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Adiponectin is an adipokine first described just over a decade ago. Produced almost exclusively by adipocytes, adiponectin circulates in high concentrations in human plasma. Research into this hormone has revealed it to have insulin-sensitizing, anti-inflammatory and cardioprotective roles. This review discusses the history, biology and physiological role of adiponectin and explores its role in disease, with specific focus on adiponectin in inflammation and sepsis. It appears that an inverse relationship exists between adiponectin and inflammatory cytokines. Low levels of adiponectin have been found in critically ill patients, although data are limited in human subjects at this stage. The role of adiponectin in systemic inflammation and critical illness is not well defined. Early data suggest that plasma levels of adiponectin are decreased in critical illness. Whether this is a result of the disease process itself or whether patients with lower levels of this hormone are more susceptible to developing a critical illness is not known. This observation of lower adiponectin levels then raises the possibility of therapeutic options to increase circulating adiponectin levels. The various options for modulation of serum adiponectin (recombinant adiponectin, thiazolidinediones) are discussed.

Iron overload is associated with increased diabetes risk. We therefore investigated the effect of iron on adiponectin, an insulin-sensitizing adipokine that is decreased in diabetic patients. In humans, normal-range serum ferritin levels were inversely associated with adiponectin, independent of inflammation. Ferritin was increased and adiponectin was decreased in type 2 diabetic and in obese diabetic subjects compared with those in equally obese individuals without metabolic syndrome. Mice fed a high-iron diet and cultured adipocytes treated with iron exhibited decreased adiponectin mRNA and protein. We found that iron negatively regulated adiponectin transcription via FOXO1-mediated repression. Further, loss of the adipocyte iron export channel, ferroportin, in mice resulted in adipocyte iron loading, decreased adiponectin, and insulin resistance. Conversely, organismal iron overload and increased adipocyte ferroportin expression because of hemochromatosis are associated with decreased adipocyte iron, increased adiponectin, improved glucose tolerance, and increased insulin sensitivity. Phlebotomy of humans with impaired glucose tolerance and ferritin values in the highest quartile of normal increased adiponectin and improved glucose tolerance. These findings demonstrate a causal role for iron as a risk factor for metabolic syndrome and a role for adipocytes in modulating metabolism through adiponectin in response to iron stores.

Adiponectin is a protein hormone produced by adipose tissue whose circulating levels are inversely related to adiposity and inflammation. Adiponectin circulates as oligomers, from the low molecular weight trimer to the high molecular weight octodecamer (18mer) Each oligomer has distinct biological activities, which include enhancement of insulin sensitivity and metabolic control, and suppression of inflammation. Adiponectin occurs in human milk at higher concentrations than leptin. The adiponectin in human milk is almost entirely of the high molecular weight form, the form with the highest activity in controlling many types of metabolic processes. Human adiponectin fed to infant mice is transported across the intestinal mucosa into the serum. An inverse relationship between adiponectin levels in milk and adiposity (weight-for-height) of the breastfed infant was observed, and could be due to modulation of infant metabolism by milk adiponectin, and may be related to the observed protection against obesity by breastfeeding. Human milk may be a medium whereby the hormonal milieu (in response to internal factors and the environment) of the mother can be used to communicate with the breastfed infant to modify infant metabolic processes. Transmission of information from mother to infant through milk may allow adaptation to fluctuating environmental conditions.

Background

The incidence of obesity has risen dramatically over the last few decades. This epidemic may be affected by exposure to xenobiotic chemicals. Bisphenol A (BPA), an endocrine disruptor, is detectable at nanomolar levels in human serum worldwide. Adiponectin is an adipocyte-specific hormone that increases insulin sensitivity and reduces tissue inflammation. Thus, any factor that suppresses adiponectin release could lead to insulin resistance and increased susceptibility to obesity-associated diseases.

Objectives

In this study we aimed to compare a) the effects of low doses of BPA and estradiol (E2) on adiponectin secretion from human breast, subcutaneous, and visceral adipose explants and mature adipocytes, and b) expression of putative estrogen and estrogen-related receptors (ERRs) in these tissues.

Methods

We determined adiponectin levels in conditioned media from adipose explants or adipocytes by enzyme-linked immunosorbant assay. We determined expression of estrogen receptors (ERs) α and β, G-protein–coupled receptor 30 (GPR30), and ERRs α, β, and γ by quantitative real-time polymerase chain reaction.

Results

BPA at 0.1 and 1 nM doses suppressed adiponectin release from all adipose depots examined. Despite substantial variability among patients, BPA was as effective, and often more effective, than equimolar concentrations of E2. Adipose tissue expresses similar mRNA levels of ERα, ERβ, and ERRγ, and 20- to 30-fold lower levels of GPR30, ERRα, and ERRβ.

Conclusions

BPA at environmentally relevant doses inhibits the release of a key adipokine that protects humans from metabolic syndrome. The mechanism by which BPA suppresses adiponectin and the receptors involved remains to be determined.

Obesity is characterized by low-grade systemic inflammation. Adiponectin is an adipose tissue-derived hormone, which is downregulated in obesity. Adiponectin displays protective actions on the development of various obesity-linked diseases. Several clinical studies demonstrate the inverse relationship between plasma adiponectin levels and several inflammatory markers including C-reactive protein. Adiponectin attenuates inflammatory responses to multiple stimuli by modulating signaling pathways in a variety of cell types. The anti-inflammatory properties of adiponectin may be a major component of its beneficial effects on cardiovascular and metabolic disorders including atherosclerosis and insulin resistance. In this reviews, we focus on the role of adiponectin in regulation of inflammatory response and discuss its potential as an antiinflammatory marker.

Obesity-related disorders are closely associated with the pathogenesis of cardiovascular disease. Adiponectin is a circulating adipose tissue-derived hormone that is down-regulated in obese individuals. Hypoadiponectinemia has been identified as an independent risk factor for type 2 diabetes, coronary artery disease, and hypertension, and experimental studies show that adiponectin plays a protective role in the development of insulin resistance, atherosclerosis, and inflammation. More recent findings have shown that adiponectin directly affects signaling in myocardial cells and exerts beneficial actions on the heart after pressure overload and ischemia–reperfusion injury. This review focuses on the role of adiponectin in the regulation of myocardial remodeling and acute cardiac injury.

Insulin resistance, which implies impairment of insulin signaling in the target tissues, is a common cause of type 2 diabetes. Adipose tissue plays an important role in insulin resistance through the dysregulated production and secretion of adipose-derived proteins, including tumor necrosis factor-α, plasminogen activator inhibitor-1, leptin, resistin, angiotensinogen, and adiponectin. Adiponectin was estimated to be a protective adipocytokine against atherosclerosis, and also to have an anti-inflammatory effect. In this study, the relationship between fasting plasma adiponectin concentration and adiposity, body composition, insulin sensitivity (ITT, HOMAIR, QUICK), lipid profile, fasting insulin concentration were examined in Korean type 2 diabetes. The difference in the adiponectin concentrations was also examined in diabetic and non-diabetic subjects, with adjustment for gender, age and body mass index. 102 type 2 diabetics and 50 controls were examined. After a 12-h overnight fast, all subjects underwent a 75gram oral glucose tolerance test. Baseline blood samples were drawn for the determinations of fasting plasma glucose, insulin, adiponectin, total cholesterol, triglyceride, LDL-cholesterol, and HDL-cholesterol. The body composition was estimated using a bioelectric impedance analyzer (Inbody 2.0). The insulin sensitivity was estimated using the insulin tolerance test (ITT), HOMAIR and QUICK methods. In the diabetic group, the fasting adiponectin concentrations were significantly lower in men than in women. They were negatively correlated with BMI (r=-0.453), hip circumference (r=-0.341), fasting glucose concentrations (r=-0.277) and HOMAIR (r=-0.233). In addition, they were positively correlated with systolic blood pressure (r=0.321) and HDL-cholesterol (r=0.291). The systolic blood pressure and HDL-cholesterol were found to be independent variables, from a multiple logistic regression analysis, which influenced the adiponectin concentration. Compared with the non-diabetic group, the adiponectin concentrations were significantly lower in the diabetic group, with the exception of obese males. In conclusion, the plasma adiponectin concentrations were closely related to the insulin resistance parameters in Korean type 2 diabetic patients.

OBJECTIVE—Adiponectin is an adipocyte-derived protein that acts to reduce insulin resistance in the liver and muscle and also inhibits atherosclerosis. Although adiponectin reportedly enhances AMP-activated protein kinase and inhibits tumor necrosis factor-α action downstream from the adiponectin signal, the precise physiological mechanisms by which adiponectin acts on skeletal muscles remain unknown.

RESEARCH DESIGN AND METHODS—We treated murine primary skeletal muscle cells with recombinant full-length human adiponectin for 12 h and searched, using two-dimensional electrophoresis, for proteins upregulated more than threefold by adiponectin compared with untreated cells.

RESULTS—We found one protein that was increased 6.3-fold with adiponectin incubation. MALDI-TOF (matrix-assisted laser desorption/ionization−top of flight) mass spectrometric analysis identified this protein as ferritin heavy chain (FHC). When murine primary skeletal muscle cells were treated with adiponectin, IκB-α phosphorylation was observed, suggesting that adiponectin stimulates nuclear factor (NF)-κB activity. In addition, FHC upregulation by adiponectin was inhibited by NF-κB inhibitors. These results suggest NF-κB activation to be involved in FHC upregulation by adiponectin. Other NF-κB target genes, manganese superoxide dismutase (MnSOD) and inducible nitric oxide synthase (iNOS), were also increased by adiponectin treatment. We performed a reactive oxygen species (ROS) assay using CM-H2DCFDA fluorescence and found that ROS-reducing effects of adiponectin were abrogated by FHC or MnSOD small-interfering RNA induction.

CONCLUSIONS—We have demonstrated that adiponectin upregulates FHC in murine skeletal muscle tissues, suggesting that FHC elevation might partially explain how adiponectin protects against oxidative stress in skeletal muscles.

Background

Adiponectin is inversely associated with obesity, insulin resistance, and atherosclerosis, but little is known about the genetic pathways that regulate the plasma level of this protein. To find novel genes that influence circulating levels of adiponectin, a genome-wide linkage scan was performed on plasma adiponectin concentrations before and after 3 weeks of treatment with fenofibrate (160 mg daily) in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) Study. We studied Caucasian individuals (n = 1121) from 190 families in Utah and Minnesota. Of these, 859 individuals from 175 families had both baseline and post-fenofibrate treatment measurements for adiponectin. Plasma adiponectin concentrations were measured with an ELISA assay. All participants were typed for microsatellite markers included in the Marshfield Mammalian Genotyping Service marker set 12, which includes 407 markers spaced at approximately 10 cM regions across the genome. Variance components analysis was used to estimate heritability and to perform genome-wide scans. Adiponectin was adjusted for age, sex, and field center. Additional models also included BMI adjustment.

Results

Baseline and post-fenofibrate adiponectin measurements were highly correlated (r = 0.95). Suggestive (LOD > 2) peaks were found on chromosomes 1p35.2 and 3q28 (near the location of the adiponectin gene).

Conclusion

Two candidate genes, IL22RA1 and IL28RA, lie under the chromosome 1 peak; further analyses are needed to identify the specific genetic variants in this region that influence circulating adiponectin concentrations.

OBJECTIVE

Adiponectin, an adipokine secreted by the adipocyte, is inversely related to adiposity and directly related to insulin sensitivity. In T1DM, however, data thus far are contradictory. We investigated the relationship between adiponectin and exercise in type 1 diabetes.

METHODS

49 children (14.5 ± 2.0yrs, range 8–17) with T1DM on an insulin pump were studied during two 75min exercise sessions with and without continuation of the basal rate within 4w. Adiponectin and epinephrine concentrations were measured before and during exercise.

RESULTS

Mean pre-exercise adiponectin concentration was 11.2 ± 4.7 mg/L (range 2.7–23.0) with a mean absolute difference of 1.7 mg/L between the 2 days. Adiponectin concentrations did not change meaningfully during exercise (mean change: −0.1 ± 1.2; P=0.17). Adiponectin correlated inversely with BMI percentile (p=0.02) but not with age, gender, duration of diabetes, HbA1c or pre-exercise glucose. However, those with higher baseline adiponectin were less likely to become hypoglycemic during exercise, 36% becoming hypoglycemic when baseline adiponectin was <10 mg/L, 42% when 10-<15, 15% when ≥15 (p=0.02). Baseline epinephrine concentrations were not associated with adiponectin, and in those whose nadir glucose was ≤100mg/dL, there was no correlation between epinephrine response and adiponectin (p=0.16).

CONCLUSIONS

Adiponectin concentrations are stable from day to day, are not affected by acute exercise or metabolic control, and vary inversely with adiposity. Higher adiponectin appears to be associated with a decrease in hypoglycemia risk during exercise. Further studies are needed to examine whether adiponectin protects against exercise-induced hypoglycemia by directly enhancing the oxidation of alternate fuels.

Adiponectin is one of several, important metabolically active cytokines secreted from adipocytes. Low circulating levels of this adipokine have been associated epidemiologically with obesity, insulin resistance, type II diabetes, and cardiovascular disease. To determine if adiponectin can modulate lipid metabolism in macrophages, we expressed the adiponectin gene in human THP-1 macrophage foam cells using a lentiviral vector expression system and demonstrated that macrophages transduced with the adiponectin gene had decreased lipid accumulation compared with control macrophages transduced with the LacZ gene. Macrophages transduced with the adiponectin gene also exhibited decreased oxidized low-density lipoprotein (oxLDL) uptake and increased HDL-mediated cholesterol efflux.

Additional studies suggest two potential mechanisms for the reduced lipid accumulation in these adiponectin-transduced macrophage foam cells. The first mechanism involves the PPARγ and LXR signaling pathways which up-regulate the expression of ABCA1 and promote lipid efflux from these cells. The second mechanism involves decreased lipid uptake and increased lipid hydrolysis which may result from decreased SR-AI and increased SR-BI and HSL gene activities in the transformed macrophage foam cells. We demonstrated also that the expression of two proatherogenic cytokines, MCP-1 and TNFα, were decreased in the adiponectin transduced macrophage foam cells.

These results suggest that adiponectin may modulate multiple pathways of lipid metabolism in macrophages. Our studies provide new insights into potential mechanisms of adiponectin-mediated alterations in lipid metabolism and macrophage foam cell formation which may impact the development of atherosclerosis.

Background and Design:

Adiponectin is an adipokine secreted primarily from adipose tissue that can influence circulating plasma glucose and lipid levels through multiple mechanisms involving a variety of organs. In humans, reduced plasma adiponectin levels induced by obesity are associated with insulin resistance and type 2 diabetes, suggesting that low adiponectin levels may contribute the pathogenesis of obesity-related insulin resistance.

Methods and Results:

The objective of the present study was to investigate whether gene therapy designed to elevate circulating adiponectin levels is a viable strategy for ameliorating insulin resistance in mice fed a high-fat, high-sucrose (HFHS) diet. Electroporation-mediated gene transfer of mouse adiponectin plasmid DNA into gastrocnemius muscle resulted in elevated serum levels of globular and high-molecular weight adiponectin compared with control mice treated with empty plasmid. In comparison to HFHS-fed mice receiving empty plasmid, mice receiving adiponectin gene therapy displayed significantly decreased weight gain following 13 weeks of HFHS diet associated with reduced fat accumulation, and exhibited increased oxygen consumption and locomotor activity as measured by indirect calorimetry, suggesting increased energy expenditure in these mice. Consistent with improved whole-body metabolism, mice receiving adiponectin gene therapy also had lower blood glucose and insulin levels, improved glucose tolerance and reduced hepatic gluconeogenesis compared with control mice. Furthermore, immunoblot analysis of livers from mice receiving adiponectin gene therapy showed an increase in insulin-stimulated phosphorylation of insulin signaling proteins.

Conclusion:

Based on these data, we conclude that adiponectin gene therapy ameliorates the metabolic abnormalities caused by feeding mice a HFHS diet and may be a potential therapeutic strategy to improve obesity-mediated impairments in insulin sensitivity.

Adiponectin is secreted from adipose tissue in response to metabolic effectors in order to sensitize the liver and muscle to insulin. Reduced circulating levels of adiponectin that usually accompany obesity contribute to the associated insulin resistance. The molecular mechanisms controlling the production of adiponectin are essentially unknown. In this report, we demonstrate that the endoplasmic reticulum (ER) oxidoreductase Ero1-Lα and effectors modulating peroxisome proliferator-activated receptor γ (PPARγ) and SIRT1 activities regulate secretion of adiponectin from 3T3-L1 adipocytes. Specifically, adiponectin secretion and Ero1-Lα expression are induced during the early phase of adipogenesis but are then down-regulated during the terminal phase, coincident with an increased expression of SIRT1. Suppression of SIRT1 or activation of PPARγ enhances Ero1-Lα expression and stimulates secretion of high-molecular-weight complexes of adiponectin in mature adipocytes. Suppression of Ero1-Lα through expression of a corresponding small interfering RNA reduces adiponectin secretion during the differentiation of 3T3-L1 preadipocytes. Moreover, ectopic expression of Ero1-Lα in Ero1-Lα-deficient 3T3 fibroblasts stimulates the secretion of adiponectin following their conversion into adipocytes and prevents the suppression of adiponectin secretion in response to activation of SIRT1 by exposure to resveratrol. These findings provide a framework to understand the mechanisms by which adipocytes regulate secretion of adiponectin in response to various metabolic states.

Background. Adiponectin, an adipokine secreted from adipose tissue, has antiobesity, anti-insulin resistance, and anticancer roles. The present study aimed to review the epidemiologic evidence about the association between adiponectin and cancers. Method. We searched in PubMed from 2002 to October 2011 by using the following key words: cancer, malignancy, cell proliferation, and adiponectin. Finally, 45 articles were recruited to review in the present paper. Findings. Several findings suggested inverse association between concentration of hormone and breast cancer risk. Low levels of adiponectin increase the risk of endometrial cancer in women. Adiponectin levels were significantly associated with prostate cancer in men. It seems that there is an inverse relationship between levels of adiponectin or its gene and colorectal cancer. Significant association between hormone and pancreatic cancer was found. Conclusion. Several findings suggested the negative correlation between adiponectin and risk of cancers. This relationship was more elucidated by the correlation between the hormone with obesity and insulin resistance. Suppression of growth and proliferation of cancer cells by adiponectin were explained via several mechanisms.

Obesity and insulin resistance have been implicated in the etiology of pancreatic cancer (PC). Whether adiponectin and/or leptin, two adipocyte-secreted hormones important in metabolic regulation, are associated with PC pathogenesis and whether adiponectin receptors are expressed in PC remains unknown. In a hospital-based case-control study, we studied 81 cases with incident, histologically confirmed PC and 81 controls matched on gender and age between 2000 and 2007 to investigate the role of adiponectin and leptin adjusting for risk factors linked to PC. In a separate study, we also studied for the first time whether adiponectin receptors 1 and 2 are expressed in PC by studying 16 PC tumor tissue samples which were analyzed using immunohistochemistry. When subjects were divided into control-defined quartiles of adiponectin and leptin, lower leptin but higher adiponectin levels were associated with PC (p=0.001 and p=0.05 respectively) before and after controlling for age, gender, BMI, smoking status, alcohol consumption, history of diabetes, and family history of pancreatic cancer. Of the PC tumor tissue samples analyzed, 87.5% had positive or strong positive expression of AdipoR1 and 93.7% had positive or strong positive expression of AdipoR2. Further prospective studies are needed to determine whether the elevated adiponectin and low leptin levels reported in this study reflect compensatory changes during PC progression and thus can be used as markers for PC or whether they are causally implicated in PC.

Adiponectin and leptin are two adipokines secreted by white adipose tissue that regulate insulin sensitivity. Previously we reported that adiponectin but not leptin release depends on GGA-coated vesicle formation, suggesting that leptin and adiponectin may follow different secretory routes. Here we have examined the intracellular trafficking pathways that lead to the secretion of these two hormones. While adiponectin and leptin displayed distinct localization in the steady-state, treatment of adipocytes with brefeldin A inhibited both adiponectin and leptin secretion to a similar level, indicating a common requirement for class III ADP-ribosylating factors and an intact Golgi apparatus. Adiponectin secretion was significantly reduced by endosomal inactivation in both 3T3L1 and rat isolated adipocytes, whereas this treatment had no effect on leptin secretion. Importantly, endosomal inactivation completely abolished the insulin stimulatory effect on adiponectin release in rat adipocytes. Confocal microscopy studies revealed colocalization of adiponectin with endogenous rab11 a marker for the recycling endosome, and with expressed rab5-GFP mutant (rab5Q75L) a marker for the early endosome compartment. Colocalization of adiponectin and rab5Q75L was increased in endosome inactivated cells. Consistent with these findings adiponectin secretion was reduced in cells expressing mutants of Rab11 and Rab5 proteins. In contrast, expression of an inactive (kinase dead) mutant of Protein Kinase D1 moderately but significantly inhibited leptin secretion without altering adiponectin secretion. Taken together, these results suggest that leptin and adiponectin secretion involve distinct intracellular compartments and that endosomal compartments are required for adiponectin but not for leptin secretion.

Circulating adiponectin reflects the degree of energy homeostasis and insulin sensitivity of adult individuals. Low abundance of the high molecular mass multimers (HMW), the most active forms mediating the insulin-sensitizing effects of adiponectin, is indicative of impaired metabolic status. The increase in fetal adiponectin HMW compared with adults is a distinctive features of human neonates. In order to further understand the functional properties of adiponectin during fetal life, we have evaluated the associations of adiponectin with insulin sensitivity, body composition and gender. Umbilical cord adiponectin, adiponectin complexes and metabolic parameters were measured at term by elective Cesarean section. The associations between adiponectin, measures of body composition and insulin sensitivity were evaluated in relation to fetal gender in 121 singleton neonates. Higher total adiponectin concentrations in females compared with male fetuses (34.3±9.5 vs 24.9±8.6, p<0.001) were associated with a 3.2-fold greater abundance in circulating HMW complexes (0.20±0.03 vs 0.08±0.03, p<0.001, n=9). Adiponectin was positively correlated with neonatal fat mass (r= 0.27, p< 0.04) and percent body fat in female fetuses (r= 0.28, p<0.03) and with lean mass in males (r= 0.28, p<0.03). There was no significant correlation between cord adiponectin and fasting insulin concentrations or fetal insulin sensitivity as estimated by HOMA-IR. The gender dimorphism for plasma adiponectin concentration and complex distribution first appears in utero. In sharp contrast to the inverse correlation found in adults, the positive relationship between adiponectin and body fat is a specific feature of the fetus.

OBJECTIVES

Leptin and adiponectin are adipocyte-secreted hormones that regulate energy homeostasis and metabolism. Because their roles in the neonatal period and in early childhood are poorly understood, we aimed in this prospective cohort study to determine the extent to which umbilical cord blood leptin and adiponectin concentrations predict measures of adiposity and growth at 3 years of age.

PATIENTS AND METHODS

We studied 588 children participating in the prospective prebirth cohort study Project Viva. We examined associations of cord blood leptin and adiponectin levels with weight changes during the first 6 months of life, 3-year circulating leptin and adiponectin concentrations, and the following adiposity-related outcomes at 3 years of age: BMI z score, height-for-age z score, and sums of triceps and subscapular skinfold thicknesses to represent overall adiposity, as well as subscapular/triceps skinfold ratio to represent central adiposity.

RESULTS

Cord blood leptin and adiponectin were each directly associated with the duration of gestation and birth weight for gestational age z scores. Cord blood leptin levels were negatively associated with change in weight-for-length, weight-for-age, and length-for-age z scores between birth and 6 months of age. Similarly, cord blood adiponectin was negatively associated with change in weight-for-length and weight-for-age z scores. After adjusting for several maternal and child factors related to obesity, each 10 ng/mL increment of cord blood leptin was associated with a reduction in BMI z score and higher leptin levels at 3 years but not with skinfold thicknesses. Each 10 µg/mL increment of cord blood adiponectin was positively associated with a higher subscapular skinfold thickness/triceps skinfold thickness ratio at 3 years.

CONCLUSIONS

Lower cord blood leptin levels are associated with smaller size at birth but more pronounced weight gain in the first 6 months of life and higher BMI at 3 years of age. Cord blood adiponectin levels are also directly associated with birth weight for gestational age, inversely associated with weight gain in the first 6 months of life, and predict an increase in central adiposity at age 3 years.

Objective

Scavenger receptors play crucial roles in the pathogenesis of atherosclerosis, but their role in insulin resistance has not been explored. We hypothesized that scavenger receptors are present in human adipose tissue resident macrophages, and their gene expression is regulated by adiponectin and thaizolidinediones.

Methods and Results

The gene expression of scavenger receptors including scavenger receptor-A (SRA), CD36, and lectin-like oxidized LDL receptor-1 (LOX-1) were studied in subcutaneous adipose tissue of nondiabetic subjects and in vitro. Adipose tissue SRA expression was independently associated with insulin resistance. Pioglitazone downregulated SRA gene expression in adipose tissue of subjects with impaired glucose tolerance and decreased LOX-1 mRNA in vitro. Macrophage LOX-1 expression was decreased when macrophages were cocultured with adipocytes or when exposed to adipocyte conditioned medium. Adding adiponectin neutralizing antibody resulted in a 2-fold increase in LOX-1 gene expression demonstrating that adiponectin regulates LOX-1 expression.

Conclusion

Adipose tissue scavenger receptors are strongly associated with insulin resistance. Pioglitazone and adiponectin regulate gene expression of SRA and LOX-1, and this may have clinical implications in arresting the untoward sequalae of insulin resistance and diabetes, including accelerated atherosclerosis.

Accumulating evidence strongly suggests that autophagy, which is induced by endoplasmic reticulum (ER) stress in adipocytes, may play an important role in obesity-induced insulin resistance and type 2 diabetes. Obesity induces ER stress in mouse adipose tissue, which correlates with reduced adiponectin levels. In 3T3-L1 adipocytes, induction of ER stress is sufficient to promote autophagy-dependent adiponectin degradation. In contrast, suppressing ER stress increases adiponectin levels in 3T3-L1 adipocytes and alleviates high fat diet-induced adiponectin downregulation in mice. The ER stress-induced adiponectin downregulation can also be suppressed by overexpression of DsbA-L, a newly identified protein involved in promoting adiponectin multimerization and stability. Taken together, our results show that ER stress-induced autophagy provides an important mechanism underlying obesity-induced adiponectin downregulation in adipocytes. In addition, increasing the expression levels of DsbA-L could be an effective approach to improve adiponectin biosynthesis and stability, thus improving insulin sensitivity in cells and in vivo.

Objective

Reduced circulating adiponectin levels contribute to the etiology of insulin-resistance. Adiponectin circulates in three different isoforms: high (HMW), medium (MMW), and low (LMW) molecular weight. The genetics of adiponectin isoforms is mostly unknown. Our aim was to investigate whether and to which extent circulating adiponectin isoforms are heritable and whether they share common genetic backgrounds with insulin resistance-related traits.

Methods

In a family based sample of 640 non diabetic White Caucasians from Italy, serum adiponectin isoforms concentrations were measured by ELISA. Three SNPs in the ADIPOQ gene previously reported to affect total adiponectin levels (rs17300539, rs1501299 and rs677395) were genotyped. The heritability of adiponectin isoform levels was assessed by variance component analysis. A linear mixed effects model was used to test association between SNPs and adiponectin isoforms. Bivariate analyses were conducted to study genetic correlations between adiponectin isoforms levels and other insulin resistance-related traits.

Results

All isoforms were highly heritable (h2=0.60−0.80, p=1×10−13–1×10−23). SNPs rs17300539, rs1501299 and rs6773957 explained a significant proportion of HMW variance (2–9%, p=1×10−3–1×10−5). In a multiple-SNP model, only rs17300539 and rs1501299 remained associated with HMW adiponectin (p=3×10−4 and 2.0×10−2). Significant genetic correlations (p=1×10−2–1×10−5) were observed between HMW adiponectin and fasting insulin, HOMAIR, HDL-cholesterol and the metabolic syndrome score. Only rs1501299 partly accounted for these genetic correlations.

Conclusion

Circulating levels of adiponectin isoforms are highly heritable. The genetic control of HMW adiponectin is shared in part with insulin resistance-related traits and involves, but is not limited to the ADIPOQ locus.

Summary

Insulin resistance is associated with impaired skeletal muscle oxidation capacity and reduced mitochondrial number and function. Here, we report that adiponectin signaling regulates mitochondrial bioenergetics in skeletal muscle. Individuals with a family history of type 2 diabetes display skeletal muscle insulin resistance and mitochondrial dysfunction; adiponectin levels strongly correlate with mtDNA content. Knockout of the adiponectin gene in mice is associated with insulin resistance and low mitochondrial content and reduced mitochondrial enzyme activity in skeletal muscle. Adiponectin treatment of human myotubes in primary culture induces mitochondrial biogenesis, palmitate oxidation, and citrate synthase activity, and reduces the production of reactive oxygen species. The inhibition of adiponectin receptor expression by siRNA, or of AMPK by a pharmacological agent, blunts adiponectin induction of mitochondrial function. Our findings define a skeletal muscle pathway by which adiponectin increases mitochondrial number and function and exerts antidiabetic effects.

OBJECTIVE

Adiponectin is an adipocyte-derived hormone that sensitizes insulin and improves energy metabolism in tissues. This study was designed to investigate the direct regulatory effects of adiponectin on lipid metabolism in adipocytes.

RESEARCH DESIGN AND METHODS

Basal and hormone-stimulated lipolysis were comparatively analyzed using white adipose tissues or primary adipocytes from adiponectin gene knockout and control mice. To further study the underlying mechanisms through which adiponectin suppresses lipolysis, cultured 3T3-L1 adipocytes and adenovirus-mediated gene transduction were used.

RESULTS

Significantly increased lipolysis was observed in both adiponectin gene knockout mice and primary adipocytes from these mice. Hormone-stimulated glycerol release was inhibited in adiponectin-treated adipocytes. Adiponectin suppressed hormone-sensitive lipase activation without altering adipose triglyceride lipase and CGI-58 expression in adipocytes. Moreover, adiponectin reduced protein levels of the type 2 regulatory subunit RIIα of protein kinase A by reducing its protein stability. Ectopic expression of RIIα abolished the inhibitory effects of adiponectin on lipolysis in adipocytes.

CONCLUSIONS

This study demonstrates that adiponectin inhibits lipolysis in adipocytes and reveals a novel function of adiponectin in lipid metabolism in adipocytes.

Background

Despite the widely reported inverse associations with insulin resistance and adiposity, adiponectin has been associated with both increased and decreased risk of cardiovascular disease. We examined whether adiponectin is associated with total and cardiovascular mortality in a large population of older adults.

Methods

We analyzed data from 3,075 well-functioning adults ages 69–79 years. Total adiponectin concentrations were measured at baseline and body composition was measured with abdominal and thigh CT scans. Mortality data was obtained over 6.6±1.6 years. We used Cox proportional hazards models adjusting for covariates in stages to examine the association between adiponectin and total and cardiovascular mortality.

Results

There were 679 deaths and 38% were from cardiovascular disease. Unadjusted levels of adiponectin were not associated with total or cardiovascular mortality. However, after adjusting for sex and race, adiponectin was associated with an increased risk of both total (HR 1.26, 95% CI 1.15–1.37, per SD) and cardiovascular mortality (HR 1.35, 95% CI 1.17–1.56, per SD). Further adjustment for study site, smoking, hypertension, diabetes, prevalent heart disease, HDL, LDL, cystatin C, fasting insulin, triglycerides, BMI, visceral fat, thigh intermuscular fat, and thigh muscle area did not attenuate this association. This association between adiponectin and increased mortality risk did not vary by sex, race, BMI, diabetes, smoking, or weight loss.

Conclusions

Higher levels of adiponectin were associated with increased risk of total and cardiovascular mortality in this study of well-functioning community-dwelling older persons. This paradoxical association needs further study of underlying factors that might explain these results including differential association for high molecular weight adiponectin.

Background

The secreted liver protein fetuin-A (AHSG) is up-regulated in hepatic steatosis and the metabolic syndrome. These states are strongly associated with low-grade inflammation and hypoadiponectinemia. We, therefore, hypothesized that fetuin-A may play a role in the regulation of cytokine expression, the modulation of adipose tissue expression and plasma concentration of the insulin-sensitizing and atheroprotective adipokine adiponectin.

Methodology and Principal Findings

Human monocytic THP1 cells and human in vitro differenttiated adipocytes as well as C57BL/6 mice were treated with fetuin-A. mRNA expression of the genes encoding inflammatory cytokines and the adipokine adiponectin (ADIPOQ) was assessed by real-time RT-PCR. In 122 subjects, plasma levels of fetuin-A, adiponectin and, in a subgroup, the multimeric forms of adiponectin were determined. Fetuin-A treatment induced TNF and IL1B mRNA expression in THP1 cells (p<0.05). Treatment of mice with fetuin-A, analogously, resulted in a marked increase in adipose tissue Tnf mRNA as well as Il6 expression (27- and 174-fold, respectively). These effects were accompanied by a decrease in adipose tissue Adipoq mRNA expression and lower circulating adiponectin levels (p<0.05, both). Furthermore, fetuin-A repressed ADIPOQ mRNA expression of human in vitro differentiated adipocytes (p<0.02) and induced inflammatory cytokine expression. In humans in plasma, fetuin-A correlated positively with high-sensitivity C-reactive protein, a marker of subclinical inflammation (r = 0.26, p = 0.01), and negatively with total- (r = −0.28, p = 0.02) and, particularly, high molecular weight adiponectin (r = −0.36, p = 0.01).

Conclusions and Significance

We provide novel evidence that the secreted liver protein fetuin-A induces low-grade inflammation and represses adiponectin production in animals and in humans. These data suggest an important role of fatty liver in the pathophysiology of insulin resistance and atherosclerosis.