Low Molecular Weight Adiponectin Research Articles

Adiponectin and Glucocorticoids Modulate Risk for Preterm Birth: The Healthy Start Study.

Adiponectin is a potent uterine tocolytic that decreases with gestational age, suggesting it could be a maternal metabolic quiescence factor. Maternal stress can influence preterm birth risk, and adiponectin levels may be stress-responsive. We characterized associations between adiponectin and glucocorticoids with preterm birth and modeled their predictive utility. We hypothesized maternal plasma adiponectin and cortisol are inversely related and lower adiponectin and higher cortisol associate with preterm birth. We performed a nested case-control study using biobanked fasting maternal plasma. We included low-risk singleton pregnancies, and matched 1:3 (16 preterm, 46 term). We quantified total, high (HMW), and low molecular weight (LMW) adiponectin using ELISA. We validated an HPLC-MS/MS serum assay for use in plasma, to simultaneously measure cortisol, cortisone, and five related steroid hormones. We used linear/logistic regression to compare group means and machine learning for predictive modeling. The preterm group had lower mean LMW adiponectin (3.07 μg/mL vs. 3.81 μg/mL at 15w0d, P=0.045) and higher mean cortisone (34.4 ng/mL vs. 29.0 ng/mL at 15w0d, P=0.031). The preterm group had lower cortisol-to-cortisone and lower LMW adiponectin-to-cortisol ratios. We found HMW adiponectin, cortisol-to-cortisone ratio, cortisone, maternal height, age, and pre-pregnancy BMI most strongly predicted preterm birth (AUROC=0.8167). In secondary analyses, we assessed biomarker associations with maternal self-reported psychosocial stress. Lower perceived stress associated with a steeper change in cortisone in the term group. Overall, metabolic and stress biomarkers associated with preterm birth in this healthy cohort. We identify a possible mechanistic link between maternal stress and metabolism for pregnancy maintenance.

FRI406 Maternal Biomarkers Of Adiposity And Stress For Preterm Birth

Abstract Disclosure: G. Mayne: None. P.E. DeWitt: None. J. Wen: None. U. Christians: None. D. Dabelea: None. J. Schulkin: None. K. Hurt: None. Background: Adiponectin is a potent uterine tocolytic and decreases with gestational age, so it could be a maternal metabolic quiescence factor during pregnancy. Maternal stress can influence risk for preterm birth, and adiponectin may be inversely related to cortisol. Therefore, we characterized a potential mechanistic link between preterm birth, adiponectin, and cortisol. In this pilot study, we hypothesized maternal plasma adiponectin and cortisol concentrations are inversely related and that lower adiponectin and higher cortisol associate with spontaneous preterm birth. Methods: We performed a nested case-control study using biobank morning fasting plasma samples, taken twice in pregnancy for the Healthy Start pre-birth cohort. We included low-risk women with singleton pregnancies and excluded mothers with major medical illness, preeclampsia, chronic hypertension, or prior preterm birth. We matched preterm cases with term controls (1:3) by gestational age at first blood sample and least variation in time between blood samples (16 preterm, 46 term). We quantified high (HMW), low molecular weight (LMW), and total adiponectin using an ELISA assay. We also quantified cortisol and five related steroid hormones from the same specimens using HPLC/mass spectrometry. We used generalized estimating equations and additive models to compare group means and associations between adiponectin and cortisol. We used machine learning with gradient boosting for predictive modeling. Results: Contrary to our hypothesis, total, HMW, and LMW adiponectin positively associated with cortisol across gestation (P<0.001 for all), however the association was reduced in the preterm compared with term group and significantly so for LMW (P=0.044). In predictive modelling, HMW adiponectin, maternal pre-pregnancy BMI, maternal age, and cortisol were the four most highly relevant predictors for preterm birth (AUROC=0.704). Conclusion: In healthy low-risk patients, we found associations between adiponectin and cortisol differ across gestation for pregnancies ending with term or preterm delivery and have some predictive value in this cohort. This suggests a possible mechanistic link between maternal metabolism and stress for pregnancy maintenance. These biomarkers may prove useful as predictors in larger studies and might indicate possible maternal metabolic therapies for preterm birth prevention. Presentation: Friday, June 16, 2023

APN Expression in Serum and Corpus Luteum: Regulation of Luteal Steroidogenesis Is Possibly Dependent on the AdipoR2/AMPK Pathway in Goats

Adiponectin (APN) is an essential adipokine for a variety of reproductive processes. To investigate the role of APN in goat corpora lutea (CLs), CLs and sera from different luteal phases were collected for analysis. The results showed that the APN structure and content had no significant divergence in different luteal phases both in CLs and sera; however, high molecular weight APN was dominant in serum, while low molecular weight APN was more present in CLs. The luteal expression of both AdipoR1/2 and T-cadherin (T-Ca) increased on D11 and 17. APN and its receptors (AdipoR1/2 and T-Ca) were mainly expressed in goat luteal steroidogenic cells. The steroidogenesis and APN structure in pregnant CLs had a similar model as in the mid-cycle CLs. To further explore the effects and mechanisms of APN in CLs, steroidogenic cells from pregnant CLs were isolated to detect the AMPK-mediated pathway by the activation of APN (AdipoRon) and knockdown of APN receptors. The results revealed that P-AMPK in goat luteal cells increased after incubation with APN (1 μg/mL) or AdipoRon (25 μM) for 1 h, and progesterone (P4) and steroidogenic proteins levels (STAR/CYP11A1/HSD3B) decreased after 24 h. APN did not affect the steroidogenic protein expression when cells were pretreated with Compound C or SiAMPK. APN increased P-AMPK and reduced the CYP11A1 expression and P4 levels when cells were pretreated with SiAdipoR1 or SiT-Ca, while APN failed to affect P-AMPK, the CYP11A1 expression or the P4 levels when pretreated with SiAdipoR2. Therefore, the different structural forms of APN in CLs and sera may possess distinct functions; APN might regulate luteal steroidogenesis through AdipoR2 which is most likely dependent on AMPK.

Relationship between adiponectin multimer levels and subtypes of cerebral infarction.

Serum adiponectin levels are decreased in patients with cerebral infarction. Adiponectin in circulation exists in three isoforms: high molecular weight (HMW), medium molecular weight (MMW), and low molecular weight (LMW) adiponectin. We measured serum levels of total adiponectin and adiponectin multimers (HMW, MMW, and LMW) in patients with cerebral infarction and compared the serum levels of the three adiponectin multimers in stroke subtypes. We also evaluated the clinical value of adiponectin multimer levels as a biomarker for cerebral infarction. We assessed a total of 132 patients with cerebral infarctions. The serum levels of total and adiponectin multimers were measured using enzyme-linked immunosorbent assay (ELISA). The total and HMW adiponectin levels were significantly lower in atherothrombotic infarction (AI) than in cerebral embolism (CE) (total, p < 0.05; HMW, p < 0.05). In male patients, the MMW adiponectin level was significantly lower in the lacunar infarction (LI) group than in the AI group (p < 0.05). The LMW adiponectin level was significantly lower in the AI group than in the LI and CE groups (LI, p < 0.001; CE, p = 0.001). However, there were no significant differences in adiponectin multimer levels among the stroke subtypes in female subjects. Additionally, in female patients with AI and LI, the LMW adiponectin levels were negatively associated with C-reactive protein (CRP; AI, p < 0.05; LI, p < 0.05). These findings suggest that a decrease in adiponectin is associated with AI and that serum LMW adiponectin level represents a potential biomarker for AI.

Constant-moderate versus high-intensity interval training on heart adiponectin levels in high-fat fed mice: a preventive and treatment approach

Context Research has described that adiponectin plays a key role in cardiomyocytes metabolism, however, the effects of exercise during obesity on cardiac adiponectin levels is unclear. Objective To investigate the effects of constant-moderate endurance (END) and high-intensity interval training (HIIT), on heart adiponectin levels in mice. Material and methods Two experiments were conducted: (1) preventive (EX1): 10 week-old male mice were fed standard (CHOW) or high-fat diet (HFD;45% fat) and simultaneously trained with END and HIIT for 10 weeks; (2) Treatment (EX2): after 10 weeks of dietary intervention, another cohort of 10 week-old mice were trained by both programmes for 10 weeks. Results In EX1, END and HIIT decreased low-molecular weight adiponectin (∼0.5-fold; p < 0.05) and increased GLUT4 levels (∼2-fold; p < .05). In EX2, HFD significantly decreased high-molecular weight adiponectin (∼0.7-fold; p < .05), and END reversed this change. Discussion and conclusion: HFD and exercise influence heart adiponectin isoforms and therefore might impact cardiomyocyte metabolism.

Middle- and high-molecular weight adiponectin levels in relation to nonalcoholic fatty liver disease.

ObjectiveAdiponectin (APN) circulates as high‐molecular weight (HMW), medium‐molecular weight (MMW), and low‐molecular weight (LMW) forms. Nonalcoholic fatty liver disease (NAFLD) is a common cause of chronic liver disease. Currently, the role of LMW, MMW, and HMW APN remains largely unclear in NAFLD.MethodsWe examined the variation of these forms and analyzed the related clinical characteristics in NAFLD. A total of 63 male NAFLD patients (mean age: 43.00 ± 6.10 years) and 70 healthy male subjects (mean age: 42.53 ± 7.98 years) were included in the study. Total APN and other clinical characteristics were measured. The changes in HMW, MMW, and LMW APN were determined in NAFLD patients and NAFLD patients on a high‐fat diet, and the association between the groups was further analyzed.ResultsDecreased levels of total APN and three APN isoforms were found in NAFLD. Significantly decreased levels of HMW (P < .01) and MMW (P < .001) were observed in NAFLD of high‐fat diet patients. In NAFLD patients, height (R = −.270, P = .032) and N‐epsilon‐(carboxymethyl) lysine (R = −.259, P = .040) significantly correlated with total APN. HMW APN was significantly associated with fasting plasma glucose (R = .350, P = .016), alanine aminotransferase (R = −.321, P = .029), and aspartate aminotransferase (R = −.295, P = .045). Additionally, MMW APN was significantly associated with total cholesterol (R = .357, P = .014) and high‐density lipoprotein (R = .556, P < .0001). Low‐density lipoprotein (R = −.283, P = .054) was also clearly associated with LMW APN in NAFLD patients.ConclusionThese results suggest that HMW and MMW APN may be involved in the pathogenesis and progression of NAFLD.

Changes of different subtypes of adiponectin in epicardial fat in patients with coronary heart disease

Objective To study the difference of the secretion and synthesis of adiponectin in different parts of adipose tissue in patients with coronary heart disease (CHD). Methods The serum, epicardial adipose tissue (EAT) and subcutaneous adipose tissue (SAT) in over 50-years old male patients with CHD or valvular heart disease as control group. The patients with CHD were excluded by coronary angiography in control group. Serum adiponectin concentrations were examined in CHD group and control group by enzyme linked immunosorbent assay (ELISA). Serum adiponectin types were classified in accordance with the molecular weight of high-molecular-weight (HMW), medium molecular weight (MMW) and low molecular weight (LMW) in CHD group and non-CHD group by gel filtration chromatography. Real-time PCR was used to detect the expression of adiponectin mRNA in epicardial adipose cells and subcutaneous adipose cells. The levels of HMW MMW LMW adiponectin in adipose cells were determined by non-hearting and non-reducing sodium dodecyl sulfate polyacrylamide gel electropheresis (SDS-PAGE). Results As compared with non-CHD group, the concentration of serum HMW in CHD group was significantly reduced [(0.55±0.18) mg/L vs. (0.31±0.12) mg/L, t=3.472, P 0.05; LMW: (0.48±0.22) mg/L vs. (0.53±0.20) mg/L, t=1.712, P>0.05]. The expression of adiponectin mRNA in CAD epicardial group was significnatly downregulated when compared with autologous subcutaneous group (0.810±0.101 vs. 1.102±0.135, t=3.351, P<0.01) and control epicardial group (0.810±0.101 vs. 1.008±0.146, t=3.363, P<0.01). The proteomics revealed that the HMW content in CHD group decreased significantly as compared with non-CHD epicardial group and subcutaneous tissue group, and the rest two types of adiponectin showed no statistically significant differences. Conclusion The low expression of adiponectin in patients with CHD is located in the EAT and mainly decreased as the form of HMW adiponectin. Key words: Adiponectin; Epicardial adipose tissue; Coronary artery disease

Plasma adiponectin array in women with Alzheimer's disease.

Introduction Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative disease. Typical features of AD include memory loss, social dysfunction and physical impairment. Although the pathological findings in the central nervous system are well established, the etiological factors are poorly known. Recent studies suggested the role of metabolic disturbances in the development of AD neurodegeneration. Adiponectin, an anti-inflammatory and metabolism regulating factor, was linked to AD. Aim The aim was to examine whether adiponectin fractions combined with insulin/insulin resistance-associated metabolic parameters correlate with AD progression. Material and methods The study comprised 98 women: 27 with moderate to severe AD, 31 with AD at early stage and 40 healthy controls, matched for age and BMI. To evaluate memory impairment, the MMSE was performed. Plasma total adiponectin and its high-, medium- and low molecular weights were measured with ELISA. Anthropometric, clinical and metabolic parameters were assessed. Correlations between adiponectin array and measured parameters were evaluated. Results In comparison to the controls, enhanced levels of total and medium molecular weight adiponectin characterized AD individuals. In AD, we found correlations between adiponectin array, and anthropometric and biochemical parameters. After adjustment to BMI, a significant increase of the total adiponectin and high- and medium molecular weight fractions was observed. A negative correlation between low molecular weight adiponectin and MMSE was found. Conclusions Our results indicate a possible link between adiponectin variations and AD. We hypothesize that changes in adiponectin profile observed in AD result from compensatory mechanism against neuropathological processes, as well as from adiponectin homeostasis impairment.

Adiponectin multimers in patients with Barrett’s Oesophagus

Barrett’s oesophagus is associated with abdominal obesity. Adiponectin is a peptide that is secreted from adipocytes and circulates in three multimeric forms: low molecular weight (LMW), middle molecular weight (MMW), and high molecular weight (HMW). The anti- inflammatory effects of adiponectin are specific to individual multimers, with the LMW being most anti-inflammatory. We investigated the possibility that circulating levels of adiponectin and its multimers would be associated with the risk of Barrett’s oesophagus. Subjects and methods This study comprised patients diagnosed to have Barrett’s oesophagus, and control subjects diagnosed to have gastrooesophageal reflux disease (GORD), all were diagnosed in the gastroenterology and endoscopy unit, King Fahd hospital, Riyadh, Saudi Arabia. Plasma adiponectin levels and its multimers were evaluated for patients with Barrett’s oesophagus and controls with GORD. Results There were 120 cases of Barrett’s oesophagus and 250 GORD controls. Total adiponectin was not significantly associated with Barrett’s oesophagus; low levels of LMW adiponectin and low LMW/total ratio were significantly present in patients with Barrett’s oesophagus. Conclusion Low levels of LMW adiponectin are significantly associated with Barrett’s oesophagus.

Differential metabolic effects of constant moderate versus high intensity interval training in high-fat fed mice: possible role of muscle adiponectin.

Exercise regimens may have differing effects in the presence of obesity. In addition to being fat derived, adiponectin has recently been described as a myokine that regulates insulin sensitivity, which may link to exercise‐related metabolic benefits in obesity. Whether skeletal muscle adiponectin varies in different exercise modalities is unclear. This study investigated the comparative effects of 10 weeks of endurance constant‐moderate intensity exercise (END) with high intensity interval training (HIIT), on metabolic outcomes, including muscle adiponectin in a mouse model of diet‐induced obesity. Ten‐week‐old male C57BL/6 mice were fed a high‐fat diet (HFD) (45% FAT) or standard CHOW diet ab libitum and underwent one of three training regimes: (1) no exercise, (2) END, or (3) HIIT (8 bouts of 2.5 min with eight periods of rest of 2.5 min) for 10 weeks (3 × 40 min sessions/week). Chow‐fed mice acted as controls. Compared with HFD alone, both training programs similarly protected against body weight gain (HFD = 45 ± 2; END = 37 ± 2; HIIT = 36 ± 2 g), preserved lean/fat tissue mass ratio (HFD = 0.64 ± 0.09; END = 0.34 ± 0.13; HIIT = 0.33 ± 0.13), and improved blood glucose excursion during an insulin tolerance test (HFD = 411 ± 54; END = 350 ± 57; HIIT = 320 ± 66 arbitrary units [AU]). Alterations in fasting glycemia, insulinemia, and AST/ALT ratios were prevented only by END. END, but not HIIT increased skeletal muscle adiponectin mRNA (14‐fold; P < 0.05) and increased protein content of high molecular weight (HMW) adiponectin (3.3‐fold), whereas HIIT induced a milder increase (2.4‐fold). Compared with HFD, neither END nor HIIT altered circulating low (LMW) or high (HMW) molecular weight adiponectin forms. Furthermore, only END prevented the HFD downregulation of PGC1α (P < 0.05) mRNA levels downstream of muscle adiponectin. These data show that different training programs affect muscle adiponectin to differing degrees. Together these results suggest that END is a more effective regimen to prevent HFD‐induced metabolic disturbances in mice.

A study of high-, middle- and low-molecular weight adiponectin in urine as a surrogate marker for early diabetic nephropathy using ultrasensitive immune complex transfer enzyme immunoassay.

Background For the early identification of patients at risk of developing diabetic nephropathy, we have developed an ultrasensitive immune complex transfer enzyme immunoassay to measure adiponectin in urine. Methods We developed immune complex transfer enzyme immunoassay for adiponectin and measured urinary adiponectin from 70 healthy subjects, 35 obese non-diabetic subjects and 20 patients with diabetes. Results The urinary adiponectin concentrations in patients with diabetes (3.3 ± 10.7 ng/mg creatinine) were significantly higher than those in obese subjects (0.54 ± 0.44; P < 0.01) and healthy subjects (0.46 ± 0.42; P < 0.001). The gel filtration elution profile of urine from healthy subjects showed traces of four immunoreactive peaks (high-, medium-, low-molecular weight and monomer molecules), despite the majority of blood adiponectin being high-molecular weight. However, urinary adiponectin molecules were more frequent in low-molecular weight as the estimate glomerular filtration rate decreased. Furthermore, as blood glucose concentrations rose, middle-molecular weight and high-molecular weight increased in urine. Further, urinary adiponectin concentrations correlated with estimate glomerular filtration rate ( r = -0.61, P < 0.001), but not urinary albumin. In addition, our analysis showed a significantly ( P < 0.001) higher value for urinary adiponectin in the G2 stage of chronic kidney disease classification where urinary albumin is not elevated. Conclusion Adiponectin increases in urine as renal function decreases, and urinary adiponectin may be useful as a surrogate marker for diabetic nephropathy risk.

Low Molecular Weight Adiponectin Increases the Mortality Risk in Very Old Patients.

Despite its beneficial role on insulin resistance and atherosclerosis, adiponectin has been frequently reported as an independent positive predictor of cardiovascular mortality. Very few information is available regarding adiponectin isoforms and mortality, in particular in advanced aging. Baseline serum levels of Total Adiponectin and its circulating isoforms (HMW-, MMW-, LMW-Adiponectin) were measured in 97 old patients (mean age: 79 years). Patients were followed up for all-cause mortality (study end-point) for an average of 76.4 ± 37.3 months. A positive association was observed for LMW-Ad and all-cause mortality (HR: 1.13, 95% CI: 1.05-1,22, p: 0.002). After multivariate adjustment for age, sex and a previous history of myocardial infarction, higher levels of LMW-Ad were significantly associated with all-cause mortality (HR: 1.11, 95% CI: 1.02-1.21; p: 0.017). Interestingly neither total adiponectin neither the other two circulating isoforms (MMW- and HMW-Ad) showed any significant association with the study end-point. Our data suggest that the association between high serum adiponectin levels and increased mortality rate in elderly is contingent to an unbalanced circulating levels of adiponectin isoforms. The present results support the hypothesis that high levels of Low Molecular Weight adiponectin are a biomarker for mortality risk in very old patients.

Impaired peripheral insulin sensitivity in non-obese Japanese patients with type 2 diabetes mellitus and fatty liver.

Aims/IntroductionType two diabetes mellitus and fatty liver (FL) are not uncommon in Asians with normal body mass index. Previous studies reported a link between FL and insulin resistance. Thus, FL could coexist with insulin resistance in Asian type two diabetes mellitus patients with a normal body mass index. However, the clinical and metabolic features of such patients have not been characterized yet.Materials and MethodsWe recruited 29 non‐obese (body mass index <25 kg/m2) Japanese patients with early type two diabetes mellitus. Based on intrahepatic lipid level measured by H‐magnetic resonance spectroscopy, the participants were divided into the FL (intrahepatic lipid ≥5%, n = 7) and non‐FL groups (intrahepatic lipid <5%, n = 22).ResultsPeripheral insulin sensitivity measured by hyperinsulinemic euglycemic clamp was ~25% lower in the FL group than in the non‐FL group, whereas hepatic insulin sensitivity was comparable between the two groups. The subcutaneous fat area was larger, free fatty acid level was higher, C‐reactive protein was higher and high molecular weight adiponectin was lower in the FL group than the non‐FL group.ConclusionsThe present study showed that the metabolic features of non‐obese Japanese type two diabetes patients with FL include impaired peripheral (mainly muscle) insulin sensitivity, fat accumulation and related metabolic disorders, such as elevated free fatty acid, low high molecular weight adiponectin and low‐grade inflammation.

Acute Vitamin D₃ Supplementation in Severe Obesity: Evaluation of Multimeric Adiponectin.

Obesity predisposes to vitamin D deficiency (VDD) and glucose abnormalities. It is currently debated if vitamin D administration may improve glucose homeostasis by interacting with modulators of insulin sensitivity, such as adiponectin and its oligomers. In a 4-week inpatient study on a metabolic rehabilitation program, consisting of individualized caloric restriction and aerobic physical exercise in obese subjects with VDD, we assessed the acute effects of 600,000 IU cholecalciferol given per os VD group, 12 subjects; body mass index (BMI) 42.7 ± 1.3 kg/m2) or placebo per os (PL group, 12 subjects, BMI 39.8 ± 0.9 kg/m2) on high (HWM-A), medium (MMW-A), and low molecular weight adiponectin (LMW-A), as quantified by western immunoblot (WIB) and ELISA. During the 4-week study, dieting promoted a similar magnitude of weight loss in VD and PL groups. Compared to the PL group, cholecalciferol administration increased 25(OH)Vit D levels (p < 0.001) and promoted a significant increase of HMW-A expression analyzed by WIB (p = 0.02). In parallel, a significant decrease of leptin/HMW-A ratio (p < 0.05), a biomarker of metabolic homeostasis, was observed. During the study, changes of MMW-A and LMW-A occurred independently of cholecalciferol administration, and were likely explained by weight loss. At odds with these findings, the ELISA assessment of adiponectin oligomers showed no modifications in the VD group or PL group. Current findings suggest that acute cholecalciferol administration selectively modifies HMW-A and the leptin/HMW-A ratio.

Changes in the Composition of Adiponectin Fractions over a 3-Year Period in Children: A Population-Based Cohort Study.

Little information is available regarding changes in adiponectin fractions. The objective of this study was to examine changes in the composition of differing adiponectin fractions using a population-based, prospective pediatric cohort. A total of 358 fourth graders (9-10 years old) from Ina town in Saitama, Japan, were followed up for 3 years. BMI and total adiponectin (TAD), high-molecular weight adiponectin (HAD), medium-molecular weight adiponectin, and low-molecular weight adiponectin levels were measured in these subjects at baseline and at the end of the follow-up. Of the fourth graders participating in the study, 326 (172 boys and 154 girls; follow-up rate, 91.1%) became available for follow-up. No significant changes were observed in TAD values after 3 years. HAD values were significantly decreased in both the boys (2.4 to 2.2 μg/mL: p < 0.001) and girls (3.1 to 2.7 μg/mL: p = 0.005). All values in the parameters examined at baseline and after 3 years were significantly correlated. A negative correlation was found between the ratios of follow-up compared to baseline values for BMI and those for TAD (boys, r = -0.322, p < 0.001; girls, r = -0.433, p < 0.001) as well as those for HAD (boys, r = -0.353, p < 0.001; girls, r = -0.351, p < 0.001). HAD had the most robust correlation between its values at baseline and those after 3 years in both boys and girls. The changes in HAD also had the most robust correlation between the changes in BMI in 3 years.

Role of adiponectin gene variants, adipokines and hydrometry-based percent body fat in metabolically healthy and abnormal obesity

Metabolically healthy obesity (MHO) subjects have better metabolic parameters than metabolically abnormal obesity (MAO) subjects, but the possible mechanisms underlying this remain unknown. Our study was designed to investigate the interrelationships among genes, adipokines, body fat and its distribution in MHO and MAO. From 2007 to 2009, 103 males and 131 females aged 18-50 years were enrolled by an intention-to-treat design in a weight management clinic. Participants were divided into MHO and MAO groups. Percent body fat (PBF) was measured by a deuterium oxide dilution method. Four polymorphic variants, including PPARγ2 (Pro12Ala and C1431T) and adiponectin (T45G and G276T) genes, and three adipokines (adiponectin, leptin and resistin) were obtained. Of the 234 obese subjects, 130 (55.6%) were MHO. In the univariate analysis, the MAO group has significantly higher anthropometric, metabolic indices and leptin levels than the MHO group. Logistic regression analysis revealed that age, male gender, the T allele of adiponectin T45G polymorphism, leptin and PBF were positively associated with MAO. ANCOVA analysis revealed that the T allele of adiponectin T45G polymorphism was associated with higher fasting and postprandial glucose levels. We further found that TT genotype has a lower high molecular weight (HMW)/low molecular weight (LMW) adiponectin ratio than GG genotype. The factors associated with MAO are age, male gender, the T allele of adiponectin T45G polymorphism, leptin, and PBF. The net effects of T45G polymorphism on the MAO phenotype may be achieved by changes in the adiponectin oligomer ratio and glucose levels.

Adiponectin Isoforms and Leptin Impact on Rheumatoid Adipose Mesenchymal Stem Cells Function.

Adiponectin and leptin have recently emerged as potential risk factors in rheumatoid arthritis (RA) pathogenesis. In this study we evaluated the effects of adiponectin and leptin on immunomodulatory function of adipose mesenchymal stem cells (ASCs) derived from infrapatellar fat pad of RA patients. ASCs were stimulated with leptin, low molecular weight (LMW) and high/middle molecular weight (HMW/MMW) adiponectin isoforms. The secretory activity of ASCs and their effect on rheumatoid synovial fibroblasts (RA-FLS) and peripheral blood mononuclear cells (PBMCs) from healthy donors have been analysed. RA-ASCs secreted spontaneously TGFβ, IL-6, IL-1Ra, PGE2, IL-8, and VEGF. Secretion of all these factors was considerably upregulated by HMW/MMW adiponectin, but not by LMW adiponectin and leptin. Stimulation with HMW/MMW adiponectin partially abolished proproliferative effect of ASC-derived soluble factors on RA-FLS but did not affect IL-6 secretion in FLS cultures. ASCs pretreated with HMW/MMW adiponectin maintained their anti-inflammatory function towards PBMCs, which was manifested by moderate PBMCs proliferation inhibition and IL-10 secretion induction. We have proved that HMW/MMW adiponectin stimulates secretory potential of rheumatoid ASCs but does not exert strong impact on ASCs function towards RA-FLS and PBMCs.

Issue Highlights

Issue Highlights

Regulation and Quality Control of Adiponectin Assembly by Endoplasmic Reticulum Chaperone ERp44

Adiponectin, a collagenous hormone secreted abundantly from adipocytes, possesses potent antidiabetic and anti-inflammatory properties. Mediated by the conserved Cys(39) located in the variable region of the N terminus, the trimeric (low molecular weight (LMW)) adiponectin subunit assembles into different higher order complexes, e.g. hexamers (middle molecular weight (MMW)) and 12-18-mers (high molecular weight (HMW)), the latter being mostly responsible for the insulin-sensitizing activity of adiponectin. The endoplasmic reticulum (ER) chaperone ERp44 retains adiponectin in the early secretory compartment and tightly controls the oxidative state of Cys(39) and the oligomerization of adiponectin. Using cellular and in vitro assays, we show that ERp44 specifically recognizes the LMW and MMW forms but not the HMW form. Our binding assays with short peptide mimetics of adiponectin suggest that ERp44 intercepts and converts the pool of fully oxidized LMW and MMW adiponectin, but not the HMW form, into reduced trimeric precursors. These ERp44-bound precursors in the cis-Golgi may be transported back to the ER and released to enhance the population of adiponectin intermediates with appropriate oxidative state for HMW assembly, thereby underpinning the process of ERp44 quality control.

The effect of multimeric adiponectin isoforms and leptin on the function of rheumatoid fibroblast-like synoviocytes

Objectives: To evaluate the effects of physiologically relevant concentrations of multimeric adiponectin isoforms and leptin on the function of fibroblast-like synoviocytes (FLS) from patients with rheumatoid arthritis (RA).Method: FLS, isolated from the synovial tissue of 21 RA patients, were stimulated for 24 h with interleukin (IL)-1β (1 ng/mL) and adiponectin isoforms [fraction enriched with high-molecular-weight (HMW) oligomers and middle-molecular-weight (MMW) hexamers or low-molecular-weight (LMW) trimers, 10 μg/mL each], or leptin (10 ng/mL), either separately or in a combination of IL-1β and the respective adipokine. Moreover, cells were pre-treated for 24 h with adipokines, then stimulated for 8 h with IL-1β. The concentrations of IL-6, IL-8, matrix metalloproteinase (MMP)-3, and dickkopf (DKK)-1, an inhibitor of osteoblastogenesis, in culture supernatants, as well as the concentrations of leptin, HMW, MMW, and LMW adiponectin in sera and synovial fluid (SF) samples, were measured by specific enzyme-linked immunosorbent assays (ELISAs).Results: In comparison with sera, SF samples contained similar amounts of leptin, lower amounts of total adiponectin but a higher proportion of the LMW isoform. Separately added IL-1β and HMW/MMW adiponectin, but not LMW adiponectin or leptin, up-regulated the release of IL-6, IL-8, and MMP-3 from FLS but no synergy was observed in co-stimulation experiments. However, pre-treatment of FLS with HMW/MMW or LMW significantly raised the IL-1β-triggered secretion of MMP-3 and IL-6 or MMP-3, respectively.Conclusions: Adiponectin not only triggers pro-inflammatory and pro-destructive activities of rheumatoid FLS but also pre-disposes these cells to a stronger response to IL-1β. Thus, it is likely that adiponectin is more important in the initiation phase than in the chronic phase of RA.