br Hypoadiponectinemia in metabolic syndrome
Hypoadiponectinemia in metabolic syndrome APN belongs structurally to the complement 1q family and is found at high concentrations (>0.01% of total protein) in the serum of healthy individuals . Given the abundance of APN in plasma, it is assumed that alterations in plasma levels of APN might affect various aspects of health and disease. Indeed, hypoadiponectinemia is observed in metabolic disorders, such as T2DM, obesity, dyslipidemia, hypertension, and atherosclerosis, and is inversely correlated with the severity of the disease (Fig. 1) . In addition, hypoadiponectinemia is associated with risks of obesity-linked diseases, including osteoporosis, depression, hyperuricemia, sleep apnea, and visceral diseases, such as nonalcoholic fatty liver disease, gastritis/gastroesophageal reflux disease, inflammatory bowel disease, and pancreatitis (Fig. 1) . Hypoadiponectinemia has also been found in endometrial cancer, postmenopausal breast cancer, and leukemia, colon, gastric, and prostate cancers (Fig. 1), and APN might have antimetabolic, antiangiogenesis, and antitumor activities in cancers 6, 11. Moreover, in osteoporosis, which is common in postmenopausal women, hypoadiponectinemia might contribute to the activation of osteoclasts and suppression of osteoblasts and osteocytes 12, 13. Finally, psychiatric diseases, such as depression and post-traumatic stress disorder, are also associated with hypoadiponectinemia 14, 15. Obesity is linked to these diseases, but not to hypoadiponectinemia, which suggests that obesity is not be the cause of hypoadiponectinemia in patients with psychiatric diseases. Given that APN signaling is required for the activity of the insulin receptor signaling pathway , it naturally follows that loss of APN function might contribute to insulin resistance, leading to metabolic disorders. Hypoadiponectinemia is likely to be the result of the decreased production and secretion of APN in adipose tissue, and epibatidine of APN mRNA in adipocytes might be affected by polymorphisms in the gene encoding APN  and by cadherin 13 genotypes . Alternatively, expression of APN in adipocytes might be suppressed by environmental factors and lifestyle patterns, such as a high-fat diet and lack of exercise . Expression of APN in adipocytes might also be decreased under hypoxic conditions induced by obesity . Hypoxia might also activate macrophages to produce inflammatory cytokines, such as TNFα and IL-6, which could inhibit the local production of APN in adipose tissue . Moreover, there are marked gender differences in the distribution of APN , with women having higher circulating levels of high-molecular-weight isoforms, because of the effect of steroid hormones .
Hyperadiponectinemia in a healthy state Given that APN can ameliorate metabolic syndrome and related disorders, increased levels of plasma APN might be beneficial for health and longevity. Consistent with this view, hyperadiponectinemia has been found in disease prevention during aging . Specifically, centenarians, a model of healthy aging , have few cardiovascular risk factors and a low prevalence of diabetes mellitus, carotid atherosclerotic plaques, and dementia, which could be associated with high levels of circulating APN (Fig. 1) . Notably, APN activated PGC-1α and mitochondria by Ca2+ and AMPK/SIRT1, indicating that APN might be involved in the regulation of mitochondria-related longevity . Thus, it is likely that APN might be beneficial for aging-related diseases. Curiously, it has also been shown that paradoxical hyperadiponectinemia is associated with a metabolically healthy obese phenotype in African-Americans with high high-density lipoprotein cholesterol, and low insulin, triglyceride, and glucose (Fig. 1) . Furthermore, a recent study found hyperadiponectinemia during therapy for pediatric Crohn’s disease , indicating that hyperadiponectinemia might cure inflammation in Crohn’s disease (Fig. 1). Taken together, these findings suggest, but do not prove, that hyperadiponectinemia could counteract obesity and contribute to health, leading to a prolonged life span.