Adiponectin Paradox Research Articles

Adiponectin Paradox as a Therapeutic Target in Alzheimer's Disease.

Despite the apparent neurotoxicity of amyloid-β (Aβ), recent clinical trials of Aβ immunotherapy have not shown any clinical benefit in Alzheimer’s disease (AD). Given this, clarification of the next generation therapeutic strategy in AD is warranted. Hypothetically, adiponectin might be involved in promoting amyloidogenic evolvability in reproduction, which may result in the adiponectin paradox through antagonistic pleiotropy mechanism in aging, leading to AD. Accordingly, preventing the adiponectin paradox by suppressing adiponectin signaling might prove therapeutic in AD.

Erratum. The Adiponectin Paradox for All-Cause and Cardiovascular Mortality. Diabetes 2018;67:12-22.

In the article listed above, the first affiliation “Research Unit of Diabetes and Endocrine Diseases, IRCCS Casa Sollievo della Sofferenza, …

Increased adiponectin is associated with cerebral white matter lesions in the elderly with cognitive impairment.

Adiponectin is an adipocyte-derived peptide that increases with age and is thought to protect against atherosclerotic vascular changes and organ damage. However, paradoxically, higher adiponectin levels are associated with increased risk for cardiovascular events and mortality. We investigated whether this adiponectin paradox occurs in elderly people with cognitive impairment. Fifty-two elderly participants with mild cognitive impairment or dementia (20 male and 32 female, aged 60-93years, mean 80.0) were recruited. We evaluated serum adiponectin levels and cerebral white matter lesions (WML), which are involved in cognitive decline and dementia, by computed tomography. Body mass index (BMI), Mini-Mental State Examination score, history of hypertension (HT), chronic kidney disease, and diabetes mellitus were also assessed. Stepwise multiple regression analysis was used to reveal the relationships between serum adiponectin and age, sex, BMI, HT, diabetes mellitus, chronic kidney disease, Mini-Mental State Examination, and WML scores. High serum adiponectin levels correlated with more severe WML (P = 0.013). Low BMI (P < 0.001), female sex (P = 0.025), and high WML scores (P = 0.039) were significant determinants of high serum adiponectin. HT (P = 0.032) and high adiponectin levels (P = 0.021) were independent risk factors for WML. Overall, we observed an association between serum adiponectin levels and WML severity in elderly people with cognitive decline. Our findings reveal that the adiponectin paradox occurs in this population, and this study may help guide future treatments for elderly people with mild cognitive impairment or dementia.

The Adiponectin Paradox in the Elderly: Associations With Body Composition, Physical Functioning, and Mortality.

To determine if adiponectin levels are associated with weight loss, low muscle mass, and physical functioning among the elderly and to determine independent associations with incident disability and death. Included were 3,044 participants from the Health, Aging and Body Composition Study, who had whole-body dual energy absorptiometry performed to evaluate appendicular lean mass index (ALMI, kg/m2) and fat mass index (FMI, kg/m2), computed tomography measures of thigh muscle density, weight histories, estimates of physical functioning, and adiponectin levels at enrollment. Associations between adiponectin levels and body composition, weight loss, and physical functioning were assessed in multivariable linear regression models. Associations between adiponectin and incident disability and mortality were assessed in mediation analyses, adjusting for other factors. Greater adiponectin at baseline was independently associated with low FMI Z-score, lower waist circumference, low ALMI Z-score, low muscle density, a history of weight loss, and poor physical functioning (all p < .05). Greater adiponectin levels (per SD) were associated with incident disability [HR: 1.14 (1.08, 1.20), p < .001] and greater mortality [HR: 1.17 (1.10, 1.25), p < .001] in models adjusting for demographic factors, adiposity, and comorbid conditions. The association was completely attenuated and no longer significant (all p > 0.05) when adjusting for body composition, muscle density, weight loss, and physical functioning at baseline. Greater serum adiponectin levels are associated with historical weight loss, low skeletal muscle mass, low muscle density, and poor physical functioning. High adiponectin is associated with a greater risk of incident disability and death, but not independently of these factors.

Nutrients restriction upregulates adiponectin in epicardial or subcutaneous adipose tissue: impact in de novo heart failure patients.

Background: Hyperadiponectinemia is an indicator of worse outcomes in advanced heart failure (HF), its role in de novo HF is less clear.Objective: Because this protein is a hormone with starvation properties, we wanted to know its association with nutritional state and its regulator factors in de novo HF.Methods: Adiponectin circulating levels were determined by ELISA at discharge in patients admitted for de novo HF (n=74). Nutritional status was determined by CONUT score. Univariate and multivariate Cox regression analyses were employed to calculate the estimated hazard ratio (HR) with 95% confidence interval (CI) for death or all-cause readmission. Stromal vascular cells (SVC) of EAT and subcutaneous adipose tissue (SAT) from patients (n=5) underwent heart surgery were induced to adipogenesis for 18 days. Then, cells were cultured with complete or starved medium for 8 hours. At the end, adiponectin expression levels were analysed by real time polymerase chain reaction.Results: Patients were grouped regarding nutritional status. There was a strong association between high adiponectin levels and failing nutritional status. Those patients with worse nutritional state had the highest adiponectin and proBNP levels at discharge (p<0.01). Both proteins were slightly correlated (p<0.05). However, only high adiponectin levels were independently associated with death or all-cause readmission. Nutrients starvation upregulated adiponectin expression levels in adipogenesis-induced SVC from EAT or SAT.Conclusions: Worse nutritional state in de novo HF patients is associated with higher adiponectin plasma levels. Their levels were upregulated in adipose cells after being nutrients-starved. These results may help us to understand the adiponectin paradox in HF.

The Adiponectin Paradox for All-Cause and Cardiovascular Mortality.

Basic science studies have shown beneficial effects of adiponectin on glucose homeostasis, chronic low-grade inflammation, apoptosis, oxidative stress, and atherosclerotic processes, so this molecule usually has been considered a salutary adipokine. It was therefore quite unexpected that large prospective human studies suggested that adiponectin is simply a marker of glucose homeostasis, with no direct favorable effect on the risk of type 2 diabetes and cardiovascular disease. But even more unforeseen were data addressing the role of adiponectin on the risk of death. In fact, a positive, rather than the expected negative, relationship was reported between adiponectin and mortality rate across many clinical conditions, comprising diabetes. The biology underlying this paradox is unknown. Several explanations have been proposed, including adiponectin resistance and the confounding role of natriuretic peptides. In addition, preliminary genetic evidence speaks in favor of a direct role of adiponectin in increasing the risk of death. However, none of these hypotheses are based on robust data, so further efforts are needed to unravel the elusive role of adiponectin on cardiometabolic health and, most important, its paradoxical association with mortality rate.

High circulating adiponectin level is associated with poor clinical outcome after catheter ablation for paroxysmal atrial fibrillation.

Circulating adiponectin is known to have anti-diabetic, anti-atherogenic, and anti-inflammatory properties. However, the predictive value of adiponectin in cardiovascular disease has been reported to be contradictory ('adiponectin paradox') and its relationship with atrial fibrillation (AF) is controversial. We hypothesized that pre-procedural plasma level of adiponectin would have prognostic value in patients who underwent AF catheter ablation. This observational cohort study included 874 patients with paroxysmal AF (PAF) (73.0% male, mean age 57.6 ± 11.2 years) who underwent catheter ablation. Quartile analyses of plasma level of adiponectin were performed to determine AF-related clinical factors. Patients in the highest quartile of plasma adiponectin were more likely to be older (P < 0.001), female (P < 0.001), and have a higher CHA2DS2-VASc score (P < 0.001) than patients in the other three quartiles. Plasma level of adiponectin was independently associated with female gender (B 2.92 [1.84∼4.00], P < 0.001), older age (B 0.06 [0.03∼0.10], P < 0.001), lower body mass index (B - 0.22 [-0.42∼-0.03], P = 0.025), and greater LA volume index (B 0.05 [0.01∼0.08], P = 0.005). During the 29.9 ± 18.0 months of follow-up, plasma adiponectin level (HR 1.17 [1.02∼1.35], P = 0.022) was independently associated with clinical recurrence of AF, and the clinical recurrence rate was significantly higher in the highest quartile of adiponectin group than the others (log rank P = 0.029), especially in age <65 years (log rank P = 0.038), but not in age ≥65. High circulating adiponectin is independently associated with AF recurrence after catheter ablation for PAF, especially younger than 65 years old.

Unravelling the adiponectin paradox: novel roles of adiponectin in the regulation of cardiovascular disease.

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.

High serum adiponectin concentration and low body mass index are significantly associated with increased all-cause and cardiovascular mortality in an elderly cohort, “adiponectin paradox”: The Korean Longitudinal Study on Health and Aging (KLoSHA)

BackgroundThe relationship between adiponectin concentration and mortality is unclear. We examined whether serum adiponectin concentration is associated with all-cause and cardiovascular mortality in elderly Asians. MethodsWe analyzed the data for community-dwelling adults ≥65years of age (439 men and 561 women) who were enrolled in the Korean Longitudinal Study on Health and Aging (KLoSHA) cohort in prospective manner. The baseline serum total and high molecular weight adiponectin were measured using an enzyme-linked immunosorbent assay. Using Cox regression, we determined the associations between serum adiponectin concentration and all-cause and cardiovascular mortality after adjusting for well-known cardiovascular risk factors. ResultsOver a mean follow-up time of 6.2years, 222 individuals died, and 52 deaths (23.4%) were by cardiovascular disease. After adjusting confounding factors, elevated baseline serum adiponectin concentration was independently associated with all-cause mortality (adjusted hazard ratio [HR] 1.38; 95% confidence interval [CI] 1.17–1.64) and cardiovascular mortality (HR 1.50; 1.06–2.14). We evaluated the effect modification by baseline body mass index (BMI). High serum adiponectin and low BMI were synergistically associated with increased all-cause mortality (HR 6.25; 3.08–12.71) and cardiovascular mortality (HR 13.94; 1.82–106.58). ConclusionsHigher serum adiponectin concentration was associated with increased all-cause and cardiovascular mortality in community-dwelling elderly Asian population. Our data supported the recent theory so called “adiponectin paradox”. This relationship was strengthened when combined with low BMI. We suggest that measurement of adiponectin concentration and BMI together could be an additional predictive marker of survival among elderly adults.

Abstract P354: Elevated Adiponectin And Tnf-alpha Levels Are Markers For Gluten And Lectin Sensitivity

Adiponectin is a protein hormone secreted by adipose cells and is thought to be a precursor for the inflammatory cytokine TNF-alpha. Although low levels of Adiponectin are associated with visceral adiposity and high levels with weight loss, there is a strong association of elevated Adiponectin and TNF-alpha levels in thin women with dementia, osteopenia, and/or coronary artery disease. This paradox led us to consider that these biomarkers correlated to sensitivity to the plant defense proteins: gluten and other lectins. We studied serial Adiponectin and TNF-alpha levels every 3 months in 1,000 pts, M:F ratio 1:1 in response to a lectin and gluten elimination diet (The Matrix Diet). All samples were sent to a core lab (Singulex, Alameda, CA). The diet consisted of avoidance of grains, sprouted grains, pseudo-grains, beans and legumes, soy, peanuts, cashews, nightshades, melons and squashes, and non-Southern European cow milk products (Casein A1), and grain and/or bean fed animals. Eight hundred pts (80%) related some history of autoimmune disease (AID) personally or among family members, including Hashimotos thyroiditis, IBS, arthritis, RA, Lupus, Crohns, colitis, GERD, CAD, Type 1 DM. Adiponectin levels were elevated in all 800 pts with family hx or personal history of AID (16.6-83 ug/ml)(nl&lt;16.5). TNF-alpha levels were elevated in 760/800pts with AID hx (95%) (&gt;3.0 pg/mL). In contrast, Adiponectin was normal in 200 remaining pts without AID history (&lt;16.5 ug/ml), while TNF-alpha was normal in 100/200 (50%) of pts without AID. When the lectin and gluten free diet was instituted, all TNF-alpha levels became normal in all 1,000 pts (&lt;3.0 pg/mL), within 6 months and remained normal, if the diet was followed, for up to one year of study. However, despite normal TNF-alpha levels, Adiponectin levels remained elevated in 790/800 pts with AID hx. Late lack of adherence to the diet occurred in 56/1,000 pts (6%) (as determined by questionnaire) resulted in re-elevation of TNF-alpha in 56/56 pts (100%). We conclude that elevated Adiponectin is a marker for lectin and gluten sensitivity, while TNF-alpha can be used as a marker for gluten/lectin exposure in sensitive individuals. These findings probably explain the Adiponectin paradox. TNF-alpha levels appear to be useful as a marker of response to a lectin/gluten limited diet, and as a marker for degree of adherence to such a diet.

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Associations of total and high-molecular-weight adiponectin with all-cause and cardiovascular mortality in older persons: the Cardiovascular Health Study.

Adiponectin shows opposite associations with adverse outcomes in healthy middle-aged populations (lower risk) and cohorts with prevalent cardiovascular disease, heart failure, or advanced age (higher risk). In a population-based study of older adults, we examined the relationships of total and high-molecular-weight adiponectin with mortality among subgroups defined by baseline cardiovascular status: No cardiovascular disease, heart failure, or atrial fibrillation (group 1); cardiovascular disease but no heart failure/atrial fibrillation (group 2); and heart failure/atrial fibrillation (group 3). We found significant differences in the associations with all-cause mortality across the groups. The association in group 1 was U-shaped; increasing levels of total adiponectin up to 12.4 mg/L were associated with lower mortality after adjustment for confounders (hazard ratio=0.81 per 1 SD [95% confidence interval, 0.65-0.95]), but above this cut point, higher levels conferred greater risk (hazard ratio=1.19 [95% confidence interval, 1.12-1.27]). Further adjustment for diabetes mellitus or insulin resistance, protection against which has been proposed to mediate the beneficial relationships of adiponectin with outcome, attenuated the association in the lower range. There was no significant association in group 2, but in group 3, total adiponectin showed a direct adjusted association. Additional adjustment for putative metabolic/inflammatory intermediates suggested a direct association for group 2, and magnified the one for group 3 (hazard ratio=1.31 [1.15-1.50]). Results were similar for high-molecular-weight adiponectin and for cardiovascular mortality. Adiponectin exhibits distinct associations with mortality in elders, which shift from U-shaped to flat to direct with greater baseline cardiovascular dysfunction but become more consistently adverse after accounting for metabolic/inflammatory factors presumed to be favorably regulated by the adipokine. These findings advance understanding of the adiponectin paradox as it relates to older adults.

Nutritional Status and Body Composition in Early Post-Renal Transplantation: Is There an Adiponectin Paradox?

Overweight, in combination with other cardiovascular risk factors, reduces survival after renal transplantation. The aim of this cross sectional study was to observe adiponectin as a predictor of body mass index (BMI) and anthropometric measurements and also as a risk factor associated with nutritional status after renal transplantation. Ninety subjects were enrolled into this study, 30 patients with end stage kidney disease on regular hemodialysis treatment, 30 patients examined one months after transplantation while 30 subjects used as control group. All diabetic patients were excluded. Full history taking was focused on social status, occupation, original renal disease, duration of transplantation, and co-morbid conditions. Physical examination included hydration status, signs of sepsis and anthropometric measurements. Assay of serum creatinine, blood urea, lipid profile, serum albumin, fasting blood sugar, was done. Quantification of serum adiponectin concentration was estimated by ELISA. We found a significant difference between nutritional status of hemodialysis patients and those after transplantation. The adiponectin level was higher in patients on regular hemodialysis than in kidney transplant group. Before transplantation, adiponectin was negatively related to albumin and body mass index. After transplantation, adiponectin level dropped significantly compared to pretransplant levels, however, it is still negatively related to body mass index. Adiponectin levels did not drop to control levels after transplantation although patients had normal renal function. There was no relationship between adiponectin levels and other nutritional parameters in this study. We can conclude that a disturbed energy metabolism persists after renal transplantation, where adiponectin is involved.

Abstract 056: Associations of Total and High-Molecular-Weight Adiponectin with All-Cause and Cardiovascular Mortality in Older Persons: The Cardiovascular Health Study (CHS)

Background: Adiponectin (APN) is inversely related to incident cardiovascular disease (CVD) in healthy middle-aged cohorts, but the opposite has been observed among older populations or those with prevalent CVD, where higher APN imparts greater risk of CVD and death. Emerging data suggest, however, that the association of total APN with mortality in elders may be U-shaped. Methods: We tested the hypotheses that both total and high-molecular-weight (HMW) APN (r=0.94) manifest different relations with mortality in subgroups of older adults defined by the presence or absence of prior CVD or heart failure (HF)/atrial fibrillation (AF). Specifically, we hypothesized that total and HMW APN would show similar U-shaped associations with all-cause and CVD death in subjects without prevalent CVD or HF/AF (Group [Gp] 1; n= 3272), but would exhibit positive monotonic associations with these outcomes in subgroups with prevalent CVD but no HF/AF (Gp 2; n=1030), and with prevalent HF/AF (Gp 3; n=383). We addressed these questions in CHS, a population-based US cohort aged 65 and older, of whom 4715 had available samples since 1992–93. Associations were examined with general additive model plots, and modeled with linear splines. Results: During 16 years of follow-up, 1947 all-cause and 634 CVD deaths occurred in Gp 1, 802 and 375 in Gp 2, and 337 and 180 in Gp 3. There was evidence of effect modification by subgroup status for both outcomes (p≤0.034), with total and HMW APN showing significant departures from linearity in their relations with all-cause and CVD mortality in Gp 1 (p≤0.043), but not Gps 2 or 3. The association between total APN and all-cause mortality was U-shaped, such that after adjustment for potential confounders, increasing levels up to 12.4 mg/L (median) were associated with a lower risk of death (HR 0.81 per SD [0.65–0.95]), but above this cutpoint, higher levels imparted a higher risk (HR 1.19 per SD [1.12–1.27]). Further adjustment for putative mediators (glucose, lipids, inflammation) abolished the association in the lower range, but left that in the upper range unaffected. The relationship was largely similar for HMW adiponectin. No significant association between total or HMW APN with mortality was apparent in Gp 2. In Gp 3, both total and HMW APN showed positive adjusted associations with mortality across their distributions, which were magnified after inclusion of putative mediators (HRs 1.31 [1.15–1.50] and 1.36 [1.20–1.55], respectively). Results were comparable for CVD mortality in all Gps. Conclusions: These findings show that total and HMW APN bear similar associations with all-cause and CVD mortality in older adults, and that these differ according to prevalent CVD or HF/AF status. These observations provide a potential explanation for the APN paradox, underscoring the need to better characterize the underpinnings of the hormone’s beneficial and harmful associations.

Adiponectin and Coronary Heart Disease: The Strong Heart Study

To the Editor: The adipocyte secreted protein, adiponectin, is of particular interest in metabolic and vascular disease because of its close associations with insulin sensitivity and obesity.1 Lower levels of adiponectin are associated with later development of type 2 diabetes.2 Recent observations from the Health Professionals Follow-Up Study3 suggest that lower adiponectin concentrations might also be associated with incident myocardial infarction, findings in keeping with prior observations in patients with end-stage renal failure.4 We examined prospective relationships of adiponectin to vascular disease in a case–control series selected from the Strong Heart Study (SHS). The SHS is the largest study of cardiovascular disease in American Indians, a group at particular risk of obesity and type 2 diabetes and in whom an increasing incidence of coronary heart disease (CHD) is seen.5 Cases and controls were selected from the SHS cohort.6 The SHS recruited 4549 volunteers of American Indian heritage from 3 geographic areas (Arizona, North and South Dakota, and Oklahoma).6 Volunteers (59% female) were invited to a study examination on three occasions (SH1, 1988 to 1992; SH2, 1993 to 1995; SH3, 1997 to 1999) and remained under continued surveillance for development of vascular disease as described previously.7,8 Because of availability of plasma samples, baseline data for this study were taken from the second examination (SH2), and participants with prevalent cardiovascular disease at SH2 (definite CHD and stroke), …