The causal impact of gut microbiota on circulating adipokine concentrations: a two-sample Mendelian randomization study.

PURPOSE: Evidence from previous experimental and observational research demonstrates that the gut microbiota is related to circulating adipokine concentrations. Nevertheless, the debate as to whether gut microbiome composition causally influences circulating adipokine concentrations remains unresolved. This study aimed to take an essential step in elucidating this issue. METHODS: We used two-sample Mendelian randomization (MR) to causally analyze genetic variation statistics for gut microbiota and four adipokines (including adiponectin, leptin, soluble leptin receptor [sOB-R], and plasminogen activator inhibitor-1 [PAI-1]) from large-scale genome-wide association studies (GWAS) datasets. A range of sensitivity analyses was also conducted to assess the stability and reliability of the results. RESULTS: The composite results of the MR and sensitivity analyses revealed 22 significant causal associations. In particular, there is a suggestive causality between the family Clostridiaceae1 (IVW: ß = 0.063, P = 0.034), the genus Butyrivibrio (IVW: ß = 0.029, P = 0.031), and the family Alcaligenaceae (IVW: ß=-0.070, P = 0.014) and adiponectin. Stronger causal effects with leptin were found for the genus Enterorhabdus (IVW: ß=-0.073, P = 0.038) and the genus Lachnospiraceae (NK4A136 group) (IVW: ß=-0.076, P = 0.01). Eight candidate bacterial groups were found to be associated with sOB-R, with the phylum Firmicutes (IVW: ß = 0.235, P = 0.03) and the order Clostridiales (IVW: ß = 0.267, P = 0.028) being of more interest. In addition, the genus Roseburia (IVW: ß = 0.953, P = 0.022) and the order Lactobacillales (IVW: ß=-0.806, P = 0.042) were suggestive of an association with PAI-1. CONCLUSION: This study reveals a causal relationship between the gut microbiota and circulating adipokines and may help to offer novel insights into the prevention of abnormal concentrations of circulating adipokines and obesity-related diseases.

Adiponectin overexpression improves metabolic abnormalities caused by acid ceramidase deficiency but does not prolong lifespan in a mouse model of Farber Disease.

Farber Disease is a debilitating and lethal childhood disease of ceramide accumulation caused by acid ceramidase deficiency. The potent induction of a ligand-gated neutral ceramidase activity promoted by adiponectin may provide sufficient lowering of ceramides to allow for the treatment of Farber Disease. In vitro, adiponectin or adiponectin receptor agonist treatments lowered total ceramide concentrations in human fibroblasts from a patient with Farber Disease. However, adiponectin overexpression in a Farber Disease mouse model did not improve lifespan or immune infiltration. Intriguingly, mice heterozygous for the Farber Disease mutation were more prone to glucose intolerance and insulin resistance when fed a high-fat diet, and adiponectin overexpression protected from these metabolic perturbations. These studies suggest that adiponectin evokes a ceramidase activity that is not reliant on the functional expression of acid ceramidase, but indicates that additional strategies are required to ameliorate outcomes of Farber Disease.

Exploring oxidative stress, immunological and metabolic biomarkers in dairy cows with postpartum pyometra.

Pyometra is a prevalent and severe infectious disease that affects the reproductive systems of cattle worldwide. This study's main goal was to investigate the biomarkers for oxidative stress (OS), adiponectin, leptin and neopterin (NPT) in cows suffering from postpartum pyometra. The study also aimed to determine which bacteria were most commonly implicated in the development of the disease. A total of 74 cows with pyometra were examined and compared to a control group of healthy cows (n = 20). In comparison to the healthy control and post-treatment groups, the pyometra group showed higher mean values of leptin, adiponectin and malondialdehyde (MDA). In contrast, the glutathione (GSH) and superoxide dismutase (SOD) mean values were lower in the pyometra group as compared to the post-treatment and control groups. NPT levels in the post-treatment groups were lower than those in cows with pyometra but comparable to the healthy control group (p > .05). When compared to the other biomarkers, NPT, leptin and adiponectin showed higher sensitivity and specificity in identifying pyometra cases (AUC ≥0.99). The predominant bacterial isolates from the ptomtra-affected cows consisted of Escherichia coli (N = 29; 39.2%), Arcanobacterium pyogenes (N = 27; 36.5%) and Fusobacterium necrophorum (N = 13; 17.6%). Mixed infection was determined in nine samples (12.2%). Conclusively, OS, adiponectin, leptin and NPT play crucial roles in comprehending the development of postpartum pyometra in cows and have the potential to serve as biomarkers for the disease.

Hypertension and diabetes, but not leptin and adiponectin, mediate the relationship between body fat and chronic kidney disease.

PURPOSE: Obesity may promote kidney damage through hemodynamic and hormonal effects. We investigated the association between body mass index (BMI), total body fat (TBF) and chronic kidney disease (CKD) and whether hypertension, diabetes, leptin and adiponectin mediated these associations. METHODS: In this cross-sectional analysis of the Netherlands Epidemiology of Obesity study, 6671 participants (45-65 y) were included. We defined CKD as eGFR <60 ml/min/1.73 m2 and/or moderately increased albuminuria. The percentage of mediation was calculated using general structural equation modeling, adjusted for potential confounding factors age, sex, smoking, ethnicity, physical activity and Dutch healthy diet index. RESULTS: At baseline mean (SD) age was 56 (6), BMI 26.3 (4.4), 44% men, and 4% had CKD. Higher BMI and TBF were associated with 1.08 (95%CI 1.05; 1.11) and 1.05-fold (95%CI 1.02; 1.08) increased odds of CKD, respectively. As adiponectin was not associated with any of the outcomes, it was not studied further as a mediating factor. The association between BMI and CKD was 8.5% (95%CI 0.5; 16.5) mediated by diabetes and 22.3% (95%CI 7.5; 37.2) by hypertension. In addition, the association between TBF and CKD was 9.6% (95%CI -0.4; 19.6) mediated by diabetes and 22.4% (95%CI 4.2; 40.6) by hypertension. We could not confirm mediation by leptin in the association between BMI and CKD (35.6% [95%CI -18.8; 90.3]), nor between TBF and CKD (59.7% [95%CI -7.1; 126.6]). CONCLUSION: Our results suggest that the relations between BMI, TBF and CKD are in part mediated by diabetes and hypertension.

Sexual Dimorphism's impact on adipogenesis: A three-dimensional in vitro model treated with 17ß-estradiol and testosterone.

Using a three-dimensional (3-D) in vitro culture model, we report the dose dependent effect of 17ß-estradiol and testosterone on the adipogenic differentiation and maturation of human adipose derived stem cells (hASCs) obtained from female and male patients. Considering sexual dimorphism, we expected male and female adipocytes to respond differently to the sex steroids. Both male and female hASC spheroids were exposed to 100 nM and 500 nM of 17ß-estradiol and testosterone either at the beginning of the adipogenic maturation (Phase I) to discourage intracellular triglyceride accumulation or exposed after adipogenic maturation (Phase II) to reduce the intracellular triglyceride accumulation. The results show that 17ß-estradiol leads to a dose dependent reduction in intracellular triglyceride accumulation in female hASC spheroids compared to the both untreated and testosterone-treated cells. Affirming our hypothesis, 17ß-estradiol prevented intracellular triglyceride accumulation during Phase I, while it stimulated lipolysis during Phase II. PPAR-γ and adiponectin gene expression also reduced upon 17ß-estradiol treatment in female cells. Interestingly, 17ß-estradiol and testosterone had only a modest effect on the male hASC spheroids. Collectively, our findings suggest that 17ß-estradiol can prevent fat accumulation in adipocytes during early and late stages of maturation in females.

The 40-min HIIT acutely induced bone formation which was likely through the increases in muscle derived interleukin 6 and adiponectin activation: The 16 weeks of HIIT intervention, longitudinal randomized controlled trial.

PURPOSE: There is some controversy regarding cytokines released from adipocytes, particularly adiponectin, leptin, and IL6 that regulate bone remodeling. In addition, IL6 is released from muscle contraction, which might have a distinct role in bone remodeling. Hence, this study investigated whether muscle contraction during a session of 40 min of high intensity interval training (40-min HIIT) and after 16 weeks of HIIT (16-wk HIIT) altered the release of those cytokines and bone remodeling in overweight women. METHODS: In total, 22 overweight, premenopausal women were randomly assigned to either the exercise or the control group. The exercise participants engaged in the 40-min HIIT session at 80-90 % of their heart rate reserve (HRR) three times weekly for 16 weeks, while the control participants performed their routine daily activities. Blood was drawn after overnight fasting and immediately after completing the 40-min HIIT sessions to investigate the association of adiponectin, leptin, IL6, CTX, and P1NP through the acute effect of the 40-min HIIT sessions. This process was repeated after the 16-wk intervention program to observe the training effect of HIIT on cytokines linkage. The bone mineral density (BMD) levels of the distal tibia, femur, and lumbar spine were determined prior to and after the 16-wk intervention using dual-energy X-ray absorptiometry. RESULTS: The P1NP level increased by 8.29-20.52 % (95 % CI) and by 2.91-15.54 % after completing the first and last bouts of the 40-min HIIT sessions, respectively. In addition, IL6 increased by 13.39-28.03 % (95 % CI), while serum CTX and adiponectin were unaltered from the acute effect of the 40-min HIIT sessions. There was an association between the increases in P1NP and adiponectin (r = 0.682, p = 0.015); however, the increase in P1NP was mostly associated with the increase in IL6 (r = 0.572, p = 0.054) after completing a 40-min HIIT session. After the 16-wk HIIT program, the resting adiponectin level of the exercise participants increased; however, this was associated with neither bone biomarkers nor BMD. The BMDs of the exercise participants were maintained; however, the tibial BMD of the control participants decreased with an increase in the resting CTX level after 16 weeks. CONCLUSION: Muscle contraction during the 40-min HIIT session elevated the IL6 level, which might have subsequently enhanced bone formation. Furthermore, the association between acute changes in adiponectin and P1NP suggested the possibility of an increase in the sensitivity of the adiponectin receptor in osteoblasts.

Administration of adiponectin receptor agonist AdipoRon relieves cancer cachexia by mitigating inflammation in tumour-bearing mice.

BACKGROUND: Cancer cachexia is a life-threatening, inflammation-driven wasting syndrome that remains untreatable. Adiponectin, the most abundant adipokine, plays an important role in several metabolic processes as well as in inflammation modulation. Our aim was to test whether administration of AdipoRon (AR), a synthetic agonist of the adiponectin receptors, prevents the development of cancer cachexia and its related muscle atrophy. METHODS: The effect of AR on cancer cachexia was investigated in two distinct murine models of colorectal cancer. First, 7-week-old CD2F1 male mice were subcutaneously injected with colon-26 carcinoma cells (C26) or vehicle (CT). Six days after injection, mice were treated for 5 days with AdipoRon (50 mg/kg/day; C26 + AR) or the corresponding vehicle (CT and C26). Additionally, a genetic model, the ApcMin/+ mouse, that develops spontaneously numerous intestinal polyps, was used. Eight-week-old male ApcMin/+ mice were treated with AdipoRon (50 mg/kg/day; Apc + AR) or the corresponding vehicle (Apc) over a period of 12 weeks, with C57BL/6J wild-type mice used as controls. In both models, several parameters were assessed in vivo: body weight, grip strength and serum parameters, as well as ex vivo: molecular changes in muscle, fat and liver. RESULTS: The protective effect of AR on cachexia development was observed in both cachectic C26 and ApcMin/+ mice. In these mice, AR administration led to a significant alleviation of body weight loss and muscle wasting, together with rescued muscle strength (P < 0.05 for all). In both models, AR had a strong anti-inflammatory effect, reflected by lower systemic interleukin-6 levels (-55% vs. C26, P < 0.001 and -80% vs. Apc mice, P < 0.05), reduced muscular inflammation as indicated by lower levels of Socs3, phospho-STAT3 and Serpina3n, an acute phase reactant (P < 0.05 for all). In addition, AR blunted circulating levels of corticosterone (-46% vs. C26 mice, P < 0.001 and -60% vs. Apc mice, P < 0.05), the predominant murine glucocorticoid known to induce muscle atrophy. Accordingly, key glucocorticoid-responsive factors implicated in atrophy programmes were-or tended to be-significantly blunted in skeletal muscle by AR. Finally, AR protected against lipid metabolism alterations observed in ApcMin/+ mice, as it mitigated the increase in circulating triglyceride levels (-38%, P < 0.05) by attenuating hepatic triglyceride synthesis and fatty acid uptake by the liver. CONCLUSIONS: Altogether, these results show that AdipoRon rescued the cachectic phenotype by alleviating body weight loss and muscle atrophy, along with restraining inflammation and hypercorticism in preclinical murine models. Therefore, AdipoRon could represent an innovative therapeutic strategy to counteract cancer cachexia.

Globular adiponectin induces esophageal adenocarcinoma cell pyroptosis via the miR-378a-3p/UHRF1 axis.

BACKGROUND: Antiapoptosis is a major factor in the resistance of tumor cells to chemotherapy and radiotherapy. Thus, activation of cell pyroptosis may be an effective option to deal with antiapoptotic cancers such as esophageal adenocarcinoma (EAC). METHODS: Differential expression of ubiquitin-like versus PHD and ring finger structural domain 1 (UHRF1) in EAC and near normal tissues was analyzed, as well as the prognostic impact on survival in EAC. Also, the same study was done for globular adiponectin (gAD). Simultaneously, the mRNA expression of UHRF1 was observed in different EAC cell lines. Real time cellular analysis (RTCA) was used to detect cell proliferation, and flow cytometry and inverted fluorescence microscopy were used to detect pyroptosis. Biocredit analysis was conducted to observe the correlation between UHRF1 and key pyroptosis proteins. OD values and CCK8 assay were used to determine the effect of miR-378a-3p on EAC cells. Quantitative real-time polymerase chain reaction and Western blot were used to detect the correlation between UHRF1, gAD, and miR-378a-3p in EAC cells. Moreover, in vivo and in vitro experiments were performed to detect the relevant effects on tumor migration and invasion after inhibiting UHRF1 expression. RESULTS: UHRF1 was negatively correlated with the survival of patients with EAC, while miR-378a-3p showed the opposite effect. Additionally, gAD promoted EAC cell pyroptosis, upregulated miR-378a-3p, and significantly inhibited the proliferation of EAC cells. gAD directly reduced UHRF1 expression in EAC cells by upregulating miR-378a-3p. In cell migration and invasion assays, inhibition of UHRF1 expression significantly suppressed EAC cell metastasis. In animal experiments, we again demonstrated that gAD induced pyroptosis in EAC cells by inhibiting the expression of UHRF1. CONCLUSION: gAD-induced upregulation of miR-378a-3p significantly inhibited the proliferation of EAC by targeting UHRF1. Therefore, gAD may serve as an alternative therapy for chemotherapy- and radiation-refractory EAC or other cancers with the same mechanism of pyroptosis action.

Obesity and Inflammatory Factors in the Progression of Early-Onset Colorectal Cancer.

Metabolic dysfunction associated with obesity leads to a chronic pro-inflammatory state with systemic effects, including the alteration of macrophage metabolism. Tumor-associated macrophages have been linked to the formation of cancer through the production of metabolites such as itaconate. Itaconate downregulates peroxisome proliferator-activated receptor gamma as a tumor-suppressing factor and upregulates anti-inflammatory cytokines in M2-like macrophages. Similarly, leptin and adiponectin also influence macrophage cytokine expression and contribute to the progression of colorectal cancer via changes in gene expression within the PI3K/AKT pathway. This pathway influences cell proliferation, differentiation, and tumorigenesis. This work provides a review of obesity-related hormones and inflammatory mechanisms leading to the development and progression of early-onset colorectal cancer (EOCRC). A literature search was performed using the PubMed and Cochrane databases to identify studies related to obesity and EOCRC, with keywords including 'EOCRC', 'obesity', 'obesity-related hormones', 'itaconate', 'adiponectin', 'leptin', 'M2a macrophage', and 'microbiome'. With this concept of pro-inflammatory markers contributing to EOCRC, increased use of chemo-preventative agents such as aspirin may have a protective effect. Elucidating this association between obesity-related, hormone/cytokine-driven inflammatory effects with EOCRC may help lead to new therapeutic targets in preventing and treating EOCRC.

Reevaluating Adiponectin's impact on obesity hypertension: a Chinese case-control study.

BACKGROUND: Obesity and hypertension are major risk factors for cardiovascular diseases that affect millions of people worldwide. Both conditions are associated with chronic low-grade inflammation, which is mediated by adipokines such as adiponectin. Adiponectin is the most abundant adipokine that has a beneficial impact on metabolic and vascular biology, while high serum concentrations are associated with some syndromes. This "adiponectin paradox" still needs to be clarified in obesity-associated hypertension. The aim of this study was to investigate how adiponectin affects blood pressure, inflammation, and metabolic function in obesity hypertension using a Chinese adult case-control study. METHODS: A case-control study that had finished recruiting 153 subjects divided as four characteristic groups. Adiponectin serum levels were tested by ELISA in these subjects among these four characteristic Chinese adult physical examination groups. Waist circumference (WC), body mass index (BMI), systolic blood pressure (SB), diastolic blood pressure (DB), and other clinical laboratory data were collected. Analyzation of correlations between the research index and differences between groups was done by SPSS. RESULTS: Serum adiponectin levels in the| normal healthy group (NH group) were significantly higher than those in the newly diagnosed untreated just-obesity group (JO group), and negatively correlated with the visceral adiposity index. With multiple linear egression analysis, it was found that, for serum adiponectin, gender, serum albumin (ALB), alanine aminotransferase (ALT) and high-density lipoprotein cholesterol (HDLC) were the significant independent correlates, and for SB, age and HDLC were the significant independent correlates, and for DB, alkaline phosphatase (ALP) was the significant independent correlate. The other variables did not reach significance in the model. CONCLUSIONS: Our study reveals that adiponectin's role in obesity-hypertension is multifaceted and is influenced by the systemic metabolic homeostasis signaling axis. In obesity-related hypertension, compensatory effects, adiponectin resistance, and reduced adiponectin clearance from impaired kidneys and liver all contribute to the "adiponectin paradox".

IL6/adiponectin/HMGB1 feedback loop mediates adipocyte and macrophage crosstalk and M2 polarization after myocardial infarction.

Background: Differences in border zone contribute to different outcomes post-infarction, such as left ventricular aneurysm (LVA) and myocardial infarction (MI). LVA usually forms within 24 h of the onset of MI and may cause heart rupture; however, LVA surgery is best performed 3 months after MI. Few studies have investigated the LVA model, the differences in border zones between LVA and MI, and the mechanism in the border zone. Methods: The LVA, MI, and SHAM mouse models were used. Echocardiography, Masson's trichrome staining, and immunofluorescence staining were performed, and RNA sequencing of the border zone was conducted. The adipocyte-conditioned medium-treated hypoxic macrophage cell line and LVA and MI mouse models were employed to determine the effects of the hub gene, adiponectin (ADPN), on macrophages. Quantitative polymerase chain reaction (qPCR), Western blot analysis, transmission electron microscopy, and chromatin immunoprecipitation (ChIP) assays were conducted to elucidate the mechanism in the border zone. Human subepicardial adipose tissue and blood samples were collected to validate the effects of ADPN. Results: A novel, simple, consistent, and low-cost LVA mouse model was constructed. LVA caused a greater reduction in contractile functions than MI owing to reduced wall thickness and edema in the border zone. ADPN impeded cardiac edema and promoted lymphangiogenesis by increasing macrophage infiltration post-infarction. Adipocyte-derived ADPN promoted M2 polarization and sustained mitochondrial quality via the ADPN/AdipoR2/HMGB1 axis. Mechanistically, ADPN impeded macrophage HMGB1 inflammation and decreased interleukin-6 (IL6) and HMGB1 secretion. The secretion of IL6 and HMGB1 increased ADPN expression via STAT3 and the co-transcription factor, YAP, in adipocytes. Based on ChIP and Dual-Glo luciferase experiments, STAT3 promoted ADPN transcription by binding to its promoter in adipocytes. In vivo, ADPN promoted lymphangiogenesis and decreased myocardial injury after MI. These phenotypes were rescued by macrophage depletion or HMGB1 knockdown in macrophages. Supplying adipocytes overexpressing STAT3 decreased collagen disposition, increased lymphangiogenesis, and impaired myocardial injury. However, these effects were rescued after HMGB1 knockdown in macrophages. Overall, the IL6/ADPN/HMGB1 axis was validated using human subepicardial tissue and blood samples. This axis could serve as an independent factor in overweight MI patients who need coronary artery bypass grafting (CABG) treatment. Conclusion: The IL6/ADPN/HMGB1 loop between adipocytes and macrophages in the border zone contributes to different clinical outcomes post-infarction. Thus, targeting the IL6/ADPN/HMGB1 loop may be a novel therapeutic approach for cardiac lymphatic regulation and reduction of cell senescence post-infarction.

Predictors of weight and waist gain in US South Asians: Findings from the Mediators of Atherosclerosis in South Asians Living in America (MASALA) Study.

Background: Weight and waist gain are significant concerns in adulthood. Both weight and waist gain are particularly important among South Asians, a high-risk group known to develop chronic cardiometabolic complications at any body mass index compared to other racial and ethnic groups. Objective: The aim of this study was to investigate factors predicting weight and waist gain in a longitudinal cohort of US South Asians, a high-risk group for developing obesity-related complications. Methods: We used data from Mediators of Atherosclerosis in South Asians Living in America study (MASALA) exam 1 (2010-2013) and exam 2 (2015-2018), with a mean 4.8 years of follow-up. Results: Of 634 participants studied (42.7% women, mean age 55 years, BMI 25.7 kg/m2, weight 70.4 kg at exam 1), 34.7% had gained ≥5% weight and 32.3% gained ≥5% waist at exam 2. In the adjusted models, older age, higher number of years of US residence, and having diabetes were associated with lower odds of weight gain; being female and having higher adiponectin were associated with higher odds of weight gain. Being female, employed full or part time, or retired were associated with lower odds of waist gain. Being single, separated/divorced, having a higher leptin and a higher C-reactive protein level were associated with higher odds of waist gain. Conclusions: South Asian subgroups with higher risk of weight and/or waist gain may benefit from targeted interventions to improve health outcomes.

Synergistic effect of genistein and adiponectin reduces fat deposition in chicken hepatocytes by activating the ERß-mediated SIRT1-AMPK signaling pathway.

Dietary supplementation with bioactive substances that can regulate lipid metabolism is an effective approach for reducing excessive fat deposition in chickens. Genistein (GEN) has the potential to alleviate fat deposition; however, the underlying mechanism of GEN's fat-reduction action in chickens remains unclear. Therefore, the present study aimed to explore the underlying mechanism of GEN on the reduction of fat deposition from a novel perspective: intercellular transmission of adipokine between adipocytes and hepatocytes. The findings showed that GEN enhanced the secretion of adiponectin (APN) in chicken adipocytes, and the enhancement effect of GEN was completely blocked when the cells were pretreated with inhibitors targeting estrogen receptor ß (ERß) or proliferator-activated receptor γ (PPARγ) signals, respectively. Furthermore, the results demonstrated that both co-treatment with GEN and APN or treatment with the medium supernatant (Med SUP) derived from chicken adipocytes treated with GEN significantly decreased the content of triglyceride and increased the protein levels of ERß, Sirtuin 1 (SIRT1) and phosphor-AMP-activated protein kinase (p-AMPK) in chicken hepatocytes compared to the cells treated with GEN or APN alone. Moreover, the increase in the protein levels of SIRT1 and p-AMPK induced by GEN and APN co-treatment or Med SUP treatment were blocked in chicken hepatocytes pretreated with the inhibitor of ERß signals. Importantly, the up-regulatory effect of GEN and APN co-treatment or Med SUP treatment on the protein level of p-AMPK was also blocked in chicken hepatocytes pretreated with a SIRT1 inhibitor; however, the increase in the protein level of SIRT1 induced by GEN and APN co-treatment or Med SUP treatment was not reversed when the hepatocytes were pretreated with an AMPK inhibitor. In conclusion, the present study demonstrated that GEN enhanced APN secretion by activating the ERß-Erk-PPARγ signaling pathway in chicken adipocytes. Subsequently, adipocyte-derived APN synergized with GEN to activate the ERß-mediated SIRT1-AMPK signaling pathway in chicken hepatocytes, ultimately reducing fat deposition. These findings provide substantial evidence from a novel perspective, supporting the potential use of GEN as a dietary supplement to prevent excessive fat deposition in poultry.

The Association of Plasma Leptin, Soluble Leptin Receptor and Total and High-Molecular Weight Adiponectin With the Risk of Perioperative Neurocognitive Disorders.

BACKGROUND: Perioperative neurocognitive disorders (NCD) are poorly characterized in terms of their risk factor profiles. Leptin and adiponectin are adipose-tissue-derived hormones with a role in inflammation and atherosclerosis whose function in perioperative NCD is unclear. Here, we used a cohort of older adults to examine the association of preoperative plasma concentrations of these biomarkers with the risk of perioperative NCD. METHODS: Prospective analysis of 768 participants aged ≥ 65 years of the BioCog study. Blood was collected before surgery for measurement of plasma total and high-molecular-weight (hmw) adiponectin, leptin, and soluble leptin receptor (sOB-R). The free leptin index (FLI, leptin:sOB-R) was calculated. Postoperative delirium (POD) was assessed twice daily until postoperative day 7/discharge. Five hundred twenty-six patients (68.5%) returned for 3-month follow-up and provided data on postoperative cognitive dysfunction (POCD). POCD was defined as a decline on six neuropsychological tests that exceeded that of a nonsurgical control group. Logistic regression analyses examined the associations of each exposure with POD and POCD risk, in separate models adjusted for age, sex, fasting, surgery type, and body mass index (BMI). RESULTS: Of 768 patients, 152 (19.8%) developed POD. Of 526 attendants of the follow-up, 54 (10.3%) had developed POCD. Leptin, sOB-R, and total and hmw adiponectin were each not associated with POD. For POCD, we observed reduced risk in patients in FLI quartile 4 compared with quartile 1 (odds ratio, 0.26; 95% CI 0.08, 0.89). Sensitivity analyses for the outcome POD revealed statistically significant interaction terms of sOB-R and total adiponectin with obesity (BMI≥30kg/m2 versus BMI<30kg/m2). For the outcome POCD, a higher sOB-R was associated with an increased risk in the obese subgroup (odds ratio, 4.00; 95% CI 1.01, 15.86). CONCLUSIONS: We did not find consistent evidence for the role of leptin, its receptor, and total and hmw adiponectin in POD and POCD risk. Future research should be used to support or refute our findings and to fully characterize any differences in the associations of these hormones with POD/POCD between obese and nonobese individuals.

Isolation and purification of high molecular weight adiponectin from human plasma fraction.

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.

Efficacy of ADIPOR1 and ADIPOR2 peptide-agonist AdipoRon in preventing contracture in a rabbit model of arthrofibrosis.

AdipoRon is an adiponectin receptor 1, 2 (ADIPOR1 and ADIPOR2) agonist with potential antifibrotic effects. Whether AdipoRon can mitigate joint stiffness in a rabbit model of arthrofibrosis is unknown. We examined the efficacy of intravenous (IV) AdipoRon at mitigating contracture in a rabbit model of knee arthrofibrosis. Fifty-six female New Zealand White rabbits were divided into three dosing groups: vehicle (dimethyl sulfoxide, DMSO), 2.5 mg/kg AdipoRon, and 5 mg/kg AdipoRon. AdipoRon, in DMSO, was administered IV preoperatively and for 5 days postoperatively (30 rabbits, Aim 1). AdipoRon was again dosed similarly after Kirschner wire (K-wire) removal at 8 weeks (26 rabbits; Aim 2). The primary outcome of joint passive extension angle (PEA,°) was measured at 8, 10, 12, 16, and 24 weeks following index surgery. At 24 weeks, rabbits were euthanized and limbs were harvested to measure posterior capsular stiffness (N cm/°). In Aim 1, the 5 mg/kg treated rabbits had a significant increase in PEA when compared to controls at 16-week (p < 0.05). In Aim 2, the 5 mg/kg treated rabbits had a significant increase in PEA when compared to controls at 10-week (p < 0.05). In both aims, no significant differences were observed at later time points. Capsular stiffness was no different in any group. We are the first to report the efficacy of IV AdipoRon in a rabbit model of arthrofibrosis. We identified a significant dose-dependent decrease in joint PEA at early time points; however, no differences were observed between groups at later time points. Clinical Significance: The present investigation provided the first assessment of AdipoRon's efficacy in mitigating knee stiffness in the current gold standard rabbit model of arthrofibrosis. Results of this investigation provided further evidence as to the potential role of AdipoRon as a preventative for arthrofibrosis in large mammals.

Serum levels of sirtuins, leptin and adiponectin in women with pregnancy-induced hypertension.

INTRODUCTION: Pregnancy-induced hypertension (PIH) and preeclampsia (PE) are associated with disturbed maternal inflammatory response, oxidative stress and vascular endothelial cell dysfunction. Obesity is one of risk factors of PE. Leptin is elevated in obesity and its level correlates positively with the amount of adipose tissue. In contrast, adiponectin levels are decreased in obesity. Sirtuins are expressed in the placenta, however their role in pregnancy-related pathology in humans is not known. AIM OF THE STUDY: The aim of our study was to measure serum concentrations of selected sirtuins, adiponectin and leptin in healthy pregnancy and in women with PIH. MATERIALS AND METHODS: The study included 70 women: 38 healthy pregnant women and 32 women with PIH. Blood samples were obtained between the 20th and 40th week of gestation. Serum levels of sirtuins 1, 3, 6, leptin and adiponectin were measured with ELISA. RESULTS: Leptin levels were significantly higher in PIH group as compared to the controls and correlated positively with BMI. Highest leptin levels were observed in women who needed a cesarean section. Levels of sirtuins 1, 3 and 6 were similar in both groups and did not correlate with BMI. CONCLUSIONS: High leptin levels in PIH women during 3rd trimester might be helpful to predict the necessity for a caesarian section. Blood levels of sirtuins 1, 3 and 6 measured after the 20th week of gestation cannot be regarded as a single diagnostic test for PIH or preeclampsia. More studies to clarify significance of sirtuins in PIH and PE development and diagnosis are needed.

Leptin's Inverse Association with Brain Morphology and Depressive Symptoms - A Discovery and Confirmatory Study Across Two Independent Samples.

BACKGROUND: Major Depressive Disorder (MDD) has a complex, bi-directional relationship with metabolic dysfunction, yet the neural correlates of this association are not well understood. METHOD: In this cross-sectional investigation, we employed a two-step 'discovery and confirmatory' strategy, utilizing two independent samples (Sample 1: 288 participants, Sample 2: 196 participants) to examine the association between circulating indicators of metabolic health (leptin and adiponectin) and brain structures in individuals with MDD. RESULTS: We found a replicable inverse correlation between leptin levels and cortical surface area within essential brain areas responsible for emotion regulation, such as the left posterior cingulate cortex, right pars orbitalis, right superior temporal gyrus, and right insula (standardized beta coefficient (SBC) ranged: -0.27 to -0.49, puncorrected <0.05). Notably, this relationship was independent of C-Reactive Protein levels. We also identified a significant interaction effect of leptin levels and diagnosis on the cortical surface area of the right superior temporal gyrus (SBC = 0.26 in sample 1, SBC = 0.30 in sample 2, puncorrected < 0.05). We also observed a positive correlation between leptin levels and atypical depressive symptoms in both MDD groups (r = 0.14 in sample 1, r = 0.29 in sample 2, puncorrected < 0.05). CONCLUSION: The inverse association between leptin and cortical surface area in brain regions that are important for emotion processing and leptin's association with sleep disturbances supports the hypothesis that metabolic processes may be related to emotion regulation. However, the molecular mechanisms through which leptin might exert these effects should be explored further.

Adiponectin as a predictor of mortality and readmission in patients with community-acquired pneumonia: a prospective cohort study.

Background: Adiponectin is secreted by adipocytes and is inversely associated with obesity. Given the association between low body mass index (BMI) and higher mortality risk after community-acquired pneumonia (CAP), we hypothesized that high adiponectin levels are associated with a higher risk of adverse clinical outcomes in patients with CAP. Methods: In a prospective cohort study of 502 patients hospitalized with CAP, adiponectin was measured in serum at admission. The associations between adiponectin and clinical outcomes were estimated with logistic regression analyses adjusted for age, sex, and measures of obesity (BMI, waist circumference or body fat percentage). Results: Adiponectin was associated with higher 90-day mortality for each 1 µg/mL increase [OR 1.02, 95% CI (1.00, 1.04), p = 0.048] independent of age and sex. Likewise, adiponectin was associated with a higher risk of 90-day readmission for each 1 µg/mL increase [OR 1.02, 95% CI (1.01, 1.04), p = 0.007] independent of age and sex. The association between adiponectin and 90-day mortality disappeared, while the association with 90-day readmission remained after adjusting for adiposity. Conclusion: Adiponectin was positively associated with mortality and readmission. The association with mortality depended on low body fat, whereas the association with readmission risk was independent of obesity.

Adiponectin-to-leptin ratio and incident chronic kidney disease: Sex and body composition-dependent association.

BACKGROUND: The association between the adiponectin-to-leptin ratio (A/L ratio) and the risk of incident chronic kidney disease (CKD) is poorly understood. This study aimed to investigate the association between A/L ratio and the risk of incident CKD and to examine whether such a relationship varied according to sex and body composition. METHODS: In this prospective community-based cohort, participants with normal kidney function were analysed (N = 5192). The association between the A/L ratio at baseline and the risk of incident CKD, defined as two or more occasions with an estimated glomerular filtration rate of <60 mL/min/m2 or proteinuria of ≥1+ on a dipstick test during the follow-up period, was evaluated using multivariable Cox proportional hazards analyses. Subgroup analyses were conducted based on sex, body mass index (BMI) and the presence of sarcopenia. RESULTS: The participants' mean age was 57.2 ± 8.3 years, and 53.2% were women. The A/L ratio was higher in men compared with women (1.5 [0.8-3.2] and 0.5 [0.3-0.9] µg/ng, P < 0.001). During a median follow-up of 9.8 [9.5-10.0] years, 417 incident CKD events occurred (8.7 per 1000 person-years). Men in the highest quartile of A/L ratio had a lower risk of incident CKD (adjusted hazard ratio [aHR], 0.57; 95% confidence interval [CI], 0.33-0.99) than those in the lowest quartile. Additionally, a 1.0 increase in A/L ratio was associated with a 12% decreased risk of incident CKD in men (aHR, 0.88; 95% CI, 0.80-0.97). However, no significant association was observed in women. In subgroup analysis stratified by BMI and the presence of sarcopenia, the association between a high A/L ratio and a reduced risk of incident CKD was consistent in men with a BMI < 23.0 kg/m2 and those with sarcopenia. However, no significant association was observed between men with a BMI ≥ 23.0 kg/m2 and those without sarcopenia. CONCLUSIONS: A high A/L ratio is an independent marker of a reduced risk of incident CKD in men, especially in those with a BMI < 23.0 kg/m2 and sarcopenia.