br Hyperadiponectinemia in disease conditions
Hyperadiponectinemia in disease conditions Other evidence indicates that hyperadiponectinemia does not necessarily always imply a healthy outcome. Indeed, a recent study suggested that hyperadiponectinemia occurs in various diseases. Given that the risk for AD and vascular dementia is increased in metabolic dysfunction, plasma levels of APN might be reduced in AD. However, several studies have described increased levels of plasma APN in AD (Fig. 1) 8, 24. In particular, the Framingham Heart Study in a prospective cohort (N =840, mean age 72 years) showed that elevated APN was a predictor for all-cause dementia and AD . Furthermore, the Mayo Clinic Study of Aging in a large prospective cohort (N=535, age ≥70 years without dementia) showed that levels of plasma APN were elevated, accompanied by amyloid deposits and cognitive deficits . Studies of autopsied brains from patients with AD were consistent with these reports, because it was found that expression of APN was upregulated and associated with accumulation in neurofibrillary tangles in the AD secretin receptor (Fig. 2a) . Collectively, these results suggest that APN is a risk factor for AD. Notably, hyperadiponectinemia has similarly, but inconsistently, been described for patients with PD. In support of this possibility, it was found that APN accumulates in Lewy bodies of brains from patients with α-synucleinopathies, such as PD and dementia with Lewy bodies (DLB) (Fig. 2c) . Similarly, circulating APN levels are increased in proportion to the disease severity of CHF and might be centrally involved in CHF-associated metabolic failure and muscle wasting . Likewise, end-stage CKD, such as polycystic kidney and renal cell carcinoma, is characterized by increased cardiovascular risk associated with hyperadiponectinemia. Therefore, common mechanisms might underlie hyperadiponectinemia in CHF and CKD because cardiovascular complications remain the main cause of mortality in the CKD population . In addition, chronic obstructive pulmonary disease (COPD) is characterized by cachexia and increased mortality because of respiratory failure, which is associated with elevated levels of circulating APN . Hyperadiponectinemia might also associate with chronic autoimmune diseases, including rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) . In addition, hyperadiponectinemia has been implicated in a variety of diseases, including type I diabetes mellitus (T1DM), cystic fibrosis, anorexia nervosa, and hepatocellular carcinoma 31, 32, 33.
Potential mechanism of hyperadiponectinemia One could predict that multiple mechanisms might contribute to hyperadiponectinemia. First, plasma APN might be upregulated because of decreased expression and/or decreased activity of APN receptor signaling; namely, APN resistance. Similar to insulin and leptin resistances, APN resistance might be caused by various mechanisms, including dysregulation of signal transduction, endoplasmic reticulum (ER) stress, and inflammation, and reduced expression of receptors AdipoR1 and -R2 . Second, upregulation of plasma APN might reflect compensatory feedback in response to reduced activity of insulin/IGF-1 receptor signaling pathways, given that the network of these pathways is crucial in various biological systems, including the nervous and cardiovascular systems . Third, based on the previous observation that APN accumulated in cytoplasmic inclusion bodies, including neurofibrillary tangles  and Lewy bodies , it is probable that hyperadiponectinemia is partially attributable to impairment of degradation systems, such as ubiquitin proteasomes and autophagy. Fourth, it is possible that some genetic factors, including single nucleotide polymorphisms, might contribute to the high expression of APN. Finally, APN might be ectopically produced. In support of this notion, production of APN was shown in extra-adipose tissue, such as osteoblast and vascular smooth muscle cells 34, 35. Thus, further studies are warranted to address this critical issue. In particular, APN receptor signaling has not been examined in terms of pathologies such as cardiovascular dysfunction and neurodegeneration.