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Depression is the most devastating mental disorder and one of the leading contributors to the global medical burden. Current antidepressant prescriptions present drawbacks, including treatment resistance, delayed onset of treatment response, and side effects. The rapid and long-lasting antidepressant effect of ketamine has brought hope to treatment-resistant major depressive disorder patients. However, ketamine has undesirable addictive properties and is a drug of abuse. There is an urgent need, therefore, to develop novel pharmacological interventions that could be as effective as ketamine, but without its side effects. Adiponectin, a pleiotropic adipocyte-secreted hormone, has insulin-sensitizing and neurotrophic properties. It can cross the blood-brain barrier and target multiple brain regions where the adiponectin receptors are detected. Emerging evidence has suggested that adiponectin and the adiponectin receptor agonist, AdipoRon, could promote adult neurogenesis, dendritic and spine remodeling, and synaptic plasticity in the hippocampus, resulting in antidepressant effects in adult mice. By summarizing the most recent clinical and animal studies, this review provides a timely insight on how modulating the adiponergic system in the hippocampus could be a potential therapeutic target for an effective and fast-acting antidepressant response.

Purpose The purpose of the study was to investigate changes in adiponectin system expression in granulosa cells (GCs) and high molecular weight adiponectin levels in serum and follicular fluid (FF) of 40 women with polycystic ovary syndrome (PCOS) compared to those in 40 women with normal ovary function. Methods Adiponectin (Adipo), adiponectin receptor 1 (AdipoR1), and adiponectin receptor 2 (AdipoR2) messenger RNA (mRNA) expression levels were measured using quantitative real-time polymerase chain reaction (qRT-PCR). High molecular weight (HMW) adiponectin protein concentration was evaluated by ELISA method. Data were analyzed using Student’s t test and one-way ANOVA in SPSS 21 software. At oocyte retrieval, FF was aspirated and GCs were obtained from a pooled collection of FF per each patient. Results PCR results showed expression of adiponectin, AdipoR1, AdipoR2, follicle-stimulating hormone receptor (FSHR), and luteinizing hormone receptor (LHR) in GCs. After controlling body mass index (BMI) values, qRT-PCR demonstrated a decreased expression of adiponectin system in GCs of PCOS patients compared to those in controls ( p  = 0.001). There was a strong positive correlation among AdipoR1 and AdipoR2 expression and also among FSH and LH receptor expression. (Both r  = 0.8, p  = 0.001). There were low levels of high molecular weight adiponectin in the serum of PCOS patients with controlled ovarian hyperstimulation (30.19 ± 4.3 ng/ml) compared to the controls (48.47 ± 5.9 ng/ml) and in the FF of PCOS patients with controlled ovarian hyperstimulation (7.86 ± 1.44 ng/ml) compared to the controls (14.22 ± 2.01 ng/ml; p  = 0.02). Conclusions Lower expression of adiponectin and its receptors in GCs might be an important manifestation in gonadotropin-stimulated PCOS patients which could influence the physiologic adiponectin roles such as interaction with insulin and LH in induction of GC gene expression.

The present study aimed to investigate the serum levels of adiponectin (APN) and adiponectin receptor 1 (AdipoR1) in patients with type 2 diabetes mellitus (T2DM) combined with macrovascular complications (MVC), as well as their correlation with clinical parameters. A total of 60 T2DM patients were divided into 2 groups according to the presence of MVC: T2DM + MVC group (n=30) and T2DM group (n=30). Additionally, 30 healthy people were selected as control group (NC group). Clinical data and biological parameters were detected and recorded. T test was performed to compare the differences between two groups, and the results were corrected using Bonferroni method. Meanwhile, the correlation analysis and multiple stepwise regression analysis were used to analyze the association of APN and AdipoR1 with clinical factors. The levels of APN and AdipoR1 were significantly decreased in T2DM group and T2DM + MVC group compared with NC group, with the lowest value in T2DM + MVC group (all P<0.01). Serum APN levels were positively correlated with FINS and TG (r = 0.412, 0.316, respectively; both P<0.05), and negatively correlated with SBP, DBP and LDL-C (r = -0.292, -0.383, -0.334, respectively; all P<0.05). Serum levels of AdipoR1 were positively correlated with APN (r = 0.726, P<0.01), and negatively correlated with BMI, SBP, DBP, FBG, TC and LDL-C (r = -0.440, -0.446, -0.374, -0.444, -0.344, -0.709, respectively; all P<0.01). Serum levels of APN and AdipoR1 are significantly lower in T2DM group and T2DM + MVC group, showing lowest value in T2DM + MVC group. APN and AdipoR1 levels may influence glucose and lipid metabolism in T2DM patients.

Background Low levels of serum adiponectin have been linked to central obesity, insulin resistance, metabolic syndrome, and type 2 diabetes. Variants in ADIPOQ , the gene encoding adiponectin, have been shown to influence serum adiponectin concentration, and along with variants in the adiponectin receptors ( ADIPOR1 and ADIPOR2 ) have been implicated in metabolic syndrome and type 2 diabetes. This study aimed to comprehensively investigate the association of common variants in ADIPOQ, ADIPOR1 and ADIPOR2 with serum adiponectin and insulin resistance syndromes in a large cohort of European-Australian individuals. Methods Sixty-four tagging single nucleotide polymorphisms in ADIPOQ , ADIPOR1 and ADIPOR2 were genotyped in two general population cohorts consisting of 2,355 subjects, and one cohort of 967 subjects with type 2 diabetes. The association of tagSNPs with outcomes were evaluated using linear or logistic modelling. Meta-analysis of the three cohorts was performed by random-effects modelling. Results Meta-analysis revealed nine genotyped tagSNPs in ADIPOQ significantly associated with serum adiponectin across all cohorts after adjustment for age, gender and BMI, including rs10937273, rs12637534, rs1648707, rs16861209, rs822395, rs17366568, rs3774261, rs6444175 and rs17373414. The results of haplotype-based analyses were also consistent. Overall, the variants in the ADIPOQ gene explained <5% of the variance in serum adiponectin concentration. None of the ADIPOR1/R2 tagSNPs were associated with serum adiponectin. There was no association between any of the genetic variants and insulin resistance or metabolic syndrome. A multi-SNP genotypic risk score for ADIPOQ alleles revealed an association with 3 independent SNPs, rs12637534, rs16861209, rs17366568 and type 2 diabetes after adjusting for adiponectin levels (OR=0.86, 95% CI=(0.75, 0.99), P=0.0134). Conclusions Genetic variation in ADIPOQ , but not its receptors, was associated with altered serum adiponectin. However, genetic variation in ADIPOQ and its receptors does not appear to contribute to the risk of insulin resistance or metabolic syndrome but did for type 2 diabetes in a European-Australian population.

A role of adiponectin in tumorigenesis has recently been appreciated. Although plasma adiponectin levels in subjects with prostate cancer have been found to be significantly lower than in subjects with benign prostatic hyperplasia or in normal healthy controls, the underlying molecular mechanisms remain unknown. Here, we not only detected significant decreases in plasma adiponectin levels in prostate cancer patients, but also showed significant decreases in adiponectin receptor I (AdipoR1) levels in the resected prostate cancer specimen. Prostate cancer cell lines examined in the current study had all lower levels of adiponectin and AdipoR1, compared to normal healthy prostate tissue. Moreover, overexpression of adiponectin in prostate cancer cells decreased production of vascular endothelial growth factor A (VEGF-A), while adiponectin depletion increased VEGF-A. Furthermore, adiponectin seemed to activate AMPK/TSC2 to inhibit mTor-mediated activation of VEGF-A. Taken together, our data suggest that adiponectin may play an essential role in suppressing growth of prostate cancer cells through inhibition of VEGF-A-mediated cancer neovascularization.

The aim of the study was to find out whether peripheral blood leukocyte adiponectin receptors 1 and 2 (AdipoR1, AdipoR2) protein expression patterns (flow cytometry) differ between the primary hypertension children (n=57) and healthy controls (n=19) and if their expression levels are related to selected clinical parameters. The group of 26 patients [AdipoR(−)] showed lower and the group of 31 patients [AdipoR(+)] showed higher AdipoRs protein expression than the control and each other (P<0.01 for neutrophils, P<0.05 for monocytes). The AdipoR(+) leukocytes expressed higher AdipoR1 mRNA levels (RT-PCR) than AdipoR(−) ones and controls (P=0.022 and P=0.007, resp.). Despite greater BMI, the AdipoR(−) patients had unchanged serum adiponectin levels. In contrast, AdipoR(+) patients had lower serum adiponectin concentrations than the AdipoR(−) ones and controls (P<0.001). The AdipoR(+) patients had higher blood pressure (P=0.042) and greater carotid intima-media thickness (P=0.017) than the AdipoR(−) ones. The stage of hypertension was associated with increased neutrophil but not monocyte AdipoR1 density (AdipoR1 MFI) (P<0.05). Severe ambulatory hypertension was presented more often in AdipoR(+) patients than in AdipoR(−) ones (51.6% versus 26.9%, resp.; P<0.01). In conclusion, neutrophil AdipoRs upregulation was associated with early stages of vascular injury, hypertension severity, and low serum levels of adiponectin.

Adiponectin (ADPN) is a plasma protein secreted by adipose tissue showing pleiotropic effects with anti-diabetic, anti-atherogenic, and anti-inflammatory properties. Initially, it was thought that the main role was only the metabolism control. Later, ADPN receptors were also found in the central nervous system (CNS). In fact, the receptors AdipoR1 and AdipoR2 are expressed in various areas of the brain, including the hypothalamus, hippocampus, and cortex. While AdipoR1 regulates insulin sensitivity through the activation of the AMP-activated protein kinase (AMPK) pathway, AdipoR2 stimulates the neural plasticity through the activation of the peroxisome proliferator-activated receptor alpha (PPARα) pathway that inhibits inflammation and oxidative stress. Overall, based on its central and peripheral actions, ADPN appears to have neuroprotective effects by reducing inflammatory markers, such as C-reactive protein (PCR), interleukin 6 (IL6), and Tumor Necrosis Factor a (TNFa). Conversely, high levels of inflammatory cascade factors appear to inhibit the production of ADPN, suggesting bidirectional modulation. In addition, ADPN appears to have insulin-sensitizing action. It is known that a reduction in insulin signaling is associated with cognitive impairment. Based on this, it is of great interest to investigate the mechanism of restoration of the insulin signal in the brain as an action of ADPN, because it is useful for testing a possible pharmacological treatment for the improvement of cognitive decline. Anyway, if ADPN regulates neuronal functioning and cognitive performances by the glycemic metabolic system remains poorly explored. Moreover, although the mechanism is still unclear, women compared to men have a doubled risk of developing cognitive decline. Several studies have also supported that during the menopausal transition, the estrogen reduction can adversely affect the brain, in particular, verbal memory and verbal fluency. During the postmenopausal period, in obese and insulin-resistant individuals, ADPN serum levels are significantly reduced. Our recent study has evaluated the relationship between plasma ADPN levels and cognitive performances in menopausal women. Thus, the aim of this review is to summarize both the mechanisms and the effects of ADPN in the central nervous system and the relationship between plasma ADPN levels and cognitive performances, also in menopausal women.

The contribution of different biological pathways to the development of type 2 diabetes was quantified in a case-cohort design based on circulating blood biomarkers from participants aged 35-65 years in the EPIC-Potsdam Study. The analytic sample included 613 participants with incident diabetes and 1965 participants without diabetes. The proportion that each biomarker contributed to the risk of diabetes was quantified using effect decomposition method. Summarized risk of each biomarker was estimated by an index based on quintiles of gamma-glutamyltransferase (GGT), HDL-cholesterol, hs-CRP, and adiponectin. Cox proportional hazard regression was used to estimate relative risks adjusted for age, sex, body mass index, waist-circumference, education, sport activity, cycling, occupational activity, smoking, alcohol intake, and consumptions of red meat, coffee and whole grain bread. Adiponectin explained a total of 32.1% (CI = 16.8, 49.1%) of the risk related to index. For the other biomarkers the corresponding proportions were 23.5% (CI = 10.1, 37.8%) by HDL-cholesterol, 21.5% (CI = 11.5, 32.8%) by GGT, and 15.5% (CI = 4.44, 27.3%) by hs-CRP. The results support the hypothesis that the different biological pathways reflected by GGT, HDL-cholesterol, hs-CRP and adiponectin independent from each other contribute to the risk of type 2 diabetes. Of these pathways the highest contribution was observed for adiponectin which contributed one-third to the risk and that equal proportion was contributed by GGT and HDL-cholesterol, although the contribution of inflammation was lower.

Background Adiponectin has insulin-sensitizing and anti-atherosclerotic effects, partly mediated through its action on monocytes. We aimed to determine adiponectin levels and expression of its receptors (AdipoR1 and AdipoR2) in peripheral monocytes from overweight and obese patients with coronary artery disease (CAD). Methods Fifty-five overweight/obese patients, suspected for CAD, underwent coronary angiography: 31 were classified as CAD patients (stenosis ≥ 50% in at least one main vessel) and 24 as nonCAD. Quantitative RT-PCR and flow cytometry were used for determining mRNA and protein surface expression of adiponectin receptors in peripheral monocytes. A high sensitivity multiplex assay (xMAP technology) was used for the determination of plasma adiponectin and interleukin-10 (IL-10) secreted levels. Results Plasma adiponectin levels were decreased in CAD compared to nonCAD patients (10.9 ± 3.1 vs. 13.8 ± 5.8 μg/ml respectively, p = 0.033). In multivariable analysis, Matsuda index was the sole independent determinant of adiponectin levels. AdipoR1 and AdipoR2 protein levels were decreased in monocytes from CAD compared to nonCAD patients (59.5 ± 24.9 vs. 80 ± 46 and 70.7 ± 39 vs. 95.6 ± 47.8 Mean Fluorescence Intensity Arbitrary Units respectively, p < 0.05). No significant differences were observed concerning the mRNA levels of the adiponectin receptors between CAD and nonCAD patients. AdipoR2 protein levels were positively correlated with plasma adiponectin and Matsuda index (r = 0.36 and 0.31 respectively, p < 0.05 for both). Furthermore, basal as well as adiponectin-induced IL-10 release was reduced in monocyte-derived macrophages from CAD compared to nonCAD subjects. Conclusions Overweight patients with CAD compared to those without CAD, had decreased plasma adiponectin levels, as well as decreased surface expression of adiponectin receptors in peripheral monocytes. This fact together with the reduced adiponectin-induced IL-10 secretion from CAD macrophages could explain to a certain extent, an impaired atheroprotective action of adiponectin.

Background Recent evidence suggests that obesity is associated with hypo-adiponectinmia and chronic inflammation. Adiponectin regulates fat storage, energy expenditure, and inflammation. We propose that high fat diet induces steatohepatitis, reduces serum adiponectin, and liver adiponectin receptors. Methods A 4-week-old C57BL male mice were fed high fat diet ( n  = 8) or regular chow (control; n  = 6) for 7 weeks. Body weight, liver weight, and serum adiponectin were measured. Liver sections were stained with hematoxylin and eosin and oil red for fat content. Liver homogenates were used for protein (immunoblotting) and mRNA (reverse transcription PCR) of Toll-like receptor 4 (TLR4), tumor necrosis factor alpha (TNF-α), interleukin (IL)-6, sterol regulatory element-binding proteins (SREBP)-1c, and adiponectin receptors (AdipoR1/AdipoR2) in addition to nuclear phorsphorylated p65NF-κB. Gels were quantified using densitometry; t test was used, and p  < 0.05 was significant. Results High fat diet increased body (50%) and liver weight (33%), as well as hepatocyte fat content and ballooning. Mice fed high fat diet exhibited reduced serum adiponectin and liver AdipoR2. High fat diet increased hepatic levels of SREBP-1c, TLR4, TNF-α, and IL-6 protein and mRNA and increased activation of p65NF-κB. Conclusions Diet-induced liver steatosis is associated with increased lipogensis, upregulation of pro-inflammatory cytokines, and transcription factors as well as downregulation of AdipoR2. Reduction in serum adiponectin suggests that adiponectin signaling may be the crosslink between high fat diet, hepatic inflammation, and nonalcoholic fatty liver disease.