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    • A number of studies suggest

    2023-01-16

    A number of studies suggest that adiponectin promotes osteoblast differentiation and bone formation by directly targeting GSK-3β and β-Catenin signaling [64], [65], favoring bone marrow mesenchymal stem cell (BMSC) differentiation toward the osteoblastic lineage [66], [67], decreasing sympathetic tone [67], [68], or inducing the production of bone morphogenetic protein 2 (BMP2) in osteoblasts [69]. APPL1 is also involved in adiponectin-induced osteogenic differentiation. In primary cultured h-JBMMSC (human jaw bone marrow mesenchymal stem cells), globular adiponectin promotes osteogenic differentiation by inducing greater expression of osteoblast- related genes such as collagen type I, osteopontin (OPN), bone sialoprotein (BSP), and osteocalcin (OCN), the effects of which are blocked by deletion of APPL1 [70]. Moreover, in the presence of APPL1/tryptophan hydroxylase 2 (TPH2), adiponectin decreases sympathetic tone, increases trabecular bone mass, and promotes osteoblastic commitment of BMSC [67]. Overall, the above findings demonstrate that APPL1 acts as an essential positive regulator of adiponectin-induced osteogenic formation. Although APPL2 interacts with both AdipoR1 and AdipoR2, it acts as a negative regulator of adiponectin signaling by antagonizing the action of APPL1 [8]. Over-expression of APPL2 inhibits the interaction between APPL1 and AdipoR1, leading to the down-regulation of adiponectin signaling. In addition, suppression of APPL2 expression by RNAi significantly enhances adiponectin-stimulated glucose uptake and fatty Azaserine mg oxidation [8]. Thus, it is possible that the APPL isoforms act as an integrated Yin-Yang regulator of adiponectin signaling in muscle cells [8]. However, it remains unclear whether this mode of action by APPLs exists in other cells.
    APPLs in insulin signaling pathways It is well established that adiponectin is a potent insulin-sensitizing factor. As an essential mediator of adiponectin signaling, APPL1 also plays an important role in insulin signaling pathways. APPL1 enhances insulin sensitivity by promoting the interaction between IR and insulin receptor substrate proteins 1 and 2 (IRS1/2) [29]. APPL1 forms a complex with IRS1/2 under basal conditions that can be recruited to the IR in response to insulin or adiponectin stimulation. The interaction between APPL1 and IR depends on insulin- or adiponectin-stimulated APPL1 phosphorylation, which is greatly impaired in the insulin target tissues in obesity [29]. Deletion of APPL1 in mice leads to systemic insulin resistance and a substantial decrease in insulin-stimulated IRS1/2 tyrosine phosphorylation, indicating that APPL1 sensitizes insulin signaling by acting at a downstream site of the IR [29]. AKT is also a downstream site of the IR and is a key factor in the insulin signaling pathway. Insulin-stimulated AKT kinase activity is dependent on its phosphorylation at Thr308 by PDK1 (phosphoinositide-dependent kinase 1) and at Ser473 by mTOR (mammalian target of rapamycin) [24]. APPL1 improves insulin sensitivity by activating AKT phosphorylation. In C2C12 myocytes, overexpression of APPL1 enhances insulin-stimulated AKT phosphorylation, whereas knockdown of APPL1 or overexpression of APPL1 with a PTB domain mutation significantly reduces the AKT phosphorylation and action of insulin [4]. Consistently, in 3T3-L1 adipocytes, suppression of APPL1 attenuates insulin-stimulated AKT phosphorylation, GLUT4 translocation, and glucose uptake [24]. In hepatocytes, the insulin-induced activation of AKT and the suppression of gluconeogenesis are enhanced by overexpression of APPL1 in comparison to the attenuation caused by APPL1 knockdown [71]. Specifically, APPL1 interacts with AKT and blocks the association of AKT with its endogenous inhibitor tribble 3 (TRB3) through direct competition, thereby promoting AKT translocation to the plasma membrane and endosomes for subsequent activation [71]. In addition, hepatic overexpression of APPL1 leads to a reduction in hyperglycemia and insulin resistance in obese mice as a consequence of the impaired interaction between AKT and TRB3 [71], suggesting that counteracting the inhibitory action of TRB3 on AKT is an important mechanism by which APPL1 enhances insulin-stimulated suppression of hepatic glucose production. Consistently, chronic exercise increases hepatic APPL1 expression and the interaction between APPL1 and AKT, reducing both TRB3 expression and the association of TRB3 and AKT, thereby contributing to the improvement of insulin sensitivity in the liver [72].