The disease stimulatory effects of hyperadiponectinemia

The disease-stimulatory effects of hyperadiponectinemia in patients contradict a previous view based on studies of preclinical models showing that APN might be beneficial for AD [8]. Indeed, despite the action of APN as a risk factor in patients with AD, APN is protective against oxidative stress-induced cytotoxicity in Aβ neurotoxicity associated with the Swedish mutation of amyloid precursor protein (APP) (Fig. 2b) [34]. Furthermore, osmotin, a plant homolog of APN, attenuates Aβ42-induced neurotoxicity and tau hyperphosphorylation in the mouse hippocampus [37], and APN-knockout mice develop an AD-like pathology during aging, suggesting that loss of APN function leads to AD [35]. Thus, the widening gap between findings in preclinical models of APN and those from clinical observations in patients with neurodegenerative diseases result in the so-called ‘APN paradox’ [39]. Similarly, APN was shown to ameliorate neuropathological features, such as protein aggregation and impaired motor activity, in a mouse model of α-synucleinopathies (Fig. 2d) [27]. The relationship between APN and AD is clearly not fully established, and further studies are needed to determine whether this might also be the case for PD. The APN paradox has already been recognized in various chronic wasting disorders. Although APN is protective for cardiomyocyte and vascular cell function [40], and is antiatherogenic in animal models [41], hyperadiponectinemia is correlated with the severity of circulatory diseases, such as CHF and CKD 28, 29. Furthermore, the APN paradox might also be involved in COPD. Despite the protective effect of APN on bronchial epithelial src inhibitors [42], hyperadiponectinemia is associated with COPD [30]. Further studies are warranted to determine whether the APN paradox is involved in other diseases with hyperadiponectinemia. The mechanism by which high levels of APN impair the normal functions of the cells is unclear. Although many studies support the beneficial effects of APN on metabolic syndrome, some have demonstrated proinflammatory and proapoptotic actions of APN 31, 43. Therefore, we speculate that similar mechanisms might be involved in the impairment of cell function by APN, underlying the APN paradox. Indeed, the discrepancy between findings from preclinical models and those from clinical observations is central to various aspects of disease biology, including that of neurodegenerative disease [44]. To the best of our knowledge, the APN paradox has been observed in patients, but not in animal models. Hypothetically, the late stages of various chronic disorders might behave in different ways in patients and experimental animals, especially given the extended postreproductive aging period in humans compared with animals [45]. In addition, a mutually nonexclusive possibility is that late-stage chronic diseases become prolonged in humans by virtue of sustained medical care in the absence of radical treatments to cure such conditions. Thus, late-stage chronic disease might exhibit a distinct human-specific pathology.
The obesity paradox and some chronic disease An ‘obesity paradox’ or ‘reverse epidemiology’ of cardiovascular risk has also been observed in cancer, AIDS, and RA, in addition to the disorders with an APN paradox (CHF, CKD, and COPD), in which morbidity and mortality in the end stage are mitigated in obese patients 46, 47. It predictably follows that AD might also be associated with the obesity paradox. In support, a retrospective cohort study from the United Kingdom Clinical Practice Research Datalink recently showed that obesity exerts a protective effect on dementia [48]. Interestingly, the obesity paradox has also been observed in metabolic disorders, such as T2DM, hypertension, and CVD 49, 50, 51. Given that serum levels of APN are decreased in obesity, it is predicted that the toxicity of APN might also be reduced. Thus, the APN paradox and the obesity paradox conceptually overlap to a significant degree. Thus, because the obesity paradox is observed in many disease types, the overlap between these two paradoxical phenomena could be a common feature of advanced stages of chronic disorders.