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  • br A novel therapeutic strategy based on the

    2024-04-12


    A novel therapeutic strategy based on the APN and obesity paradoxes As shown above, the relationship of the serum APN concentration with health and disease states shows an inverted-U correlation, suggesting that moderate concentrations of serum APN are beneficial (Fig. 3). Given that both hypo- and hyperadiponectinemia might promote chronic disease states, both should be targeted therapeutically. Given that loss of function of APN might associate with metabolic syndrome, stimulating the APN ESI-09 using an agonist could be effective for disease prevention (Fig. 3). Indeed, a small-molecule APN receptor agonist, adipoRon, has been shown to be beneficial in animal models of T2DM and obesity [53]. By contrast, hyperadiponectinemia might be a risk factor of AD and other chronic diseases, in which APN gain of function could be mitigated by suppression of APN receptor signaling (Fig. 3). Based on a previous report showing that serum APN was increased in both AD and mild cognitive impairment, a prodromal stage of AD [54], it is assumed that APN receptor antagonists might be initiated from the early stage of the disease. Collectively, the differential use of APN receptor agonists and antagonists depending on the types of disease might be important. Notably, there are few reports on APN receptor antagonists compared with the extensive studies on agonists. However, recent advances in computer modeling software (e.g., docking methods) should allow easier identification of APN receptor antagonists for clinical application 55, 56. In this context, molecular docking methods have recently been applied for G-protein-coupled receptors (GPCRs) [57]. Given that adipo-R1 and -R2 are GPCRs [58], antagonists of APN receptors should be identifiable without difficulty. Given that serum APN levels are expected to shift from hypo- to hyperadiponectinemia during disease progression, serum APN might also be a promising disease biomarker. Many studies are underway to identify and use biomarkers for diagnosis and assessment of therapeutic effects in AD. These include a variety of neuroimaging candidate markers, such as hippocampus and entorhinal cortex volumes, basal forebrain nuclei, cortical thickness, deformation-based and voxel-based morphometry, and structural and effective connectivity [59]. Cerebrospinal fluid (CSF) might also be promising as a source of biomarkers, such as Aβ42, BACE1, and total-/phospho-tau [59]. However, there are still no good candidates identified in blood and, thus, APN might be an attractive target in this respect. Conceivably, therapeutic compounds based on the APN paradox might not only be effective for aging-associated chronic disorders, but also for other conditions, especially for cancers. For instance, it is generally believed that metabolic syndrome is a risk factor for obesity-liked cancers [60]. By contrast, it is firmly established that hormonal alterations, such as hyperinsulinism and elevated insulin-like growth factor levels, are associated with breast cancer [60]. Furthermore, increased APN might contribute to hepatocellular carcinoma at least in part through its activation of AKT signaling [33]. Given that APN sensitizes the insulin receptor signaling pathway associated with activation of AKT signaling, it is intriguing to consider that a similar dual strategy of APN receptor stimulation and inhibition can be applied to malignancies. However, for balance, our proposed therapeutic strategy might also have several disadvantages. Most notably, any form of APN antagonist therapy must ‘trade off’ any derived benefits against the protective effects of APN on other cell types. Thus, APN signaling blockade might instead promote metabolic dysfunction and cancer. Second, current preclinical disease paradigms might be incomplete because they have not reproduced the APN paradox. Lastly, the simplest of APN biological interactions in AD are still poorly understood, especially the differential roles of APN oligomers and of the heterogeneous APN receptors, Adipo-R1 and -R2, in addition to T-cadherin on the cell membrane 58, 61.