently available knowledge autophagy supports ad

    2024-03-15

    Based on currently available knowledge, autophagy supports adipocytes development and differentiation. In animals with specific skeletal muscle Sulbactam of Atg7, reduced adipogenesis was shown. In rodents, autophagy was decreased in adipose tissue of animals fed with high-fat diet (HFD). In contrast, obese and diabetic humans showed elevated autophagy in adipocyte and non-adipocytes tissues. However, until recently, it is not clear whether activation of autophagy in adipose tissue during obesity is beneficial or deleterious [9]. In type 2 diabetes (T2D), insulin resistance resulted in a decrease in glucose transporter 4 (GLUT4) (integral membrane protein) in adipose and muscle tissue. Many evidences support the importance of GLUT4 as a responder for insulin signalling and its association with T2D. Furthermore, GLUT4 was found to be diminished in the adipocytes of T2D patients. The importance of GLUT4 in maintaining insulin sensitivity was also demonstrated in transgenic mice. GLUT4 gene ablation or heterozygous knockout specifically in adipocyte, results in whole-body insulin resistance and eventually diabetes [10]. Therefore, targeting GLUT4 via the regulation of autophagy process could potentially control its translocation and recycling to overcome insulin resistance in T2D. In line with these evidences, this review focuses on autophagy as a carrier for GLUT4. It is known that insulin mediates translocation of GLUT4 to cell membrane to enhance the uptake of glucose in adipose and muscle cells. Additionally, insulin controls endocytosis of GLUT4 and its trafficking through endosomal compartments and the trans-Golgi network (TGN). However, many studies suggest that not only insulin controls this translocation. In basal conditions, GLUT4 accumulates in GLUT4 storage vesicles (GSV) and other intracellular, endosomal compartments and TGN, which appear to be similar to intracellular distribution of autophagy [11]. This review highlights the crosslink between intracellular localisation and trafficking of autophagy with Glut4 recycling and translocation (Fig.1), as well as the involvement of PI3K and AMPK as a control for both autophagy and GLUT4.
    The role of PI3K and AMPK in autophagy and GLUT4
    The mechanism of autophagy and GLUT4 endocytosis
    Early endosome (EE), recycle endosome (RE) and Golgi involved in autophagy and GLUT4 recycle Budding of clathrin-coated vesicles (CCV) from the plasma membrane is considered as a precursor for early endosomes formation (EEA1: early endosome marker). In autophagy, after budding, ATG16L1 and ATG9 follow different itinerary, while mATG9 traffics through EEA1-positive early endosome before reaching recycle endosome, ATG16L1 traffics immediately to recycle endosome. mATG9 and ATG16L1 fusion occur in RE, and is mediated by vesicle-associated membrane protein 3 (VAMP3). Knockdown of VAMP3 leads to decreased autophagosome formation [29]. A study indicated that RE shares in the biogenesis of autophagosome. In this study Atg9 and ULK1 are found on transferrin (Tfn) receptor (TfnR)-positive REs. However, during starvation, the colocalization of Atg9 with TfnR decreased, while ULK1 stays binding to TfnR. Furthermore, endogenous TfnR was detected to be co-localize at the edge of autophagy structure (GFP-LC3–positive structures) [36]. Taken together, these results indicate that the RE membrane contributed in autophagosome biogenesis. Studies indicated that GLUT4 pool not only is involve in GSV compartment, but also endosomal (non-GSV) compartments, as half of the total cellular GLUT4 pool existed in endosomal compartments [37]. GLUT4 is also found to be located in early endosome compartment. In myoblast cells, surface GLUT4 myc labelled with anti-Myc antibodies revealed that GLUT4 was found to be localised on early endosome at 37 °C [38]. Previous study revealed that GLUT-4 is colocalized with transferrin receptor in endosomal system. Using Tf-HRP ablation technique to assess the percentage of GLUT-4 in recycling endosome leads to suppression of GLUT-4 by about 40% [39]. These data confirm that autophagy and GLUT4 are found in RE.