High Molecular Weight Adiponectin Levels Research Articles

Relationships between fat deposition in the liver and skeletal muscle and insulin sensitivity in Japanese individuals: a pilot study

Purpose:To evaluate the relationships between insulin sensitivity (IS), body fat accumulation, and aerobic capacity in middle- to older-aged Japanese participants with visceral adiposity.Participants and methods:Aerobic capacity was measured during an incremental ramp exercise test. Computed tomography was used to measure visceral (VFA) and subcutaneous (SFA) fat area, the fat in liver-to-spleen ratio (L/S), and low-density skeletal muscle area (LDMA). IS was assessed using euglycemic-hyperinsulinemic clamps.Results:A total of 11 males and 9 females, age 58 ± 9 years (mean ± standard deviation), body mass index 29 ±4.1 kg/m2, and VFA 190 ±53 cm2 participated in this study. In unadjusted models, VFA, LDMA, and L/S were significantly correlated with IS, which remained in adjusted models for LDMA and L/S, but not for VFA. In multiple stepwise regression analysis including sex, age, body fat, VFA, SFA, alcohol consumption, and aerobic capacity (oxygen uptake at the lactate threshold), L/S, and LDMA accounted for 70% of the total variance in IS. Percentage body fat and SFA, but not VFA, were significantly correlated with high molecular-weight adiponectin levels (r = 0.58, P < 0.01 and r = 0.54, P < 0.05, respectively). IS and L/S were significantly and negatively correlated with tumor necrosis factor-α (r = −0.67 and −0.63, respectively; both P < 0.01) and plasminogen activator inhibitor-1 (r = −0.58, P < 0.01 and −0.52, P < 0.05, respectively), whereas LDMA was not.Conclusion:These findings indicate that ectopic fat deposition in the liver and skeletal muscle may be associated with peripheral IS independently of body fat accumulation and aerobic capacity in middle- to older-aged Japanese individuals with visceral adiposity. Because of the small sample size, additional larger studies are needed to provide further insight into these preliminary findings.

Serum High Molecular Weight Adiponectin Correlates with Arterial Stiffness in Community-Dwelling Persons

Introduction. Serum high molecular weight (HMW) adiponectin, an adipocytokine, which is a protein secreted specifically by adipose tissue, improves insulin sensitivity and plays an important role in the development of metabolic syndrome and cardiovascular disease (CVD). Pulse wave velocity (PWV) is a noninvasive method of measuring arterial stiffness for the assessment of CVD in high-risk populations. We investigated whether serum HMW adiponectin is independently associated with arterial stiffness when evaluated using PWV. Methods. We randomly recruited 99 men aged 69 ± 9 (mean ± standard deviation) years and 170 women aged 68 ± 7 years during their annual health examination in a single community. Peripheral arterial stiffness was evaluated by mean PWV determined at three points: from the heart to the carotid artery, to the brachial artery, and to the ankle. Results and conclusions. Age-adjusted PWV in all sites other than the heart to the carotid artery decreased progressively with increased serum HMW adiponectin. Age-adjusted mean PWV significantly decreased from the lowest to the highest serum HMW adiponectin group. Multiple linear regression analyses for mean PWV revealed that decreased serum HMW adiponectin levels were significantly associated with increased mean PWV as well as age, BMI, SBP, DBP, prevalence of antihypertensive medication, and eGFR. Inclusion of serum HMW adiponectin into the model further increased the coefficient of determination (R2). Multivariate-adjusted mean PWV was significantly lowest in the highest serum HMW adiponectin group.

Low serum levels of total and high-molecular-weight adiponectin predict the development of metabolic syndrome in Japanese-Americans.

Adiponectin is thought to play a significant role in the development of both insulin resistance and metabolic syndrome. Yet, there is very few evidence about the association plasma adiponectin and metabolic syndrome in the prospective study. Adiponectin exists as multimers in serum, and high-molecular-weight (HMW) adiponectin is particularly considered to be the active form of the protein. We investigated whether serum HMW adiponectin as well as total adiponectin is associated with the development of metabolic syndrome in a longitudinal study. We enrolled 224 men and 312 women of Japanese- Americans without metabolic syndrome at baseline who were followed for an average of 3.2 yr. The association of plasma total and HMW adiponectin with a progression to metabolic syndrome was examined. Subjects who developed metabolic syndrome had significantly lower plasma total and HMW adiponectin levels at baseline than those who did not develop metabolic syndrome. In a Cox proportional hazards model, lower total and HMW adiponectin levels were independent risk factors for the development of metabolic syndrome after adjusting for age, body mass index, classification of 75-g glucose tolerance test, and homeostasis model assessment (hazards ratio: total, 0.684, p=0.017, in men; 0.606, p=0.003, in women; HMW, 0.687, p=0.014, in men; 0.704, p=0.029, in women, respectively). Low circulating levels of total and HMW adiponectin may be a possible predictor for the development of metabolic syndrome.

Effects of Losartan/Hydrochlorothiazide Treatment, After Change from ARB at Usual Dosage, on Blood Pressure and Various Metabolic Parameters Including High-Molecular Weight Adiponectin in Japanese Male Hypertensive Subjects

Losartan, an angiotensin II receptor blocker (ARB), has been reported to increase serum level of high-molecular weight (HMW) adiponectin, which has beneficial effects on insulin resistance and atherosclerosis. On the other hand, treatment with diuretics was reported to decrease the adiponectin level. In the present study, we investigated the effects of changing the treatment to losartan/hydrochlorothiazide (HCTZ) on blood pressure (BP) and various metabolic parameters in Japanese male hypertensive subjects. This study included 15 subjects whose therapy was changed from a usual dosage of ARB to losartan 50mg/HCTZ 12.5mg daily, and also 14 subjects who continued losartan treatment (50mg/day). Serum HMW-adiponectin concentration was assayed using a commercially available HMW-specific ELISA kit. In the losartan/HCTZ patient group, systolic/diastolic BP decreased from 146/95 to 130/84 mmHg (P = 0.0012 for both). The HbA1c level tended to increase from 5.44 ± 0.39 to 5.55 ± 0.44% (P = 0.0554) and serum creatinine level slightly increased from 0.82 ± 0.12 to 0.87 ± 0.12 mg/dl (P = 0.0015). In contrast, serum TG (125 ± 77 to 149 ± 112 mg/dl), uric acid, and HMW-adiponectin levels (3.24 ± 2.97 to 3.36 ± 2.43 μg/ml) were unchanged. In the 14 patients who continued losartan treatment, systolic/diastolic BP was unchanged from 134/86 to 129/80 mmHg. The HbA1c level tended to increase from 5.26 ± 0.63 to 5.39 ± 0.71% (P = 0.0880), serum creatinine and uric acid levels were unchanged, serum lipids tended to improve, and serum HMW-adiponectin levels increased from 3.03 ± 1.06 to 3.46 ± 1.28 μg/ml (P = 0.0105). In summary, changing treatment to losartan/HCTZ, when changed from a usual dosage of ARB, exerted good BP control, while the HMW-adiponectin level was unchanged in male hypertensive subjects.

Hemoglobin is Associated with Serum High Molecular Weight Adiponectin in Japanese Community-Dwelling Persons

Serum high molecular weight (HMW) adiponectin improves insulin sensitivity, and a decreased level of serum HMW adiponectin has been reported as a risk factor for the development of diabetes and coronary heart disease. This association may be further confounded by the hemoglobin status, which is involved in the development of atherosclerosis. A cross-sectional study was carried out in 2002. Study participants, consisting of 897 men aged 61±14 (mean±standard deviation) years and 1,148 women aged 63±12 years, were randomly recruited from a single community at the time of their annual health examination. Serum HMW adiponectin levels were lowered dose-dependently with an increased hemoglobin level. Stepwise multiple linear regression analyses for serum HMW adiponectin revealed that the hemoglobin status was independently and significantly associated with serum HMW adiponectin levels as well as sex, age, body mass index (BMI), alcohol consumption, total cholesterol, triglycerides, high density lipoprotein cholesterol, antilipidemic medication, uric acid, serum gamma glutamyltransferase, and insulin resistance. Inclusion of hemoglobin levels in the model further increased the coefficient of determination. In stratified analysis, mean serum HMW adiponectin levels were significantly and similarly decreased as hemoglobin levels increased in men, ages ≥ 65 years, BMI < 23.0 kg/m(2), alcohol drinkers, and lower insulin resistance, and there were significant interactions between the two groups for BMI, alcohol consumption and insulin resistance. Hemoglobin status is inversely associated with serum HMW adiponectin levels in community-dwelling persons, especially those aged ≥ 65 years, BMI < 23.0 kg/m(2), alcohol drinkers, and lower insulin resistance groups.

Exploring the molecular mechanisms underlying the potentiation of exogenous growth hormone on alcohol-induced fatty liver diseases in mice

BackgroundGrowth hormone (GH) is an essential regulator of intrahepatic lipid metabolism by activating multiple complex hepatic signaling cascades. Here, we examined whether chronic exogenous GH administration (via gene therapy) could ameliorate liver steatosis in animal models of alcoholic fatty liver disease (AFLD) and explored the underlying molecular mechanisms.MethodsMale C57BL/6J mice were fed either an alcohol or a control liquid diet with or without GH therapy for 6 weeks. Biochemical parameters, liver histology, oxidative stress markers, and serum high molecular weight (HMW) adiponectin were measured. Quantitative real-time PCR and western blotting were also conducted to determine the underlying molecular mechanism.ResultsSerum HMW adiponectin levels were significantly higher in the GH1-treated control group than in the control group (3.98 ± 0.71 μg/mL vs. 3.07 ± 0.55 μg/mL; P < 0.001). GH1 therapy reversed HMW adiponectin levels to the normal levels in the alcohol-fed group. Alcohol feeding significantly reduced hepatic adipoR2 mRNA expression compared with that in the control group (0.71 ± 0.17 vs. 1.03 ± 0.19; P < 0.001), which was reversed by GH therapy. GH1 therapy also significantly increased the relative mRNA (1.98 ± 0.15 vs. 0.98 ± 0.15) and protein levels of SIRT1 (2.18 ± 0.37 vs. 0.99 ± 0.17) in the alcohol-fed group compared with those in the control group (both, P < 0.001). The alcohol diet decreased the phosphorylated and total protein levels of hepatic AMP-activated kinase-α (AMPKα) (phosphorylated protein: 0.40 ± 0.14 vs. 1.00 ± 0.12; total protein: 0.32 ± 0.12 vs. 1.00 ± 0.14; both, P < 0.001) and peroxisome proliferator activated receptor-α (PPARα) (phosphorylated protein: 0.30 ± 0.09 vs. 1.00 ± 0.09; total protein: 0.27 ± 0.10 vs. 1.00 ± 0.13; both, P < 0.001), which were restored by GH1 therapy. GH therapy also decreased the severity of fatty liver in alcohol-fed mice.ConclusionsGH therapy had positive effects on AFLD and may offer a promising approach to prevent or treat AFLD. These beneficial effects of GH on AFLD were achieved through the activation of the hepatic adiponectin-SIRT1-AMPK and PPARα-AMPK signaling systems.

Diurnal variation and effect of insulin on circulating high molecular weight (HMW) adiponectin and NF-κB activity in human endothelial cells

ObjectiveTo study the diurnal variation and the effect of insulin on adiponectin multimers and nuclear factor-kappaB (NF-κB) activity in human endothelial cells. Methods and resultsWe utilized a prolonged insulin–glucose infusion in six healthy human subjects. HMW and total adiponectin levels were higher in the morning and lower at night; NF-κB activities in serum treated human microvascular endothelial cells (HMEC-1) cells were lower in the morning and higher at night. Hyperinsulinemic induction significantly decreased HMW and total adiponectin levels but increased NF-κB activity in serum treated HMEC-1 cells (P<0.05, P<0.01). There were no significant changes to MMW and LMW adiponectin levels (P>0.05). ConclusionCircadian rhythm of HMW adiponectin and NF-κB activity are altered by hyperinsulinemia providing novel insights adiponectin and NF-κB biology, which may be pertinent to insulin resistant states, e.g. obesity and type 2 diabetes mellitus.

High-Molecular-Weight Adiponectin Is Selectively Reduced in Women With Polycystic Ovary Syndrome Independent of Body Mass Index and Severity of Insulin Resistance

Common pathophysiologic characteristics associated with polycystic ovary syndrome (PCOS) include insulin resistance (IR) and hyperinsulinemia. Previous studies have suggested that decreased secretion of high-molecular-weight (HMW) adiponectin from adipocytes contributes to both obesity (elevated body mass index [BMI]) and IR in patients with PCOS. Some investigators have hypothesized that additional variables other than IR and BMI may be involved in the regulation of HMW adiponectin in PCOS. This cross-sectional study investigated potential variables in plasma and adipose tissue that may regulate HMW adiponectin in a cohort of women with PCOS. The study subjects were a well-characterized cohort with PCOS (n = 98) and BMI-matched controls (n = 103). A second cohort included a subset of 136 patients (68 age-, BMI-, and IR-matched pairs of PCOS women and controls). Each participant was given a 75-g oral glucose tolerance test. Gene expression in adipose tissue was examined using biopsied tissue samples from a subset of women with (n = 8) and without PCOS (n = 9). The primary study outcome measures included the relationship between serum levels of HMW adiponectin and variables associated with PCOS for the following: (1) indices of insulin sensitivity, body composition, and plasma androgens and (2) adipose tissue levels of the adiponectin gene (ADIPOQ), peroxisome proliferator-activated receptor γ, tumor necrosis factor α, and androgen receptor(AR). Multiple linear regression analysis was conducted to assess the relationship between HMW adiponectin and variables associated with PCOS. Plasma levels of HMW adiponectin were significantly lower in women with PCOS compared with both BMI-matched controls (P = 0.02) and BMI- and IR-matched controls (P = 0.027). Although BMI and IR were the primary independent predictors of HMW adiponectin, other variables were also involved. A significant interaction occurred between plasma testosterone and waist-to-hip ratio that had a combined influence on plasma levels of HMW adiponectin (P = 0.026). Gene expression analysis in adipose tissue showed that ADIPOQ mRNA levels were not increased in PCOS compared with controls; however, levels of tumor necrosis factor α and androgen receptor mRNA were significantly upregulated (P = 0.003) and P = 0.008, respectively). These findings confirm previous studies showing that plasma HMW adiponectin is reduced in PCOS women compared with controls, independent of BMI and IR. Combined effects of waist-to-hip ratio and plasma testosterone may also regulate HMW adiponectin. In addition, the data suggest that several key genes in adipose tissue may also contribute to reduced HMW adiponectin in PCOS.

The Effects of Macronutrient Intake on Total and High‐molecular Weight Adiponectin: Results From the OMNI‐Heart Trial

Higher levels of the adipocyte-specific hormone adiponectin have been linked to increased high-density lipoprotein (HDL) and lower insulin resistance. This study was conducted to determine the influence of macronutrient intake on adiponectin levels. One hundred and sixty-four pre- and stage-1 hypertensive adults participated in the Optimal Macro-Nutrient Intake Heart (OMNI-Heart) trial, a crossover feeding study originally testing the effects of macronutrients on blood pressure. Participants underwent three 6-week feeding periods: one rich in carbohydrates (CARB), one rich in monounsaturated fat (MUFA), and one rich in protein (PROT), while maintaining body weight. Their median plasma high molecular weight (HMW) and total adiponectin levels were 2.3 and 8.2 microg/ml, respectively, resulting in an average of 27% HMW adiponectin. Both HMW and total adiponectin levels decreased after baseline while the percent HMW adiponectin remained unchanged. Between diets, the MUFA diet maintained a higher level of both HMW and total adiponectin levels than either the CARB (HMW: +6.8%, P = 0.02; total: +4.5%, P = 0.001) or PROT (HMW: +8.4%, P = 0.003; total: +5.6%, P < 0.001) diets. Changes in total adiponectin levels were positively correlated to changes in HDL cholesterol irrespective of diets (Spearman r = 0.22-0.40). No correlation was found between changes in lipids, blood pressure, or insulin resistance by the homeostasis model assessment (HOMAIR). Macronutrient intake has effects on HMW and total adiponectin levels independent of weight loss. A diet rich in MUFA was associated with higher levels of total and HMW adiponectin in comparison to a carbohydrate- or protein-rich diet. Effects seen in adiponectin paralleled those found with HDL cholesterol.

Clinical effectiveness and safety evaluation of long-term pioglitazone treatment for erythropoietin responsiveness and insulin resistance in type 2 diabetic patients on hemodialysis

Background: We aimed to assess the effect of long-term pioglitazone treatment on erythropoietin responsiveness and insulin resistance in type 2 diabetic patients on hemodialysis.Methods: We conducted a prospective, open-label, parallel-group, controlled study of 63 type 2 diabetic hemodialysis patients who were randomly assigned to two groups: pioglitazone group (P-group; 15 – 30 mg/day pioglitazone plus conventional oral hypoglycemic agents) and control group (C-group; conventional oral hypoglycemic agents alone). We determined the efficacy of pioglitazone by monitoring anemia, glycemic control, insulin resistance, and levels of inflammatory cytokines and high-molecular-weight (HMW) adiponectin for 96 weeks.Results: Pioglitazone effectively reduced erythropoietin dose and maintained the target hemoglobin levels by improving insulin resistance up to the end of the study. In the P-group, hemoglobin A1c, glycated albumin, and triglycerides significantly decreased compared with the C-group. There was a significant reduction in homeostasis model assessment for insulin resistance and the level of high-sensitivity C-reactive protein, and a significant increase in HMW adiponectin level in the P-group; these changes were significantly different compared with values for the C-group. No serious adverse effects such as hypoglycemia, liver impairment, or heart failure were observed in any of the patients.Conclusion: Pioglitazone treatment resulted in better glycemic control, improved lipid levels, an increase in insulin sensitivity and adiponectin levels, and a decrease in inflammatory markers, thus improving the risk factors of cardiovascular disease. Erythropoietin responsiveness improved with a reduction in erythropoietin dose and may be associated with the improvement in insulin resistance due to long-term pioglitazone treatment.

Effects of acute hyperinsulinaemia on total and high-molecular-weight adiponectin concentration in metabolically healthy but obese postmenopausal women: A Montreal–Ottawa New Emerging Team (MONET) study

Aim The aim of this study was to determine the differences and changes in total and high-molecular-weight (HMW) adiponectin levels among metabolically healthy but obese (MHO) postmenopausal women in response to acute hyperinsulinaemia. Method In this cross-sectional study, 55 non-diabetic overweight and obese postmenopausal women underwent a hyperinsulinaemic–euglycaemic clamp test to evaluate insulin sensitivity. Subjects within the upper tertile of insulin sensitivity were described as ‘MHO’ ( n = 18), whereas those within the lowest tertile were considered ‘at risk’ ( n = 18). Plasma total and HMW adiponectin levels were measured by ELISA at 0 (baseline), 90, 160 and 180 min during the clamp. Results At baseline and at all time points during the clamp, MHO individuals had significantly higher total and HMW adiponectin levels than at-risk subjects (AUC: total adiponectin = 2506 ± 1010 vs 1616 ± 830; HMW adiponectin = 909 ± 307 vs 604 ± 349; P < 0.05). In addition, a significant reduction in total adiponectin was observed at 160 min and 180 min in at-risk and MHO subjects, respectively, while HMW adiponectin significantly decreased at 160 min in at-risk subjects, and at 90 min as well as 160 min in MHO women. Conclusion MHO postmenopausal women had higher levels of plasma total and HMW adiponectin than at-risk subjects at baseline and during the clamp. Furthermore, significant decreases in total and HMW adiponectin were observed at certain time points in both the MHO and at-risk subjects.

High-Molecular-Weight Adiponectin and Incident Ischemic Stroke in Postmenopausal Women

Although low levels of adiponectin are associated with coronary heart disease and cardiovascular disease risk factors, it is unclear whether adiponectin levels are related to the risk of developing ischemic stroke. We examined the relationship between baseline high-molecular-weight (HMW) adiponectin levels and incident ischemic stroke in postmenopausal women using data and specimens from the Hormones and Biomarkers Predicting Stroke Study, a case-control study nested within the Women's Health Initiative Observational Study. Included were 855 incident ischemic stroke cases and 855 control subjects matched for age, race-ethnicity, date of entry into the cohort, and follow-up time. ORs of incident ischemic stroke associated with baseline HMW adiponectin levels were calculated using conditional logistic regression modeling adjusting for body mass index, type 2 diabetes, hypertension, smoking, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, physical activity, C-reactive protein, and aspirin use. Lower levels of HMW adiponectin were significantly associated with type 2 diabetes, hypertension, higher body mass index, waist circumference, glucose, and insulin levels and lower high-density lipoprotein cholesterol levels. The distribution of incident stroke cases by HMW adiponectin quartiles was 49.9%, 50.5%, 50.7%, and 48.9%, respectively (P=0.96). Multivariable-adjusted ORs of stroke associated with the top 3 quartiles of HMW adiponectin versus the first quartile were 0.99 (95% CI, 0.71 to 1.37), 1.37 (0.99 to 1.91), and 1.25 (0.88 to 1.79), respectively (P trend=0.14). Despite moderate associations between HMW adiponectin and cardiovascular disease risk factors, we found no evidence of an association between HMW adiponectin levels and incident ischemic stroke in these postmenopausal women.

Similar Associations of Total Adiponectin and High Molecular Weight Adiponectin with Cardio-metabolic Risk Factors in a Population of Overweight and Obese Postmenopausal Women: A MONET Study

The aim of the study was to examine the association between total adiponectin and high molecular weight (HMW) adiponectin levels with cardio-metabolic risk factors in a population of sedentary, overweight, and obese postmenopausal women. Cross-sectional study was carried out on 55 nondiabetic sedentary overweight and obese postmenopausal women aged between 50 and 70 years. Insulin sensitivity was assessed by euglycemic-hyperinsulinemic clamp technique. Body composition and visceral fat were measured using dual X-ray absorptiometry and computed tomography, respectively. Other cardio-metabolic risk factors included: plasma lipids, hsC-reactive protein, energy expenditure (doubly labeled water), peak oxygen consumption, muscle strength (using weight training equipment) as well as total and HMW adiponectin. Correlations of total and HMW adiponectin with various cardio-metabolic risk factors were comparable. In addition, regression analysis results showed similar independent predictors of total and HMW adiponectin. Finally, the receiver operator characteristic (ROC) curves for total and HMW adiponectin to predict insulin sensitivity showed no difference between the areas under curve (AUC) (AUC total adiponectin=0.80 [95% CI: 0.66-0.95] versus AUC HMW adiponectin=0.76 [95% CI: 0.60-0.91], p=0.36). The present study indicates that HMW adiponectin does not seem to provide additional information than total adiponectin in relation to cardio-metabolic risk factors in overweight/obese postmenopausal women.

Withdrawal of pioglitazone in patients with type 2 diabetes mellitus

The remodelling of the adipose tissue by pioglitazone may be associated with the sustained therapeutic effects. We studied the effects of withdrawal of pioglitazone after 3-month treatment on glucose, lipid and high-molecular weight (HMW) adiponectin levels as well as liver function in patients with type 2 diabetes mellitus. Forty-nine Japanese patients with type 2 diabetes mellitus were randomly assigned into the withdrawal group after 3-month treatment with pioglitazone (15 or 30 mg daily) and the non-withdrawal group. Three-month treatment with pioglitazone improved glycaemic control, homeostasis model assessment for insulin resistance (HOMA), dyslipidaemia and liver function tests in association with a marked increase in serum HMW adiponectin level. Three months later after the withdrawal of pioglitazone, however, fasting plasma glucose and HOMA increased, whereas serum HMW adiponectin decreased to the pretreatment levels. Dyslipidaemia also returned to the pretreatment level. On the other hand, liver enzymes at 3 months after the withdrawal remained lower after a mild rebound. In addition, the bone formation marker, serum bone-specific alkaline phosphatase, was significantly reduced by pioglitazone treatment in post-menopausal women. The present study suggests that 3-month treatment with pioglitazone has no sustained beneficial effects except in liver function tests in patients with type 2 diabetes mellitus.

Effects Of Exercise Training On High Molecular Weight Adiponectin In The Healthy Male Rat

PURPOSE: The high-molecular weight (HMW) form of adiponectin has been reported to be the most active form of this hormone and low plasma HMW adiponectin levels have been found to be associated with insulin resistance..This study was intended to investigate the effects of exercise intensity on plasma HMW adiponectin concentrations. METHODS: Thirty-two male Wistar rats (age 8 wks, wt. 185±50 g) were randomly assigned to one of four groups as follows: high intensity (HI: 34m/min ∼%80-%85 VO2max), moderate intensity (MI: 28m/min ∼ %70-%75 VO2max), low intensity (LI: 20m/min ∼ %50-%55 VO2max), and sedentary control (SED) groups. All experimental groups performed 12 weeks of exercise consisting of treadmill running on a 0° slope for 1 hr/day, 5 days/week. Fasting levels of circulating HMW adiponectin, testosterone, insulin resistance index (HOMA-IR) were measured after the exercise program. Data were analyzed using one-way ANOVA while Pearson's correlations were performed to identify possible relationships among the assessed variables. RESULTS: HMW adiponectin plasma concentration increased significantly at HI and MI exercise training groups (p<0.05). Also, HMW adiponectin was inversely related to HOMA-IR (r = -0.37, p=0.003), insulin (r = -0.46, p=0.008) and testosterone (r = -0.38, p=0. 03). CONCLUSIONS: It concluded that exercise intensity appear to be important parameter to increase plasma HMW adiponectin level in healthy male rat.

Total and high molecular weight adiponectin levels in mice with altered GH signaling

Adiponectin, which negatively correlates to fat mass and insulin resistance, associates into high molecular weight (HMW) and low molecular weight forms. The HMW form possesses the predominate insulin sensitizing bioactivity, yet most mouse studies have reported only total levels. This study evaluates total and HMW adiponectin concentrations in giant bovine GH transgenic (bGH), dwarf GH receptor gene disrupted (GHR−/−), dwarf GH antagonist (GHA) transgenic mice fed either a high fat (HF) or low fat (LF) diet as compared to littermate controls. The bGH and GHR−/− strains represent opposites in GH signaling, with GHR−/− mice being highly insulin sensitive, obese and long‐lived in the absence of GH signaling and with bGH mice being insulin resistant, lean and short‐lived with excess GH signaling. GHA mice have repressed GH signaling are dwarf and obese, like GHR−/− mice, but do not have increased longevity or improved insulin sensitivity. GHR−/− mice on a HF and LF diet and GHA females have increased HMW, total and HMW/total adiponectin levels. Total adiponectin levels are increased in GHA males and decreased in bGH males, but there is no difference in HMW or HMW/total ratio as compared to littermate controls. The increase in total, HMW, and HMW/total adiponectin levels in the long‐lived male GHR−/− mice suggests that elevated adiponectin concentrations could contribute to their improved lifespan.Research was supported via funds from NIDDK (DK064905, DK075436), NIA (AG031736, AG19899), State of Ohio's Eminent Scholar Program that includes a gift from Milton and Lawrence Goll, DiAthegen, Diabetes Research Initiative at Ohio University, and AMVETS.Grant Funding Source: DEB was supported in part by funds from NIDDK (DK064905) and NIA (AG031736). EOL is supported by funds from NIA (AG031736) and NIDDK (DK075436). JJK is supported by funds from NIA (AG19899 and AG031736), NIDDK (DK075436), the State of Ohio's Eminent Scholar Program that includes a gift from Milton and Lawrence Goll, and a grant from DiAthegen LLC. All work was further supported by the Diabetes Research Initiative at Ohio University and by a grant from AMVETS.

Diet‐induced obesity leads to decreased hepatic iron storage associated with inflammation

Increased risk for iron deficiency has been reported in obese subjects. We investigated the effects of high fat diet‐induced obesity on hepatic iron status and serum adipokine and inflammatory marker levels. Four‐ week old C57BL mice were fed diets containing 10 (ND) or 60 (HFD)% energy from fat for 16 wks. Consumption of HFD resulted in higher weight gain (16.3 vs. 30.4g). Serum leptin, total adiponectin, high molecular weight (HMW) adiponectin, and serum amyloid A (SAA) and hepatic non‐heme iron, ferritin, and hepcidin mRNA levels were measured. HFD group had higher leptin (42.6 vs. 104.3 ng/mL), and lower HMW adiponectin (4.80 vs. 3.67 ug/mL) levels. Higher level of SAA in HFD group (57.8 vs. 117.9 ug/mL) suggests inflammation in HFD‐induced obese animals. HFD group had lower hepatic non‐heme iron (3.12 vs 0.869 ug/mg protein) and ferritin levels. HFD group had lower hepcidin expression at 54% level of ND group, however, ratio of hepcidin expression to non‐heme iron was higher (2.5 fold higher in HFD than ND). Hepcidin is a homeostatic regulator of iron metabolism by restricting intestinal iron absorption, but, also known as a mediator of inflammation. Leptin and SAA showed positive correlation with weight gain while HMW adiponectin showed negative correlation. Increased SAA levels and higher hepcidin ratio to iron suggests that lower hepatic iron status in obese animals might be associated with inflammation. Supported by Korea Research Foundation Grant (C00305) and by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2009‐0063409).

Hepatic adiponectin receptor R2 expression is up-regulated in normal adult male mice by chronic exogenous growth hormone levels

Previous studies investigating the effects of exogenous growth hormone (GH) on the expression of adiponectin and the adiponectin receptors have generated seemingly conflicting results. Here, to determine the effects of chronic exogenous GH levels, we investigated the expression of adiponectin receptor R1 (adipoR1) in skeletal muscle and adiponectin receptor R2 (adipoR2) in the liver of normal C57BL/6 adult male mice 24 weeks after a single injection of rAAV2/1-CMV-GH1 viral particles. AdipoR1 and adipoR2 mRNA expression levels were determined by quantitative real-time reverse transcription-polymerase chain reaction. AdipoR1 and adipoR2 proteins were analyzed by Western blotting. Serum total and high molecular weight (HMW) adiponectin concentrations were measured by enzyme-linked immunosorbent assay (ELISA) kits for mice. The results demonstrated that the injection of rAAV2/1-CMV-GH1 within the concentration range of 1.0x1011 to 4.0x1011 viral particles significantly up-regulated hepatic adipoR2 gene expression. The serum HMW adiponectin level increased significantly with the concentration range of 2.0x1011 to 4.0x1011 rAAV2/1-CMV-GH1 viral particles. The injection of 4.0x1011 rAAV2/1-CMV-GH1 viral particles induced a significant increase in both serum glucose and insulin concentrations (p<0.05), and the homeostasis model assessment of insulin resistance (p<0.01). This may decrease body insulin sensitivity and therefore raise the potential risk of insulin resistance. However, exogenous GH levels did not significantly affect adipoR1 expression in skeletal muscle. In conclusion, chronic exogenous GH up-regulates hepatic adipoR2, rather than adipoR1, in vivo, and raises the serum HMW adiponectin level. However, the elevation of exogenous GH concentrations may increase the risk of insulin resistance.

Total and high–molecular weight adiponectin in women with the polycystic ovary syndrome

Adiponectin, an adipokine with antidiabetic properties, forms multimers; and the high–molecular weight (HMW) form most closely correlates with insulin sensitivity ( S i). Therefore, we hypothesize that HMW adiponectin levels are decreased in women with polycystic ovary syndrome (PCOS), a condition characterized by insulin resistance, compared with healthy controls and that HMW adiponectin correlates with testosterone and S i. A cross-sectional study involving 13 women with PCOS and 13 age- and body mass index–matched healthy controls was performed. Waist-to-hip ratios (WHRs), glucose, insulin, sex hormone–binding globulin, total testosterone, and total and HMW adiponectin levels were measured after an overnight fast. Free testosterone was calculated from sex hormone–binding globulin and total testosterone, and S i was determined using a frequently sampled intravenous glucose tolerance test. The study's primary outcomes were differences in total and HMW adiponectin between women with PCOS and healthy control women. Total adiponectin ( P < .01), HMW adiponectin ( P < .01), and the ratio of HMW to total adiponectin ( P = .03) were lower in women with PCOS compared with healthy women. Total and HMW adiponectin levels correlated inversely with WHR ( P < .01) and free testosterone ( P < .01) and positively with S i ( P < .001). Using forward stepwise multivariate analysis, HMW adiponectin and WHR, but not PCOS status, were independent predictors of S i. Women with PCOS have lower total and HMW adiponectin levels compared with healthy women. High–molecular weight adiponectin also comprises a smaller proportion of total circulating adiponectin in women with PCOS. Alterations in HMW adiponectin levels in women with PCOS may contribute to the insulin resistance intrinsic to the syndrome.

Novel adipokines, high molecular weight adiponectin and resistin, are associated with outcomes following lower extremity revascularization with autogenous vein

A significant portion of patients undergoing lower extremity bypass surgery (LEB) for peripheral arterial disease (PAD) will have cardiovascular or graft-related events. It has been previously demonstrated that systemic inflammation is associated with PAD and its clinical outcomes. We hypothesized that serum biomarkers of insulin resistance and inflammation would identify a subgroup at elevated risk for graft failure, limb loss, and mortality. This was a prospective longitudinal study of patients (n = 225) undergoing LEB using autogenous vein. Baseline blood samples were obtained prior to surgery in the fasting state. High-sensitivity C-reactive protein (hsCRP) and the adipokines resistin and high-molecular weight adiponectin (HMWA) were measured by enzyme-linked immunosorbent assay (ELISA). Median follow-up was 893 days. The major endpoints of primary patency (PP) and amputation-free survival (AFS) were examined using multivariable methods. Endpoints were screened against biomarkers and patient characteristics for univariate associations. Promising explanatory variables (P < .1) were included in multivariable Cox proportional hazard models. The mean age of subjects was 67.6 years; 71.6% were male and 87.1% were Caucasian. One hundred thirty-three (59.1%) subjects underwent bypass for critical limb ischemia (CLI) and 73 (32.4%) had tissue loss. Patients with CLI and diabetes demonstrated elevated resistin and hsCRP levels. HMWA levels correlated with CLI and with a measure of insulin resistance (HOMA-IR) but not with clinical diabetes. Baseline biomarkers were higher in those presenting with tissue loss and in patients with postoperative events (mortality, limb loss). After multivariable analysis (including CLI, diabetes, age, estimated glomerular filtration rate [eGFR], adiponectin, resistin, and CRP), resistin (hazard ratio [HR] 1.75, 95% confidence interval [CI], 1.07-2.85; P = .025) and CRP (HR 2.39, 95% CI, 1.30-4.39; P = .005) were independently predictive of reduced AFS. However, only resistin maintained its significance when restricted to the diabetic cohort (HR 2.10, 95% CI, 1.10-3.99; P = .025). Higher levels of HMWA were found to be associated with primary graft patency (HR 0.73 for graft failure; 95% CI, 0.55 to 0.97; P = .031) in a multivariable model adjusting for diabetes, CRP, African-American race, CLI, high-risk conduits, and redo bypass procedures. These findings suggest that serum biomarkers of insulin resistance and inflammation may be predictive of clinical outcomes following LEB. Improving the systemic milieu of insulin resistance and inflammation in these high-risk patients may lead to reduced morbidity and mortality.