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Adiponectin, a crucial protein hormone originating from adipose tissue, regulates key metabolic processes, including lipid metabolism, mitochondrial activity, and insulin sensitivity. These pleiotropic roles of adiponectin, along with its inverse correlation with metabolic disorders such as obesity, type II diabetes, and atherosclerosis, establish this protein as a potential therapeutic target. However, due to this complexity, challenges have arisen in its production with a natural conformation in bacterial or mammalian expression systems, hindering clinical translation. Furthermore, while inducers for adiponectin secretion or chemical agonists targeting adiponectin receptors have shown promise in laboratory settings, clinical studies with these agents have not yet been conducted. This study proposes a method for isolating and purifying natural high molecular weight (HMW) adiponectin from discarded plasma fractions during the conventional pharmaceutical protein manufacturing process. The process involved Cohn-Oncley fractionation, initial chromatography using reduced cellufine formyl, and subsequent purification via DEAE Sepharose chromatography. Characterization involved gel electrophoresis and biological assays on a hepatocyte cell-line. The purification process effectively captured adiponectin from the I + III paste, demonstrating that this fraction contained a significant portion of total plasma adiponectin. The two-step chromatography led to highly purified HMW adiponectin, confirmed by native-PAGE showing a 780 kDa multimeric complex. Biological assessments demonstrated normal downstream signaling, with HMW adiponectin inducing AMPK phosphorylation. This study demonstrates the feasibility of obtaining purified HMW adiponectin by repurposing plasma fractionation processes. It offers a promising avenue for the HMW adiponectin production, tapping into HMW adiponectin's therapeutic potential against metabolic disorders while optimizing plasma resource utilization in healthcare., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Inflammation can be triggered by a variety of factors, including pathogens, damaged cells, and toxic compounds. It is a biological response of the immune system, which can be successfully assessed in clinical practice using some molecular substances. Because adiponectin, a hormone released by adipose tissue, influences the development of inflammation, its evaluation as a potential measure of inflammation in clinical practice is justified. In the present contribution, statistical comparison of adiponectin concentration and selected molecular substances recognized in clinical practice as measures of inflammation were utilized to demonstrate whether adipose tissue hormones, as exemplified by adiponectin, have the potential to act as a measure of rapidly changing inflammation when monitoring older hospitalized patients in the course of bacterial infection. The study showed no statistically significant differences in adiponectin levels depending on the rapidly changing inflammatory response in its early stage. Interestingly, the concentration of adiponectin is statistically significantly higher in malnourished patients than in people with normal nutritional levels, assessed based on the MNA. According to the results obtained, adiponectin is not an effective measure of acute inflammation in clinical practice. However, it may serve as a biomarker of malnutrition in senile individuals.

Objective: The research is to investigate the expression and the relationship between serum endothelial cell-specific molecular molecule-1 (ESM-1), high molecular weight adiponectin (HMWA), and late glycosylation terminal product (AGEs) in patients with gestational hypertension., Methods: 75 patients with pregnant hypertension who were treated in our hospital from June 2019 to June 2020 were selected as the case group, and 70 healthy pregnant women with pregnancy examination at the same period in our hospital were selected as the control group to analyze the changes in serum ESM-1, HMWA, and AGEs levels and the correlation with the degree of illness and their predictive value., Results: Serum ESM-1 and AGEs were significantly higher in the case group than in the control group. Serum HMWA was significantly lower than that in the control group ( P < 0.05). The gestational hypertensive serum ESM-1 and AGEs was significantly lower than in patients with mild preeclampsia and severe preeclampsia. Serum HMWA was significantly higher than in patients with mild preeclampsia and severe preeclampsia. Serum ESM-1 and AGEs of mild preeclampsia were significantly lower than in patients with severe preeclampsia. Serum HMWA was significantly higher than in patients with severe preeclampsia ( P < 0.05). The result of correlation analysis shows a positive correlation between serum ESM-1 and AGEs ( P < 0.05). A negative correlation was observed between HMWA and the degree of illness ( P < 0.05)., Conclusion: Serum ESM-1, HMWA, and AGEs are abnormally expressed in gestational hypertension, are closely related to the degree of condition, and have important clinical significance for condition control., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2021 Yun Yan et al.)

The homogeneously glycosylated 76-amino acid adiponectin collagenous domains (ACDs) with all of the possible 15 glycoforms have been chemically and individually synthesized using stereoselective glycan synthesis and chemical peptide ligation. The following biological and pharmacological studies enabled correlating glycan pattern to function in the inhibition of cancer cell growth as well as the regulation of systemic energy metabolism. In particular, hAdn-WM6877 was tested in detail with different mouse models and it exhibited promising in vivo antitumor, insulin sensitizing, and hepatoprotective activities. Our studies demonstrated the possibility of using synthetic glycopeptides as the adiponectin downsized mimetic for the development of novel therapeutics to treat diseases associated with deficient adiponectin.

Deregulation of adiponectin is found in systemic autoimmune rheumatic diseases (SARDs). Its expression is downregulated by various inflammatory mediators, but paradoxically, elevated serum levels are present in SARDs with high inflammatory components, such as rheumatoid arthritis and systemic lupus erythematosus. Circulating adiponectin is positively associated with radiographic progression in rheumatoid arthritis as well as with cardiovascular risks and lupus nephritis in systemic lupus erythematosus. However, in SARDs with less prominent inflammation, such as systemic sclerosis, adiponectin levels are low and correlate negatively with disease activity. Regulators of adiponectin gene expression (PPAR-γ, Id3, ATF3, and SIRT1) and inflammatory cytokines (interleukin 6 and tumor necrosis factor α) are differentially expressed in SARDs and could therefore influence total adiponectin levels. In addition, anti-inflammatory therapy could also have an impact, as tocilizumab treatment is associated with increased serum adiponectin. However, anti-tumor necrosis factor α treatment does not seem to affect its levels. Our review provides an overview of studies on adiponectin levels in the bloodstream and other biological samples from SARD patients and presents some possible explanations why adiponectin is deregulated in the context of therapy and gene regulation.

Accumulating evidence suggests that adipokines, a group of hormones secreted from adipose tissue, modulate tumor growth in a complicated manner. Among diverse adipokines, adiponectin exerts potent anti-tumor activities, whereas leptin exhibits pro-tumorigenic properties. Herein, we have examined the opposing effect of adiponectin on leptin-induced growth of cancer cells and investigated the underlying mechanisms, particularly in the context of inflammasomes activation, which plays a role in the growth of cancer cells. Globular adiponectin (gAcrp) significantly suppressed leptin-induced growth of human breast (MCF-7) and hepatic (HepG2) cancer cells by modulating both cell cycle and apoptosis. To elucidate the underlying mechanisms, we examined the modulatory effects of gAcrp and leptin on inflammasomes. Herein, we showed that gAcrp substantially abolished leptin-induced inflammasomes activation, as evidenced by suppression of IL-1β maturation, caspase-1 activation, and downregulation of inflammasomes components, including NLRP3 and ASC, in both MCF-7 and HepG2 cancer cells. Interestingly, suppression of inflammasomes activation by gAcrp was almost completely restored by blockade of heme oxygenase-1 (HO-1) signaling. In addition, suppressive effects of gAcrp on ROS production and NADPH oxidase activation, both of which critically contribute to leptin-induced inflammasomes activation, disappeared by inhibition of HO-1 signaling. Moreover, gAcrp downregulated estrogen receptor-α (ER-α) expression and blocked leptin-induced ER-α activation, which also plays an important role in inflammasomes activation. Finally, the opposing effects of gAcrp on leptin-induced inflammasomes activation and tumor growth were further confirmed in MCF-7 tumor xenografts. In summary, treatment with gAcrp prevents leptin-induced cancer cell growth by modulating inflammasome activation, which is mediated, at least in part, via HO-1 induction and modulation of ER-α signaling., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Glomerular filtration rate (GFR) and urinary albumin excretion rate (UAER) are used to diagnose and classify the severity of chronic kidney disease. Total adiponectin (T-AN) and high molecular weight adiponectin (H-AN) assays were developed using the fully automated immunoassay system, HI-1000 and their significance over conventional biomarkers were investigated. The T-AN and H-AN assays had high reproducibility, good linearity, and sufficient sensitivity to detect trace amounts of adiponectin in the urine. Urine samples after gel filtration were analyzed for the presence of different molecular isoforms. Low molecular weight (LMW) forms and monomers were the major components (93%) of adiponectin in the urine from a diabetic patient with normoalbuminuria. Urine from a microalbuminuria patient contained both high molecular weight (HMW) (11%) and middle molecular weight (MMW) (28%) adiponectin, although the LMW level was still high (52%). The amount of HMW (32%) and MMW (42%) were more abundant than that of LMW (24%) in a diabetic patient with macroalbuminuria. T-AN (r = - 0.43) and H-AN (r = - 0.38) levels showed higher correlation with estimated GFR (eGFR) than UAER (r = - 0.23). Urinary levels of both T-AN and H-AN negatively correlated with renal function in diabetic patients and they may serve as new biomarkers for diabetic kidney disease.

Adiponectin (ApN) is a hormone abundantly secreted by adipocytes and it is known to be tightly linked to the metabolic syndrome. It promotes insulin-sensitizing, fat-burning, and anti-atherosclerotic actions, thereby effectively counteracting several metabolic disorders, including type 2 diabetes, obesity, and cardiovascular diseases. ApN is also known today to possess powerful anti-inflammatory/oxidative and pro-myogenic effects on skeletal muscles exposed to acute or chronic inflammation and injury, mainly through AdipoR1 (ApN specific muscle receptor) and AMP-activated protein kinase (AMPK) pathway, but also via T-cadherin. In this review, we will report all the beneficial and protective properties that ApN can exert, specifically on the skeletal muscle as a target tissue. We will highlight its effects and mechanisms of action, first in healthy skeletal muscle including exercised muscle, and second in diseased muscle from a variety of pathological conditions. In the end, we will go over some of AdipoRs agonists that can be easily produced and administered, and which can greatly mimic ApN. These interesting and newly identified molecules could pave the way towards future therapeutic approaches to potentially prevent or combat not only skeletal muscle disorders but also a plethora of other diseases with sterile inflammation or metabolic dysfunction.

Melinjo seed extract (MSE) contains large amounts of polyphenols, including dimers of trans-resveratrol (e.g. gnetin C, L, gnemonoside A, B and D), and has been shown to potentially improve obesity. However, there is no clinical evidence regarding the anti-obesity effects of MSE, and its mechanisms are also unclear. We investigated the hypothesis that MSE supplementation increases the adiponectin (APN) multimerization via the up-regulation of disulfide bond A oxidoreductase-like protein (DsbA-L) under either or both physiological and obese conditions. To investigate the effect of MSE on the physiological condition, 42 healthy young volunteers were enrolled in a randomized, double-blind placebo-controlled clinical trial for 14 days. The participants were randomly assigned to the MSE 150 mg/day, MSE 300 mg/day or placebo groups. Furthermore, in order to investigate the effect of MSE on APN levels under obese conditions, we administered MSE powder (500 or 1000 mg/kg/day) to control-diet- or high-fat-diet (HFD)-fed C57BL/6 mice for 4 weeks. All participants completed the clinical trial. The administration of MSE 300 mg/day was associated with an increase in the ratio of HMW/total APN in relation to the genes regulating APN multimerization, including DsbA-L. Furthermore, this effect of MSE was more pronounced in carriers of the DsbA-L rs191776 G/T or T/T genotype than in others. In addition, the administration of MSE to HFD mice suppressed their metabolic abnormalities (i.e. weight gain, increased blood glucose level and fat mass accumulation) and increased the levels of total and HMW APN in serum and the mRNA levels of ADIPOQ and DsbA-L in adipose tissue. The present study suggests that MSE may exert beneficial effects via APN multimerization in relation to the induction of DsbA-L under both physiological and obese conditions.

Adiponectin is a highly abundant protein hormone secreted by adipose tissue. It elicits diverse biological responses, including anti-diabetic, anti-inflammatory, anti-tumor, and anti-atherosclerotic effects. Adiponectin consists of a globular domain and a collagen-like domain, and it occurs in three major oligomeric forms that self-assemble: trimers, hexamers, and high-molecular-weight oligomers. Adiponectin has been reported to bind to two seven-transmembrane domain receptors, AdipoR1 and AdipoR2, as well as to the protein T-cadherin, which is highly expressed in the cardiovascular system and binds only the high-molecular-weight form of adiponectin. The molecular mechanisms underlying this specificity remain unclear. Here we used a combination of X-ray crystallography and protein engineering to define the details of adiponectin's interaction with T-cadherin. We found that T-cadherin binds to the globular domain of adiponectin, relying on structural stabilization of this domain by bound metal ions. Moreover, we show that the adiponectin globular domain can be engineered to enhance its binding affinity for T-cadherin. These results help to define the molecular basis for the interaction between adiponectin and T-cadherin, and our engineered globular domain variants may be useful tools for further investigating adiponectin's functions., (© 2020 Pascolutti et al.)

Objectives: While weight gain is known as a predictor of non-alcoholic fatty liver disease (NAFLD) incidence, it remains controversial whether adipokine levels predict the development of NAFLD. We aimed to investigate the relationship of total adiponectin, high-molecular-weight (HMW) adiponectin, and leptin with the development and improvement of non-alcoholic fatty liver (NAFL) independent of sex and weight change over a maximum of 8.5 years., Methods: This prospective study enrolled 2735 participants in a hospital health check-up setting. Adipokine levels were measured at baseline. NAFL was assessed with liver ultrasonography, and the development or improvement of NAFL was determined by repeated ultrasonography at follow-ups., Results: Cross-sectional analyses revealed that total and HMW adiponectin levels were inversely associated with NAFL prevalence. In longitudinal analyses, the incidence of NAFL was 5.6 per 100-person-years during the observation period. The hazard ratios (HRs) per 1 μg/mL increase in the levels of total and HMW adiponectin were 0.900 (0.836-0.969) and 0.846 (0.754-0.948), respectively. Sex-stratified analyses showed that total and HMW adiponectin levels were significantly related to NAFL incidence only in women. In the subgroup of minimal weight change, only HMW adiponectin was a significant predictor for NAFL. Leptin predicted NAFL in the subgroup with weight gain. The improvement of NAFL was influenced by weight change, but not by adipokine levels., Conclusions: Low levels of total and HMW adiponectin may predict the development of NAFL independent of pathophysiological factors including obesity and insulin resistance. This predictability was evident in women. Leptin was a significant predictor for NAFL in the subjects with weight gain., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Osmotin-Like Proteins (OLPs) have been purified and characterized from different plant tissues, including latex fluids. Besides its defensive role, tobacco osmotin seems to induce adiponectin-like physiological effects, acting as an agonist. However, molecular information about this agonistic effect on adiponectin receptors has been poorly exploited and other osmotins have not been investigated yet., Objective and Methods: The present study involved the characterization of three OLPs from Plumeria rubra latex and molecular docking studies to evaluate the interaction between them and adiponectin receptors (AdipoR1 and AdipoR2)., Results: P. rubra Osmotin-Like Proteins (PrOLPs) exhibited molecular masses from 21 to 25 kDa and isoelectric points ranging from 4.4 to 7.7. The proteins have 16 cysteine residues, which are involved in eight disulfide bonds, conserved in the same positions as other plant OLPs. The threedimensional (3D) models exhibited the three typical domains of OLPs, and molecular docking analysis showed that two PrOLP peptides interacted with two adiponectin receptors similarly to tobacco osmotin peptide., Conclusion: As observed for tobacco osmotin, the latex osmotins of P. rubra exhibited compatible interactions with adiponectin receptors. Therefore, these plant defense proteins (without known counterparts in humans) are potential tools to study modulation of glucose metabolism in type II diabetes, where adiponectin plays a pivotal role in homeostasis., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: The sTNFRII-adiponectin fusion protein previously showed strong TNFα antagonistic activity. However, the fusion protein exists as mixture of different multimers. The aim of the present study was to characterize its active components., Methods: In this study, the fusion protein was isolated and purified by Ni-NTA affinity and gel exclusion chromatography, and further identified by Coomassie staining and western blotting. The TNFα antagonistic and glucose uptake-promoting activities were determined in vitro. The glucose detection kit and 2- NBDG (2-deoxy-2-[(7-nitro-2,1,3-benzoxadiazol-4-yl)amino]-D-glucose) were used to measure their effects on glucose metabolism (including glucose consumption and glucose uptake in HepG2 and H9C2 cells). The effect of the fusion protein on glucose uptake was also examined in free fatty acid (FFA)- induced insulin resistance cell model., Results: The sTNFRII-adiponectin fusion protein was found to exist in three forms: 250 kDa (hexamer), 130 kDa (trimer), and 60 kDa (monomer), with the final purity of 90.2%, 60.1%, and 81.6%, respectively. The fusion protein could effectively antagonize the killing effect of TNFα in L929 cells, and the multimer was found to be superior to the monomer. In addition, the fusion protein could increase glucose consumption without impacting the number of cells (HepG2, H9C2 cells) in a dosedependent manner. Mechanistically, glucose uptake was found to be enhanced by the translocation of GLUT4. However, it could not improve glucose uptake in the cell model of insulin resistance., Conclusion: In summary, the active components of the fusion protein are hexamers and trimers. The hexamer and trimer of sTNFRII-adiponectin fusion protein had both TNFα-antagonizing and glucose uptake-promoting activities, although neither of them could improve glucose uptake in the cell model of insulin resistance., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Adiponectin (ADP) is an adipokine secreted by adipose tissue with anti-inflammatory, antiatherogenic, and antidiabetic properties. In human serum, it is presented as three different forms: low molecular weight (LMW), medium molecular weight (MMW), and high molecular weight (HMW). High molecular weight isomer is the most active form of ADP and is more closely related with obesity-induced insulin resistance and metabolic syndrome than total ADP. Selective protease treatment can be used in humans to isolate the different ADP isoforms but this has not been applied in any veterinary species. Therefore, the objective of this study was to evaluate if the selective protease digestion is able to differentiate serum ADP isomers in dog samples, and if these isomers could change in obese dogs after a weight loss program. A Western blotting analysis confirmed that digestion with protease K showed only the HMW forms of ADP, whereas the use of protease A showed the HMW and MMW forms. This specific protease digestion was applied to serum obtained from 14 obese beagle dogs before and after a weight loss program and total ADP, HMW, and LMW forms increased significantly after the weight reduction. In conclusion, the use of selective protease digestion can be applied in canine serum as a procedure for detecting the different ADP isomers. In addition, by this procedure, it was showed that the HMW and LMW forms were increased after a weight loss program in our experimental conditions., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Breast milk constitutes a dietary source of leptin, adiponectin and microRNAs (miRNAs) for newborns. Expression of miRNAs previously associated with maternal obesity, leptin or adiponectin function were assessed and their impact on infant weight analyzed. Milk samples were collected (at month 1, 2, and 3) from a cohort of 59 healthy lactating mothers (38 normal-weight and 21 overweight/obese (BMI ≥ 25)), and infant growth was followed up to 2 years of age. Thirteen miRNAs, leptin and adiponectin were determined in milk. Leptin, adiponectin and miRNA showed a decrease over time of lactation in normal-weight mothers that was altered in overweight/obesity. Furthermore, negative correlations were observed in normal-weight mothers between the expression of miRNAs in milk and the concentration of leptin or adiponectin, but were absent in overweight/obesity. Moreover, miRNAs negatively correlated with infant BMI only in normal-weight mothers (miR-103, miR-17, miR-181a, miR-222, miR-let7c and miR-146b). Interestingly, target genes of milk miRNAs differently regulated in overweight/obesity could be related to neurodevelopmental processes. In conclusion, a set of miRNAs present in breast milk, in close conjunction with leptin and adiponectin, are natural bioactive compounds with the potential to modulate infant growth and brain development, an interplay that is disturbed in the case of maternal overweight/obesity.

Background: Persons with schizophrenia and schizoaffective disorder (PwS) have high rates of cardiometabolic pathology that contributes to premature mortality. Adiponectin is a metabolic hormone affecting insulin sensitivity and inflammation, and is active in the brain. High-molecular weight (HMW) adiponectin is considered a more sensitive marker of metabolic dysfunction than total adiponectin, but has been poorly studied in schizophrenia., Methods: This was a cross-sectional study of 100 PwS, age range 26-68 years (46 women), and 93 age- and sex-comparable non-psychiatric comparison (NC) subjects. Assessments included measures of psychopathology, physical health, cognitive function, and circulating biomarkers of metabolic dysfunction (HMW adiponectin, lipids, insulin resistance) and inflammation (high-sensitivity C-reactive protein or hs-CRP, Tumor Necrosis Factor-α, Interleukin-6, and Interleukin-10)., Results: HMW adiponectin levels were lower in PwS compared to NCs. Lower HMW adiponectin levels were associated with higher body mass index (BMI), higher Framingham risk for coronary heart disease, higher number of metabolic syndrome criteria, greater insulin resistance, lower HDL cholesterol, and higher hs-CRP in both groups. Only in PwS, lower HMW adiponectin correlated with younger age. In the best-fit regression models of HMW adiponectin, lower levels were associated with lower HDL cholesterol and minority race/ethnicity in both groups; but with younger age, non-smoking, higher insulin resistance, and a diagnosis of schizoaffective disorder only among PwS, and with male sex, better cognitive functioning, and higher hs-CRP levels in NCs only., Discussion: HMW adiponectin may be a promising biomarker of cardiometabolic health, especially among PwS. Adiponectin is a potential target for lifestyle and pharmacological interventions. Research on the possible role of HMW adiponectin in modifying cardiometabolic pathology in schizophrenia is needed., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Adiponectin (APN) is an important cytokine secreted by fat cells that is responsible for regulating numerous biological functions. However, the APN gene in lamprey and its precise function remain unidentified. In this study, the full-length cDNA sequence of L-APN was cloned, and it encoded a protein of 267 amino acid residues with a globular domain. The results of immunohistochemistry and FACS assays showed that APN protein was distributed in multiple tissues. L-APN expression in the supraneural body (SB) and leukocytes was differentially upregulated in response to Gram-negative bacteria, Gram-positive bacteria and poly (I:C). The expression levels of inflammatory cytokines were upregulated, and a proapoptotic effect was stimulated in SB cells treated with recombinant APN. Furthermore, L-APN could inhibit cell proliferation and arrest cell growth in the G1 phase. In summary, the APN protein from the lamprey plays an important role in inhibiting cell proliferation, inducing the production of inflammatory cytokines and promoting cell apoptosis, and it is also involved in immune responses and immune defenses. Our data provide insights into the evolutionary origin of the structure and function of APN gene., (Copyright © 2019. Published by Elsevier Ltd.)

Adiponectin is an adipocytokine with insulin-sensitizing, anti-atherogenic, and anti-inflammatory properties. Adiponectin secretion-inducing compounds have therapeutic potential in a variety of metabolic diseases. Phenotypic screening led to the discovery that 5,7-dihydroxy-8-(1-(4-hydroxy-3-methoxyphenyl)allyl)-2-phenyl-4H-chromen-4-one (compound 1) had adiponectin secretion-inducing activity during adipogenesis in human bone marrow mesenchymal stem cells (hBM-MSCs). Compound 1 was originally reported to be an anti-cancer chemical isolated from natural honeybee propolis, and its adiponectin secretion-inducing activity was found in non-cytotoxic concentrations. In a target identification study, compound 1 and its potent synthetic derivative compound 5 were shown to be novel pan-peroxisome proliferator-activator receptor (PPAR) modulators. Molecular docking models with PPARs have indicated that the binding modes of chromenone compounds preferentially interacted with the hydrophobic ligand binding pocket of PPARs. In addition, chromenone compounds have been shown to result in different phenotypic outcomes in the transcriptional regulation of lipid metabolic enzymes than those of selective PPAR mono-agonists for PPARα, PPARγ, and PPARδ. In line with the pharmacology of adiponectin and PPAR pan-modulators, compounds 1 and 5 may have diverse therapeutic potentials to treat cancer and metabolic diseases., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Adipose tissue has been recognized as a complex organ with endocrine and metabolic roles. The excess of fat mass, as occurs during overweight and obesity states, alters the regulation of adipose tissue, contributing to the development of obesity-related disorders. In this regard, many epidemiological studies shown an association between obesity and numerous types of malignancies, comprising those linked to the endocrine system (e.g., breast, endometrial, ovarian, thyroid and prostate cancers). Multiple factors may contribute to this phenomenon, such as hyperinsulinemia, dyslipidemia, oxidative stress, inflammation, abnormal adipokines secretion and metabolism. Among adipokines, growing interest has been placed in recent years on adiponectin (APN) and on its role in carcinogenesis. APN is secreted by adipose tissue and exerts both anti-inflammatory and anti-proliferative actions. It has been demonstrated that APN is drastically decreased in obese individuals and that it can play a crucial role in tumor growth. Although literature data on the impact of APN on carcinogenesis are sometimes conflicting, the most accredited hypothesis is that it has a protective action, preventing cancer development and progression. The aim of the present review is to summarize the currently available evidence on the involvement of APN and its signaling in the etiology of cancer, focusing on endocrine malignancies.

Polyetheretherketone (PEEK)-based implants have become popular in hard tissue orthopedic and dental field. However, its inherent bio-inertness limited its applications for bone repair/substitution of osteoporosis patients, with poor osteogenesis capability. In order to ameliorate their bioactivity, the 3D porous PEEK substrate was created by sulfonate processing, and the substrate was subsequently incorporated with strontium (Sr) through a hydrothermal reaction in Sr(OH) 2 solutions. The adiponectin (APN) protein membrane was deposited on the substrate via polydopamine-assisted deposition. Surface characterization results disclosed that the nanostructures had been formed on sPEEK-Sr-APN surafces, and APN coatings on the substrates could adjust Sr release rate and further mediate cell-material interactions. in vitro experiments indicated that the cellular effects (proliferation and differentiation) of MC3T3-E1 were significantly increased with Sr/APN coordinated regulation. This study provides bioactive Sr and APN as promising active components for bio-functional bone regeneration/substitution, and optimizes the osteointegration of PEEK implants in clinic., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Adiponectin is the most abundant plasma adipokine. It mainly derives from white adipose tissue and plays a key role in the control of energy metabolism thanks to its insulin-sensitising, anti-inflammatory, and antiatherogenic properties. In vitro and in vivo evidence shows that adiponectin could also be one of the hormones controlling the interaction between energy balance and fertility in several species, including humans. Indeed, its two receptors-AdipoR1 and AdipoR2-are expressed in hypothalamic⁻pituitary⁻gonadal axis and their activation regulates Kiss, GnRH and gonadotropin expression and/or secretion. In male gonads, adiponectin modulates several functions of both somatic and germ cells, such as steroidogenesis, proliferation, apoptosis, and oxidative stress. In females, it controls steroidogenesis of ovarian granulosa and theca cells, oocyte maturation, and embryo development. Adiponectin receptors were also found in placental and endometrial cells, suggesting that this adipokine might play a crucial role in embryo implantation, trophoblast invasion and foetal growth. The aim of this review is to characterise adiponectin expression and its mechanism of action in male and female reproductive tract. Further, since features of metabolic syndrome are associated with some reproductive diseases, such as polycystic ovary syndrome, gestational diabetes mellitus, preeclampsia, endometriosis, foetal growth restriction and ovarian and endometrial cancers, evidence regarding the emerging role of adiponectin in these disorders is also discussed.

Objectives: To evaluate salivary adiponectin and adenosine deaminase (ADA) in women suffering from Sjögren's syndrome (SS)., Methods: Salivary adiponectin and ADA were measured in patients with SS (n = 17) and compared to their values in healthy controls (n = 13) and patients suffering from drug-induced xerostomia (non-SS sicca group; n = 19). A clinical history was made for each patient, patients were examined clinically, and xerostomia inventory (XI) was performed., Results: Salivary adiponectin corrected by total protein was higher in patients with SS than in healthy individuals (P < 0.05) or patients with non-SS sicca (P < 0.01) and correlated with XI (r = 0.555; P < 0.05). Salivary ADA was higher in patients with SS and non-SS sicca compared to controls (P < 0.05 in both cases)., Conclusion: The results of the present study indicate that adiponectin and ADA are increased in the saliva of patients with SS., Clinical Relevance: Salivary adiponectin corrected by total protein can be a potential biomarker of SS., Trial Registration: NCT03156569.

Adiponectin is one of the most widely studied adipokines to date. First described in the mid-1990's, studying its regulation, biogenesis and physiological effects has proven to be extremely insightful and improved our understanding of the mechanisms that ensure systemic metabolic homeostasis. Here, we provide a brief overview of the current state of the field with respect to adiponectin, its history, sites and mechanisms of action, and the critical questions that will need to be addressed in the future., Competing Interests: Competing Interests The authors report no conflicts of interest

Adipose tissue is a key regulator of energy balance playing an active role in lipid storage as well as in synthesizing several hormones directly involved in the pathogenesis of obesity. Obesity represents a peculiar risk factor for a growing list of cancers and is frequently associated to poor clinical outcome. The mechanism linking obesity and cancer is not completely understood, but, amongst the major players, there are both chronic low-grade inflammation and deregulation of adipokines secretion. In obesity, the adipose tissue is pervaded by an abnormal number of immune cells that create an inflammatory environment supporting tumor cell proliferation and invasion. Adiponectin (APN), the most abundant adipokine, shows anti-inflammatory, anti-proliferative and pro-apoptotic properties. Circulating levels of APN are drastically decreased in obesity, suggesting that APN may represent the link factor between obesity and cancer risk. The present review describes the recent advances on the involvement of APN and its receptors in the etiology of different types of cancer.

Background: Inhibiting TNF-α is an effective therapy for inflammatory diseases such as rheumatoid arthritis. However, systemic, nondiscriminatory neutralization of TNF-α is associated with considerable adverse effects., Methods: Here, we developed a trimeric chimeric TNF receptor by linking an N-terminal mouse Acrp30 trimerization domain and an MMP-2/9 substrate sequence to the mouse extracellular domain of TNF receptor 2 followed by a C-terminal mouse tetranectin coiled-coil domain (mouse Acrp-MMP-TNFR-Tn)., Results: Here, we show that the Acrp30 trimerization domain inhibited the binding activity of TNFR, possibly by closing the binding site of the trimeric receptor. Cleavage of the substrate sequence by MMP-9, an enzyme highly expressed in inflammatory sites, restored the binding activity of the mouse TNF receptor. We also constructed a recombinant human chimeric TNF receptor (human Acrp-MMP-TNFR-Tn) in which an MMP-13 substrate sequence was used to link the human Acrp and the human TNF receptor 2. Human Acrp-MMP-TNFR-Tn showed reduced binding activity, and MMP-13 digestion recovered its binding activity with TNF-α., Conclusion: Acrp-masked chimeric TNF receptors may be able to be used for inflammatory tissue-selective neutralization of TNF-α to reduce the adverse effects associated with systemic neutralization of TNF-α., (Copyright © 2018. Published by Elsevier Ltd.)

Background: Cervical Cancer (CC) is the most common leading cancer in women globally. This is considered to be the type of cancer that is restricted to women. Any women in the reproductive age range can develop CC. However, women between the ages of 25 and 39 are at a higher risk., Objective: In comparison with developed countries, the screening and awareness of CC in developing countries are significantly low. Infection with Human papillomavirus (HPV) is the main cause of CC, especially HPV-16 and HPV-18. Other than HPV, there are other factors that can contribute to CC, such as Human simplex virus (HSV) infection and immunocompromised patients with HIV., Conclusion: Cervical cancer can be detected by molecular techniques such as (1) PCR, (2) visual acetic acid method, (3) DNA Hybrid II test, (4) liquid-based cytology, (5) Pap-Smear techniques, and (6) colposcopy techniques. Early detection of CC is very much needed; cryotherapy or LEEP (Loop electro surgical excision procedure) can be conducted during the pre-invasive stage of CC. Some metabolic changes in the human body such as fluctuating levels of insulin and triglycerides and increased activity of adiponectin may lead to CC. These contributing factors, such as adipokines, can be used as biomarkers for CC detection., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: In metabolic disorders, adiponectin and adiponectin receptors (AdipoR1/R2) signaling has a key role in improving nonalcoholic fatty liver disease (NAFLD) in obesity-associated diabetes., Objective: To the best of our knowledge, here, we reported for the first time the underlying mechanistic therapeutic efficacy of the novel osmotin, a homolog of mammalian adiponectin, against NAFLD in leptin-deficient ob/ob and db/db mice., Methods: The ob/ob and db/db mice were treated with osmotin at a dose of 5 μg/g three times a week for two weeks. To co-relate the in vivo results we used the human liver carcinoma HepG2 cells, subjected to knockdown with small siRNAs of AdipoR1/R2 and PPARα genes and treated with osmotin and palmitic acid (P.A.). MTT assay, Western blotting, immunohistofluorescence assays, and plasma biochemical analyses were applied., Results: Osmotin stimulated AdipoR1/R2 and its downstream APPL1/PPAR-α/AMPK/SIRT1 pathways in ob/ob and db/db mice, and HepG2 cells exposed to P.A. Mechanistically, we confirmed that knockdown of AdipoR1/R2 and PPARα by their respective siRNAs abolished the osmotin activity in HepG2 cells exposed to P.A. Overall, the in vivo and in vitro results suggested that osmotin protected against NAFLD through activation of AdipoR1/R2 and its downstream APPL1/PPAR-α/AMPK/SIRT1 pathways as shown by the reduced body weight, blood glucose level and glycated hemoglobin, improved glucose tolerance, attenuated insulin resistance and hepatic glucogenesis, regulated serum lipid parameters, and increased fatty acid oxidation and mitochondrial functions., Conclusion: Our findings strongly suggest that novel osmotin might be a potential novel therapeutic tool against obesity/diabetes-induced NAFLD and other metabolic disorders., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Circulating adiponectin concentrations were lower in ponies with a history of endocrinopathic laminitis and in nonlaminitic ponies that subsequently developed laminitis. The assays used in these studies have been discontinued or are no longer valid., Objectives: (1) to determine the validity of immunoturbidimetric (IT) and enzyme linkedimmunosorbent (ELISA) assays for equine total and high molecular weight (HMW) [adiponectin] measurement and (2) to investigate the association between [adiponectin] measured using these assays and endocrinopathic laminitis., Study Design: Method validation and cohort study., Methods: Accuracy and precision of IT and ELISA assays for measuring total (TAC) and HMW (HMWAC) [adiponectin] were determined. Using the IT assay, the effects of anti-coagulant and storage temperature were assessed, TAC was measured in previously laminitic (PL) and never laminitic (NL) ponies (n = 6/group). Comparison with a previously validated radioimmunoassay was made in NL ponies (n = 223). Association between TAC and subsequent laminitis development in NL ponies was investigated using univariable logistic regression and ROC curve analysis., Results: The IT assay was precise and demonstrated good agreement with the previously validated radioimmunoassay. TAC was significantly (P<0.01) lower in PL (mean ± s.d. 8.9 ± 2.9 μg/mL) compared to NL (24.2 ± 11.8 μg/mL) ponies and in NL ponies that developed laminitis within 12 months (median 4.8 μg/mL; IQR 2.65-13.4 μg/mL) compared to those that remained nonlaminitic (19.9 μg/mL; 9.95-31.5 μg/mL). TAC was significantly (P = 0.01) associated with laminitis occurrence within 12 months. Use of the area under the ROC curve to distinguish animals that did and did not develop laminitis showed good accuracy (0.76). None of the ELISA methods validated satisfactorily., Main Limitations: Laminitis risk is based on data from ponies in one region., Conclusions: The IT method is suitable for measurement of equine TAC. TAC is lower in ponies with previous or future laminitis. The ELISA methods are not suitable for measurement of equine HMWAC or TAC., (© 2018 EVJ Ltd.)

Adiponectin (ADP), a regulator of the innate immune system, plays a role in the progression of inflammation and metabolic disorders in mammals. However, the role of ADP in fish is poorly understood. Here, we cloned the cDNA sequence of a ADP homolog (PaADP) gene from ayu. Multiple sequence alignment revealed that PaADP presented typical characteristics of ADPs. Phylogenetic tree analysis showed that PaADP was most closely related to that of rainbow trout. In healthy ayu, the transcripts of PaADP were detected in most of the tested tissues and cells, with the highest level in the adipose tissue. Upon V. anguillarum infection, the mRNA expression of PaADP was significantly up-regulated in the tissues and cells except adipose tissue. Subsequently, the full-length mature PaADP (fPaADP) and the globular domain fragment (gPaADP) were prokaryotically expressed in bacteria and purified, and anti-PaADP antibodies were produced. Western blot analysis revealed that three fragments including fPaADP and gPaADP were existed in ayu serum. The recombinant fPaADP (rfPaADP) had an anti-inflammatory effect on ayu MO/MФ by upregulating anti-inflammatory cytokine expressions, downregulating pro-inflammatory cytokine expressions, inhibiting the phagocytosis and subsequent bacterial killing. In contrast, the recombinant gPaADP (rgPaADP) presented a pro-inflammatory effect on ayu MO/MФ by upregulating pro-inflammatory cytokine expression, downregulating anti-inflammatory cytokine expressions, enhancing the phagocytosis and subsequent bacterial killing. These results suggested that fPaADP and gPaADP have opposite roles in the regulation of MO/MФ functions in ayu., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Donor human milk (DHM) is submitted to Holder pasteurization (HoP) to ensure its microbiological safety in human milk banks but this treatment affects some of its bioactive compounds. The objective of this work was to compare the effects of HoP and high temperature short time (HTST) treatments on some bioactive compounds found in DHM. A total of 24 DHM batches were processed in a continuous HTST system (70, 72, and 75°C for 5-25 s) and by HoP (62.5°C for 30 min). The concentrations of immunoglobulins (Igs) A, G, and M, transforming growth factor-beta 2 (TGF-β 2 ), adiponectine, ghrelin, and leptin were measured using a multiplex system, whereas the concentration of epidermal growth factor (EGF) was determined by ELISA. In relation to Igs, IgG showed the highest preservation rates (87-101%) after HTST treatments, followed by IgA (54-88%) and IgM (25-73%). Ig retention after any of the HTST treatments was higher than after HoP ( p < 0.001). Treatment times required to reduce the concentration of IgM by 90% ( D -value) were 130, 88, and 49 s at 70, 72, and 75°C, while the number of degrees Celsius required to change the D -value by one factor of 10 ( z -value) was 11.79°C. None of the heat treatments had a significant effect on the concentrations of TGF-β 2 , EGF, adiponectin, and ghrelin. In contrast, leptin was detected only in 4 of the samples submitted to HoP, whereas it was present in all samples after the different HTST treatments, with retention rates ranging between 34 and 68%. Globally, the concentration of IgA, IgG, IgM, and leptin in DHM was significantly higher after HTST pasteurization performed in a continuous system designed to be used in human milk banks than after the HoP procedure that is routinely applied at present.

As the close paralog of adiponectin, C1q/TNF-Related Protein 9 (CTRP9) has been reported to be involved in the regulation of glucose and fat metabolism, immunization and endothelial cell functions. However, information regarding the actions of Ctrp9 on reproduction is extremely limited in fish. As a first step, Ctrp9, adiponectin receptor 1 (Adipor1) and Adipor2 were identified from Nile tilapia. The open reading frame (ORF) of ctrp9 was 1020 bp which encoded a 339 amino acids. Moreover, the ORFs of adipor1 and adipor2 were 1131 bp and 1134 bp encoding 376 and 377 amino acids, respectively. Tissue distribution showed that ctrp9 mRNA levels were highest in the kidney in both sexes. And, the expression of adipor1 and adipor2 were widely distributed in all tissues examined, exhibiting high levels in the brain, gonad, gut and stomach. In addition, intraperitoneal (i.p.) injection of gCtrp9 (globular Ctrp9) suppressed the hypothalamic expression of gnrh2 (gonadotropin-releasing hormone 2) and gnrh3, as well as gthα (gonadotropic hormone α), fshβ (follicle-stimulating hormone β), lhβ (luteinizing hormone β), lhr (LH receptor) and fshr (FSH receptor) mRNA levels in the pituitary. The mRNA levels of adipor1, but not adipor2, in the gonads were also inhibited after injection. Moreover, the levels of serum E2 (estrogen) in female and T (testosterone) in male were significantly decreased after injection of gCtrp9. Overall, our data provides novel data indicating, for the first time, a regulatory effect of CTRP9 on teleost reproduction., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Adiponectin is a fat tissue-derived adipokine with beneficial effects against diabetes, cardiovascular diseases, and cancer. Accordingly, adiponectin-mimetic molecules possess significant pharmacological potential. Oligomeric states of adiponectin appear to determine its biological activity. We identified a highly conserved, 13-residue segment (ADP-1) from adiponectin's collagen domain, which comprises G XX G motifs and has one asparagine and two histidine residues that assist in oligomeric protein assembly. We therefore hypothesized that ADP-1 promotes oligomeric assembly and thereby mediates potential metabolic effects. We observed here that ADP-1 is stable in human serum and oligomerizes in aqueous environments. We also found that ADP-1 activates AMP-activated protein kinase (AMPK) in an adaptor protein, phosphotyrosine interacting with PH domain and leucine zipper 1 (APPL1)-dependent pathway and stimulates glucose uptake in rat skeletal muscle cells (L6 myotubes). ADP-1-induced glucose transport coincided with ADP-1-induced biosynthesis of glucose transporter 4 and its translocation to the plasma membrane. ADP-1 induced an interaction between APPL1 and the small GTPase Rab5, resulting in AMPK phosphorylation, in turn leading to phosphorylation of p38 mitogen-activated protein kinase (MAPK), acetyl-CoA carboxylase, and peroxisome proliferator-activated receptor α. Similar to adiponectin, ADP-1 increased the expression of the adiponectin receptor 1 ( AdipoR1 ) gene. Of note, ADP-1 decreased blood glucose levels and enhanced insulin production in pancreatic β cells in db/db mice. Further, ADP-1 beneficially affected lipid metabolism by enhancing lipid globule formation in mouse 3T3-L1 adipocytes. To our knowledge, this is the first report on identification of a short peptide from adiponectin with positive effects on glucose or fatty acid metabolism., (© 2018 Sayeed et al.)

Activation of adiponectin receptors (AdipoRs) by its natural ligand, adiponectin has been known to be involved in modulating critical metabolic processes such as glucose metabolism and fatty acid oxidation as demonstrated by a number of in vitro and in vivo studies over last two decades. These findings suggest that AdipoRs' agonists could be developed into a potential therapeutic agent for metabolic diseases, such as diabetes mellitus, especially for type II diabetes, a long-term metabolic disorder characterized by high blood sugar, insulin resistance, and relative lack of insulin. Because of limitations in production of biologically active adiponectin, adiponectin-mimetic AdipoRs' agonists have been suggested as alternative ways to expand the opportunity to develop anti-diabetic agents. Based on crystal structure of AdipoR1, we designed AdipoR1's peptide agonists using protein-peptide docking simulation and screened their receptor binding abilities and biological functions via surface plasmon resonance (SPR) and biological analysis. Three candidate peptides, BHD1028, BHD43, and BHD44 were selected and confirmed to activate AdipoR1-mediated signal pathways. In order to enhance the stability and solubility of peptide agonists, candidate peptides were PEGylated. PEGylated BHD1028 exhibited its biological activity at nano-molar concentration and could be a potential therapeutic agent for the treatment of diabetes. Also, SPR and virtual screening techniques utilized in this study may potentially be applied to other peptide-drug screening processes against membrane receptor proteins., Competing Interests: B.B.K. is a salaried employee of EncuraGen, S.K. is a salaried employee of Polus Inc., and Y.J.S. is a salaried employee of Samhyun Inc. With regards to the patent related to the submission, there is a registered patent in Korea. The patent number is 10-1838622 and the title is Agonist Peptide for Adiponectin Receptor. Also, a PCT application was filed as of April 10, 2017 and the application number is 10-2017-0037762. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

Objective: to investigate influence of different forms of adiponectin on carotid intima-media thickness (CIMT) in women with abdominal obesity (AO) in St.‑Petersburg. It has been recognized before that AO is associated with cardiovascular diseases, including atherosclerosis, but mechanism of this association remains unclear. AO leads to imbalance of adipokines, in particularly decrease of adiponectin, which may lead to atherosclerotic lesion of carotid arteries., Materials and Methods: We investigated 81 women with AO (IDF criteria, 2005) and 21 women with normal waist circumference. СIMT was evaluated by an ultrasound scanner., Results: Among patients with AO 54.9 % had CIMT >0.9 mm and 38.5 % had atherosclerotic plaques in common carotid arteries. The total adiponectin level (TA) was lower in women with CIMT> 0.9 mm, than in women with normal CIMT (23.20 [2.55; 40.65] and 18.09 [1.60; 38.92] μg/ml, respectively; р0.9 mm, than in women with normal CIMT (2.21 [0.50; 6.85] and 2.88 [1.29; 15.45] μg/ml, respectively; р0.9 mm, than in women with CIMT >0.9 mm and atherosclerotic plaques in carotid arteries (3.09 [1.34; 6.85] and1.82 [0.50; 2.94] mcg/ml, respectively; р0.9 mm depended on waist circumference, diastolic blood pressure and level of C-reactive protein (CRP), while presence of atherosclerotic plaques was associated with levels of HMWA and CRP., Conclusions: Factors that make the greatest contribution at early stages of atherosclerosis development in carotid arteries in women with AO can be increased waist circumference, high diastolic blood pressure, and high level of CRP. At later stages of atherosclerosis development lowered HMWA level can contribute to the formation of atherosclerotic plaques.

Background: Adiponectin (ADPN) prevents the development/recurrence of cardiovascular events via its anti-atherogenic effects. However, few long-term studies have examined the changes in serum ADPN levels and arterial calcification seen in renal allograft recipients., Subjects and Methods: The effects of the serum ADPN level on arterial calcification were examined in 51 Japanese renal allograft recipients. Abdominal aorta calcification was evaluated on computed tomography using the aortic calcification area index (ACAI). The change in the ACAI and serum high-molecular-weight (HMW)-ADPN fractions were studied over an 8-year period. The arterial expression of ADPN, ADPN receptors (AdipoR)1 and 2, and T-cadherin (cadherin-13) were also examined by immunohistochemistry., Results: The change in the ACAI were grouped into quartiles and compared with the alterations in the serum levels of each ADPN fraction over an 8-year period. The change in the ACAI was much lower in the patients with highly elevated HMW-ADPN levels.Multiple regression analysis demonstrated that an advanced age at transplant and a history of cardiovascular complications were associated with an increased change in the ACAI, while higher HMW-ADPN concentrations were associated with improvements in the ACAI. Serum HDL-C level was also identified as a positive factor to increase serum HMW-ADPN level.In immunohistochemical examinations, ADPN was detected on CD31-positive arterial endothelial cells from renal allograft biopsy samples. ADPN co-localized with T-cadherin and AdipoR1, but only partially co-localized with AdipoR2., Conclusion: Both HMW-ADPN and HDL-C might inhibit the progression of vascular calcification by promoting ADPN binding to vascular endothelial cells via T-cadherin and AdipoR in Japanese renal allograft recipients.

The aim of this study was to evaluate the associations between dietary pattern, adiponectin and insulin resistance. The study population consisted of 612 men and women aged 35-69 years old who had participated in the baseline survey of Japan Multi-Institutional Collaborative Cohort (J-MICC) Study in Tokushima Prefecture. Diets and lifestyle related variables were assessed by questionnaires. Multiple regression analyses were used to analyse the relations between dietary patterns and high molecular weight (HMW) adiponectin. For further analysis, path analysis was used to test the hypothesised model of association between dietary pattern, serum adiponectin and insulin resistance. The result showed that higher score of bread and dairy pattern was directly associated with increased serum level of adiponectin in women, which was inversely related to homeostasis model assessment of insulin resistance (HOMA-IR). In conclusion, higher consumption of bread and dairy products, and low intake of rice may be associated with increased serum adiponectin in women.

Reduced plasma levels of the high-molecular weight (HMW) form of adiponectin, rather than total adiponectin levels, have been shown to be closely associated with various metabolic diseases including insulin resistance, type 2 diabetes, and cardiovascular disease. Therefore, we sought to explore active, naturally occurring compounds that promote the recovery of HMW adiponectin secretion suppressed by palmitic acid in our model. A total of 90 crude drug extracts were screened for the ability to augment HMW adiponectin secretion from 3T3-L1 adipocytes treated with palmitic acid. Panaxynol was isolated from Saposhnikovia divaricata as an active compound with HMW adiponectin promoting properties. Peroxisome proliferator-activated receptor-γ (PPARγ) agonists are reported to increase the secretion of HMW adiponectin, although the effects of panaxynol were found to be independent of PPARγ activation. When the underlying mechanisms were further examined, panaxynol was found to inhibit the palmitic-acid-induced downregulation of forkhead box O1 (FoxO1) protein, and the anti-lipotoxic effects were abolished by a FoxO1 inhibitor. Furthermore, CCAAT/enhancer-binding protein-α (C/EBPα) mRNA levels were also increased by panaxynol. Reactive oxygen species have critical roles in the reduction in HMW adiponection secretion by palmitic acid; however, panaxynol reduced this increase in reactive oxygen species generation, followed by reductions in markers of endoplasmic reticulum stress and inflammation. Taken together, these findings suggest that panaxynol ameliorates the impaired HMW adiponection secretion in adipocytes treated with palmitic acid by restoring FoxO1 expression, owing to inhibition of reactive oxygen species generation, in a PPARγ-independent manner., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background and Aims: Obesity is regulated by different metabolic factors like leptin, adiponectin insulin and neuropeptide orexin-A. The aim of this study is to assess the role of these hormones and their interrelationship with obesity in north Indian women., Method: A total of 168 obese women with Body Mass Index (BMI)>30kg/m 2 and 150 lean women (BMI<25kg/m 2 ) as control were recruited in this study. Women with obesity were further subdivided into two groups according to their BMI, 71 overweight women with the BMI 25-29.9kg/m 2 (mean±S.D: 27.87±0.71) and the 97 obese women with BMI>30kg/m 2 (34.68±1.90). Orexin -A, leptin and adiponectin were estimated using quantitative sandwich enzyme linked immunoassay and insulin was estimated by using an immuno-radiometric assay., Result: Orexin -A and adiponectin level were significantly lower however, leptin and inulin level were significantly higher in obese women as compared with control group. Further, the one- way group analysis showed that the orexin -A and adiponectin level were significantly lower but leptin and insulin level was significantly higher in obese women as compared to overweight and control group respectively., Conclusion: Result showed that the level of adiponectin, leptin, orexin-A and insulin play an important role in the regulation of energy expenditure. In obesity, the activity of these peptides is disturbed., (Copyright © 2017 Diabetes India. Published by Elsevier Ltd. All rights reserved.)

Scope: Maternal vitamin D deficiency has been implicated in adverse pregnancy outcomes. However, the association between vitamin D and inflammation, particularly adipokines, remains unexplored in pregnancy., Methods and Results: In 102 overweight or obese pregnant women at high-risk of gestational diabetes mellitus (GDM), we investigated relationships between maternal 25-hydroxyvitamin D (25(OH)D) concentrations at 12-15 wk gestation (baseline) and serum lipids, inflammatory markers, novel adipokines (omentin-1, visfatin, high molecular weight (HMW) adiponectin), and subsequent pregnancy outcomes (GDM, preeclampsia, preterm birth [PTB]). After adjustment for maternal factors (age, BMI, parity, ethnicity, and smoking status), baseline 25(OH)D concentrations were inversely associated with total cholesterol and triglycerides, and positively associated with HMW-adiponectin. Higher baseline 25(OH)D concentrations were associated with decreased fasting and 1-h post-OGTT glucose and reduced risk of GDM at 26-28 wk, as well as with longer gestation and reduced risk of PTB upon additional adjustment for caesarean section. Adding HMW-adiponectin to the multivariable models attenuated most associations, and HMW-adiponectin was a significant predictor in the models., Conclusion: Our findings suggest that lower maternal 25(OH)D concentrations in overweight/obese pregnant women at high-risk of GDM are associated with increased cardiometabolic risks during pregnancy and adverse pregnancy outcomes, and that these associations may be mediated by HMW-adiponectin., (© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Adipose tissue (AT) has recently been identified as a dynamic endocrine organ secreting a wide range of adipokines. Adiponectin is one such hormone, exerting endocrine and paracrine effects on the cardiovascular system. At a cellular and molecular level, adiponectin has anti-inflammatory, antioxidant and anti-apoptotic roles, thereby mitigating key mechanisms underlying cardiovascular disease (CVD) pathogenesis. However, adiponectin expression in human AT as well as its circulating levels are increased in advanced CVD states, and it is actually considered by many as a 'rescue hormone'. Due to the complex mechanisms regulating adiponectin's biosynthesis in the human AT, measurement of its levels as a biomarker in CVD is highly controversial, given that adiponectin exerts protective effects on the cardiovascular system but at the same time its increased levels flag advanced CVD. In this review article, we present the involvement of adiponectin in CVD pathogenesis and we discuss its role as a clinical biomarker., Linked Articles: This article is part of a themed section on Targeting Inflammation to Reduce Cardiovascular Disease Risk. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.22/issuetoc and http://onlinelibrary.wiley.com/doi/10.1111/bcp.v82.4/issuetoc., (© 2016 The British Pharmacological Society.)

High molecular weight (HMW) adiponectin (APN) is closely correlated with the development of fatty liver and is modulated by the Akt/forkhead box protein O1 (FOXO1) pathway through disulfide‑bond A oxidoreductase‑like protein (DsbA‑L). The Chinese herb extract, QSHX, is used to treat liver diseases. The present study investigated the effects of QSHX on non‑alcoholic fatty liver disease (NAFLD) and its underlying mechanism. A rat model of NAFLD was established by feeding of a high‑fat and high‑sugar diet for 20 weeks. From week 13, the rats were administered with QSHX, or saline as a control, for 8 weeks. The liver function, blood fat and plasma APN were measured using a radioimmunoassay. The hepatic tissue score was measured following staining for pathology. The expression and activities of Akt, FOXO1, DsbA‑L and HMW APN in the adipose tissue and primary adipocytes of the rats were measured using western blot analysis. It was found that QSHX significantly decreased the body weight, liver index, and serum levels of aspartate aminotransferase, alanine aminotransferase and triglyceride; and increased the serum level of APN in the NAFLD rats. Following 8 weeks of treatment with QSHX, the hepatic steatosis in the liver tissue improved and the score of hepatic steatosis was significantly decreased. The results of the western blot analysis indicated that QSHX promoted the expression of DsbA‑L and HMW APN, and reduced the expression levels of phosphorylated FOXO1 and FOXO1 in adipose tissue and primary adipocytes. It was concluded that QSHX reduced hepatic steatosis by promoting the expression of HMW APN and DsbA‑L, which may have been induced by inhibiting the activation and expression of FOXO1 in adipocytes.

Adiponectin, an adipokine with insulin-sensitizing effect, is secreted from adipocytes into circulation as high, medium, and low molecular weight forms (HMW, MMW, and LMW). The HMW adiponectin oligomers possess the most potent insulin-sensitizing activity. WSF-P-1(N-methyl-1,2,3,4,5,6-hexahydro-1,1,5,5-tetramethyl-7H-2,4α-methanonaphthalen-7-amine) is derived from natural sesquiterpene longifolene by chemical modifications. We found that WSF-P-1 activates AMPK in both 3T3-L1 adipocytes and 293T cells in this study. Activation of AMPK by WSF-P-1 promotes the assembly of HMW adiponectin and increases the HMW/total ratio of adiponectin in 3T3-L1 adipocytes. We demonstrated that the Ca 2+ -dependent CaMKK signaling pathway is involved in WSF-P-1-induced AMPK activation and adiponectin multimerization. WSF-P-1 also activates GLUT1-mediated glucose uptake in 3T3-L1 adipocytes, making it a potential drug candidate for the treatment of type 2 diabetes, obesity, and other obesity-related metabolic diseases.

Metabolic syndrome (MetS) has an important epidemiological relevance due to its increasing prevalence and association with type 2 diabetes and cardiovascular disease. Insulin resistance is a core feature of the MetS. HOMA-IR is a robust clinical and epidemiological marker of MetS. Adiponectin is an adipokine with insulin-sensitizing and anti-inflammatory functions; its levels decrease as number of components of MetS increases. High-molecular weight adiponectin (HMWA) is the multimer responsible for the relationship of adiponectin with insulin sensitivity. HOMA-IR and HMWA are suitable candidates for MetS biomarkers. The ratio of adiponectin to HOMA-IR has been validated as a powerful index of MetS and considered a better marker of its presence, than either HOMA-IR or adiponectin alone, in selected homogeneous populations. We compared the strength of association between HMWA, HOMA-IR and HMWA/HOMA-IR ratio with MetS and its key components. Our data have shown that the median (25th, 75th percentile) of HMWA/HOMA-IR ratio was lower in subjects with MetS [0.51 (0.33, 1.31)] as compared to those without it [2.19 (1.13, 4.71)]. The correlation coefficient (r) was significantly higher for HMWA/HOMA-IR ratio as compared to HMWA for waist circumference (-0.65; -0.40, respectively); mean blood pressure (-0.27; -0.14, respectively); fasting glucose (-0.38; -0.19, respectively); HDL-cholesterol (0.44; 0.40, respectively); and triglycerides (-0.35; -0.18, respectively). In a multivariable logistic regression analysis, the HMWA/HOMA-IR ratio was a sensitive predictor for MetS, being the only marker that was significantly associated with each and all the individual components of the syndrome. These results expand on previous studies in that we used the active circulating form of adiponectin, i.e. HMWA, and represent a typical Brazilian cohort characterized by intense interethnic admixture. Thus, the HMWA/HOMA-IR ratio is a minimally invasive biomarker for MetS that could be clinically useful in prognosing patient outcome.

Adiponectin (Adpn) has been shown to be a possible therapeutic for Type II diabetes, however the production of a therapeutic version of Adpn has proved to be challenging. Biological studies have highlighted the importance of the glycosylated lysine residues for the formation of bioactive high molecular weight oligomers of Adpn. Through the use of 'click' glycopeptide mimetics, we investigated the role of glycosylated lysine and serine residues for the formation of triple helical structures of the collagenous domain of Adpn, in the context of a collagen model peptide scaffold. The physical properties of the unglycosylated lysine and serine peptides are compared with their glycosylated analogues. Our results highlight the crucial role of lysine residues for formation of the triple helical structure of Adpn, possibly due to the extension of both intra- and interstrand hydrogen bonding networks. Strikingly, we observed a significant decrease in thermal stability upon incorporation of triazole-linked analogues of glycosylated lysine residues into the adiponectin collageneous domain, indicating possible uses of 'click' glycomimetics for bioengineering applications.

Adiponectin (APN), also known as apM1, Acrp30, GBP28 and adipoQ, is a circulating hormone that is predominantly produced by adipose tissue. Many pharmacological studies have demonstrated that this protein possesses potent anti-diabetic, anti-atherogenic and anti-inflammatory properties. Although several studies have demonstrated the antioxidative activity of this protein, the regulatory mechanisms have not yet been defined in skeletal muscles. The aim of the present study was to examine the cytoprotective effects of APN against damage induced by oxidative stress in mouse-derived C2C12 myoblasts. APN attenuated H 2 O 2 -induced growth inhibition and exhibited scavenging activity against intracellular reactive oxygen species that were induced by H 2 O 2 . Furthermore, treating C2C12 cells with APN significantly induced heme oxygenase-1 (HO-1) and nuclear factor-erythroid 2 related factor 2 (Nrf2). APN also suppressed H 2 O 2 -induced mitophagy and partially inhibited the colocalization of mitochondria with autophagosomes/lysosomes, correlating with the expression of Pink1 and Parkin and mtDNA. Moreover, APN protected C2C12 myoblasts against oxidative stress-induced apoptosis. Furthermore, APN significantly reduced the mRNA and protein expression levels of Bax. These data suggest that APN has a moderate regulatory role in oxidative stress-induced mitophagy and suppresses apoptosis. These findings demonstrate the antioxidant potential of APN in oxidative stress-associated skeletal muscle diseases.

Adiponectin, an adipocyte-derived circulating protein, accumulates in the heart, vascular endothelium, and skeletal muscles through an interaction with T-cadherin (T-cad), a unique glycosylphosphatidylinositol-anchored cadherin. Recent studies have suggested that this interaction is essential for adiponectin-mediated cardiovascular protection. However, the precise protein-protein interaction between adiponectin and T-cad remains poorly characterized. Using ELISA-based and surface plasmon analyses, we report here that T-cad fused with IgG Fc as a fusion tag by replacing its glycosylphosphatidylinositol-anchor specifically bound both hexameric and larger multimeric adiponectin with a dissociation constant of ∼1.0 nm and without any contribution from other cellular or serum factors. The extracellular T-cad repeats 1 and 2 were critical for the observed adiponectin binding, which is required for classical cadherin-mediated cell-to-cell adhesion. Moreover, the 130-kDa prodomain-bearing T-cad, uniquely expressed on the cell surface among members of the cadherin family and predominantly increased by adiponectin, contributed significantly to adiponectin binding. Inhibition of prodomain-processing by a prohormone convertase inhibitor increased 130-kDa T-cad levels and also enhanced adiponectin binding to endothelial cells both by more preferential cell-surface localization and by higher adiponectin-binding affinity of 130-kDa T-cad relative to 100-kDa T-cad. The preferential cell-surface localization of 130-kDa T-cad relative to 100-kDa T-cad was also observed in normal mice aorta in vivo In conclusion, our study shows that a unique key feature of the T-cad prodomain is its involvement in binding of the T-cad repeats 1 and 2 to adiponectin and also demonstrates that adiponectin positively regulates T-cad abundance., (© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.)

We established the role of the GPCR relaxin/insulin-like family peptide receptor 1 (RXFP1 receptor) as a novel active receptor in human glioblastoma (GB), a fatal brain tumour. We identified C1q/TNF-related protein 8 (CTRP8) as a novel agonist of the RXFP1 receptor. CTRP8 enhanced the motility and matrix invasion of GB, and this involved PKC-mediated up-regulation of cathepsin B, a marker for poor prognosis in GB patients. We conclude that the absence of relaxin isoforms does not preclude the activation of the RXFP1 receptor, as the least known member of the CTRP family, CTRP8, can effectively target and activate RXFP1 receptors., Linked Articles: This article is part of a themed section on Recent Progress in the Understanding of Relaxin Family Peptides and their Receptors. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.10/issuetoc., (© 2016 The British Pharmacological Society.)

Adiponectin is the most abundant adipose-released protein that circulates in human plasma at high concentrations. The neuropeptides orexin A (OXA, hypocretin-1) and orexin B (OXB, hypocretin-2) are derived from a common precursor peptide, prepro-orexin and are produced mainly by neurons located in the lateral hypothalamus. It has been demonstrated that the peptides such as adiponectin and orexins have an important role in the regulation of energy metabolism and neuroendocrine functions. These hormones appear to be implicated in both normal and disturbed pregnancy. The objectives of this study were to determine adiponectin and orexin concentrations in the plasma and uterine luminal fluid (ULF) of pigs during early gestation and to explore the relationships between hormone concentrations and stages of pregnancy. The greatest plasma concentrations of adiponectin were observed on days 15-16 and 27-28 of pregnancy, and the least concentrations were on days 30-32 of gestation and on days 10-11 of the oestrous cycle. In ULF, adiponectin concentrations were greater on days 15-16 of pregnancy and on days 10-11 of the oestrous cycle than on days 10-11 and days 12-13 of pregnancy. The greatest OXA concentrations in the blood plasma were noted on days 10-16 of gestation, and the least OXA concentrations were on days 27-32 of pregnancy and on days 10-11 of the oestrous cycle. Orexin A concentrations in ULF were greater on days 10-11 of the cycle than throughout pregnancy. Serum OXB concentrations were greatest on days 10-11 and 30-32 of pregnancy, and least on days 12-28 of gestation. The greatest OXB concentrations in ULF were on days 10-13 of gestation, and the least OXB concentrations were on days 15-16 of pregnancy. This is first study to demonstrate the presence of adiponectin and orexins in the serum and ULF during early pregnancy of pigs as well as the relationships between adiponectin and orexin concentrations and the stage of pregnancy. The fluctuations in adiponectin and orexin concentrations in the plasma and ULF suggest that the hormones present in ULF are mostly of local origin and that these hormones participate in the processes that accompany early pregnancy., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Haemorrhagic fever with renal syndrome (HFRS) is characterised by an uncontrolled immune response that causes vascular leakage. Adiponectin (APN) is an adipocytokine involved in prorevascularisation and immunomodulation. To investigate the possible effects of APN in the pathogenesis of HFRS, total and high molecular weight (HMW) APN levels in the plasma of patients with HFRS were quantified using enzyme-linked immunosorbent assay (ELISA). Compared with those in healthy controls, the plasma total and HMW APN levels in patients were elevated to different degrees from the fever onset and remained high at the convalescent phase. Consistent with these results, western blot analysis additionally showed that low molecular weight (LMW), middle molecular weight (MMW), and HMW APN levels were all elevated and contributed to the elevation of the total APN level. Importantly, sustained high levels of total and HMW APN at the convalescent phase were significantly higher in patients with critical disease than those in patients with mild or moderate disease. Moreover, total and HMW APN levels negatively correlated with white blood cell count and positively correlated with platelet count and serum albumin level. These results may provide insights into understanding the roles of total and HMW APN in the pathogenesis of HFRS.