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1.  Adiponectin: a manifold therapeutic target for metabolic syndrome, diabetes, and coronary disease? 
Adiponectin is the most abundant peptide secreted by adipocytes, being a key component in the interrelationship between adiposity, insulin resistance and inflammation. Central obesity accompanied by insulin resistance is a key factor in the development of metabolic syndrome (MS) and future macrovascular complications. Moreover, the remarkable correlation between coronary artery disease (CAD) and alterations in glucose metabolism has raised the likelihood that atherosclerosis and type 2 diabetes mellitus (T2DM) may share a common biological background. We summarize here the current knowledge about the influence of adiponectin on insulin sensitivity and endothelial function, discussing its forthcoming prospects and potential role as a therapeutic target for MS, T2DM, and cardiovascular disease. Adiponectin is present in the circulation as a dimer, trimer or protein complex of high molecular weight hexamers, >400 kDa. AdipoR1 and AdipoR2 are its major receptors in vivo mediating the metabolic actions. Adiponectin stimulates phosphorylation and AMP (adenosin mono phosphate) kinase activation, exerting direct effects on vascular endothelium, diminishing the inflammatory response to mechanical injury and enhancing endothelium protection in cases of apolipoprotein E deficiency. Hypoadiponectinemia is consistently associated with obesity, MS, atherosclerosis, CAD, T2DM. Lifestyle correction helps to favorably modify plasma adiponectin levels. Low adiponectinemia in obese patients is raised via continued weight loss programs in both diabetic and nondiabetic individuals and is also accompanied by reductions in pro-inflammatory factors. Diet modifications, like intake of fish, omega-3 supplementation, adherence to a Mediterranean dietary pattern and coffee consumption also increase adiponectin levels. Antidiabetic and cardiovascular pharmacological agents, like glitazones, glimepiride, angiotensin converting enzyme inhibitors and angiotensin receptor blockers are also able to improve adiponectin concentration. Fibric acid derivatives, like bezafibrate and fenofibrate, have been reported to enhance adiponectin levels as well. T-cadherin, a membrane-associated adiponectin-binding protein lacking intracellular domain seems to be a main mediator of the antiatherogenic adiponectin actions. The finding of novel pharmacologic agents proficient to improve adiponectin plasma levels should be target of exhaustive research. Interesting future approaches could be the development of adiponectin-targeted drugs chemically designed to induce the activaton of its receptors and/or postreceptor signaling pathways, or the development of specific adiponectin agonists.
PMCID: PMC4230016  PMID: 24957699
Adipokines; Adiponectin; Atherosclerosis; Coronary artery disease; Diabetes mellitus; Metabolic syndrome; Obesity; T-cadherin
2.  Adiponectin protects against myocardial ischemia-reperfusion injury through AMPK- and COX-2—dependent mechanisms 
Nature medicine  2005;11(10):1096-1103.
Obesity-related disorders are associated with the development of ischemic heart disease. Adiponectin is a circulating adipose-derived cytokine that is downregulated in obese individuals and after myocardial infarction. Here, we examine the role of adiponectin in myocardial remodeling in response to acute injury. Ischemia-reperfusion in adiponectin-deficient (APN-KO) mice resulted in increased myocardial infarct size, myocardial apoptosis and tumor necrosis factor (TNF)-α expression compared with wild-type mice. Administration of adiponectin diminished infarct size, apoptosis and TNF-α production in both APN-KO and wild-type mice. In cultured cardiac cells, adiponectin inhibited apoptosis and TNF-α production. Dominant negative AMP-activated protein kinase (AMPK) reversed the inhibitory effects of adiponectin on apoptosis but had no effect on the suppressive effect of adiponectin on TNF-α production. Adiponectin induced cyclooxygenase (COX)-2–dependent synthesis of prostaglandin E2 in cardiac cells, and COX-2 inhibition reversed the inhibitory effects of adiponectin on TNF-α production and infarct size. These data suggest that adiponectin protects the heart from ischemia-reperfusion injury through both AMPK- and COX-2–dependent mechanisms.
PMCID: PMC2828682  PMID: 16155579
3.  Adiponectin as a potential biomarker of vascular disease 
The increasing prevalence of diabetes and its complications heralds an alarming situation worldwide. Obesity-associated changes in circulating adiponectin concentrations have the capacity to predict insulin sensitivity and are a link between obesity and a number of vascular diseases. One obvious consequence of obesity is a decrease in circulating levels of adiponectin, which are associated with cardiovascular disorders and associated vascular comorbidities. Human and animal studies have demonstrated decreased adiponectin to be an independent risk factor for cardiovascular disease. However, in animal studies, increased circulating adiponectin alleviates obesity-induced endothelial dysfunction and hypertension, and also prevents atherosclerosis, myocardial infarction, and diabetic cardiac tissue disorders. Further, metabolism of a number of foods and medications are affected by induction of adiponectin. Adiponectin has beneficial effects on cardiovascular cells via its antidiabetic, anti-inflammatory, antioxidant, antiapoptotic, antiatherogenic, vasodilatory, and antithrombotic activity, and consequently has a favorable effect on cardiac and vascular health. Understanding the molecular mechanisms underlying the regulation of adiponectin secretion and signaling is critical for designing new therapeutic strategies. This review summarizes the recent evidence for the physiological role and clinical significance of adiponectin in vascular health, identification of the receptor and post-receptor signaling events related to the protective effects of the adiponectin system on vascular compartments, and its potential use as a target for therapeutic intervention in vascular disease.
PMCID: PMC4303398  PMID: 25653535
obesity; adiponectin; vascular disease
4.  Impact of a Single Intracoronary Administration of Adiponectin on Myocardial Ischemia/Reperfusion Injury in a Pig Model 
Adiponectin plays a protective role in the development of obesity-linked disorders. We demonstrated that adiponectin exerts beneficial actions on acute ischemic injury in mice hearts. However, the effects of adiponectin treatment in large animals and its feasibility in clinical practice have not been investigated. This study investigated the effects of intracoronary administration of adiponectin on myocardial ischemia-reperfusion (I/R) injury in pigs.
Methods and Results
The left anterior descending coronary artery was occluded in pigs for 45 minutes and then reperfused for 24 hours. Recombinant adiponectin protein was given as a bolus intracoronary injection during ischemia. Cardiac functional parameters were measured by a manometer-tipped catheter. Apoptosis was evaluated by terminal deoxynucleotidyltransferase-mediated dUTP nick end-labeling staining. Tumor necrosis factor-α and interleukin-10 transcripts were analyzed by real-time polymerase chain reaction. Serum levels of derivatives of reactive oxygen metabolites and biological antioxidant potential were measured. Adiponectin protein was determined by immunohistochemical and Western blot analyses. Intracoronary administration of adiponectin protein led to a reduction in myocardial infarct size and improvement of left ventricular function in pigs after I/R. Injected adiponectin protein accumulated in the I/R-injured heart. Adiponectin treatment resulted in decreased tumor necrosis factor-α and increased interleukin-10 mRNA levels in the myocardium after I/R. Adiponectin-treated pigs had reduced apoptotic activity in the I/R-injured heart and showed increased biological antioxidant potential levels and decreased derivatives of reactive oxygen metabolite levels in the blood stream after I/R.
These data suggest that adiponectin protects against I/R injury in a preclinical pig model through its ability to suppress inflammation, apoptosis, and oxidative stress. Administration of intracoronary adiponectin could be a useful adjunctive therapy for acute myocardial infarction.
PMCID: PMC3668696  PMID: 20332381
adiponectin; myocardial infarction; reperfusion
5.  The cardio-protective signaling and mechanisms of adiponectin 
Adiponectin is an endogenous insulin-sensitizing hormone which has been found to regulate energy metabolism throughout the body, including the heart. However, low levels of adiponectin are found in patients with diabetes, hypertension and cardiovascular diseases. Thus it has been suggested to be an independent predictor for cardiovascular risk. Paradoxically, recent studies have also determined that adiponectin has cardioprotective effects against various cardiac related pathologies which lead to heart failure. These cardioprotective effects of adiponectin are attributed to its anti-inflammatory, anti-oxidant and anti-apoptotic properties. Further findings suggest that locally produced adiponectin in cardiomyocytes are functional and biologically significant. This ectopic derived adiponectin exerts its protective effects through an autocrine mechanism. These data suggest adiponectin may serve as a potential therapeutic target against the development of pathologies which develop into heart failure. The current manuscript has summarized the key findings to date which explore the cardioprotective mechanisms of adiponectin against various cardiac pathologies. Further we explore the roles of both circulating and endogenous heart specific adiponectin and their physiological importance in various heart diseases.
PMCID: PMC3499932  PMID: 23173099
Adiponectin; diabetes; diabetic cardiomyopathy; ischemia reperfusion; myocardial infarction
6.  Adiponectin is essential for lipid homeostasis and survival under insulin deficiency and promotes β-cell regeneration 
eLife  2014;3:e03851.
As an adipokine in circulation, adiponectin has been extensively studied for its beneficial metabolic effects. While many important functions have been attributed to adiponectin under high-fat diet conditions, little is known about its essential role under regular chow. Employing a mouse model with inducible, acute β-cell ablation, we uncovered an essential role of adiponectin under insulinopenic conditions to maintain minimal lipid homeostasis. When insulin levels are marginal, adiponectin is critical for insulin signaling, endocytosis, and lipid uptake in subcutaneous white adipose tissue. In the absence of both insulin and adiponectin, severe lipoatrophy and hyperlipidemia lead to lethality. In contrast, elevated adiponectin levels improve systemic lipid metabolism in the near absence of insulin. Moreover, adiponectin is sufficient to mitigate local lipotoxicity in pancreatic islets, and it promotes reconstitution of β-cell mass, eventually reinstating glycemic control. We uncovered an essential new role for adiponectin, with major implications for type 1 diabetes.
eLife digest
Fat tissue is essential for health. Fat cells store energy and release it when it is needed; they also release hormones that are important for the health of our heart and for regulating our metabolism. One of these hormones, adiponectin, helps cells to remove fat molecules from the bloodstream. This allows the body to maintain appropriate cholesterol levels and prevents fatty build-ups from blocking blood vessels, which is associated with heart disease. Adiponectin also helps cells respond to insulin, a hormone that regulates blood sugar levels, and thus helps to prevent diabetes.
Despite this hormone's important roles in health, mice that lack adiponectin can thrive under normal conditions. Adiponectin becomes essential, however, when blood sugar or fat levels are considerably altered. For example, when mice without adiponectin are fed a high fat-content diet, they become insulin-resistant. Moreover, certain diabetes drugs that boost insulin sensitivity only work if adiponectin is present in the body.
Adiponectin helps to keep the β-cells that produce insulin alive. In patients with diabetes, β-cells slowly die, and this leads to a poor insulin response and an imbalance in the amount of fats and sugars in the cells. This is toxic to the β-cells; and as more β-cells die, less insulin is produced to control sugar levels, and the condition worsens. Adiponectin appears to protect the β-cells against this vicious cycle, but the details of how it does so are unclear.
Ye et al. used a mouse model in which β-cells were destroyed to see what adiponectin does when insulin is in short supply. When insulin levels were extremely low, adiponectin was found to help one type of fat tissue absorb fat molecules from the bloodstream, which reduced blood cholesterol levels. It also protects fat cells from being destroyed when insulin levels are low. Ye et al. also found that mice that lack both insulin and adiponectin lose excessive amounts of fat tissue and develop high blood cholesterol levels, which lead to death.
Increasing adiponectin levels in insulin-deficient mice, however, improves their blood cholesterol levels and protects β-cells from being destroyed. This allows the β-cells to begin regenerating. As the β-cells regenerate, the insulin-deficient mice developed better control over their blood sugar.
Many people with type-1 diabetes (which is caused by their own immune system destroying their β-cells) currently rely on insulin injections and restricted diets to manage their condition. Ye et al.'s findings might lead to new strategies to restore β-cell production and blood sugar control; as such these findings will have important implications for the management of type-1 diabetes.
PMCID: PMC4228265  PMID: 25339419
adiponectin; insulin deficiency; lipid metabolism; islet lipotoxicity; β-cell regeneration; mouse
7.  Maternal Serum Adiponectin Multimers in Preeclampsia 
Journal of perinatal medicine  2009;37(4):349-363.
Obesity, insulin resistance, and dyslipidemia are associated with preeclampsia. Recently, “adipose tissue failure”, characterized by dysregulation of adipokine production, has been implicated in the pathophysiology of these metabolic complications. Adiponectin, an insulin-sensitizing, anti-atherogenic, anti-inflammatory and angiogenic adipokine, circulates in oligomeric complexes including: low-molecular-weight (LMW) trimers, medium-molecular-weight (MMW) hexamers and high-molecular-weight (HMW) isoforms. These multimers exert differential biological effects, and HMW to total adiponectin ratio (SA) has been reported to be a specific marker of adiponectin activity. The aim of this study was to determine whether preeclampsia is associated with changes in circulating adiponectin multimers.
Study design
This cross-sectional study included women with: 1) normal pregnancy (n=225); and 2) patients with mild preeclampsia (n=111). The study population was further stratified by first trimester BMI (normal weight <25 kg/m2 vs. overweight/obese ≥25 kg/m2). Serum adiponectin multimers (total, HMW, MMW and LMW) concentrations were determined by ELISA. Non-parametric statistics were used for analysis.
1) The median maternal HMW and LMW adiponectin concentrations were lower in patients with preeclampsia than in those with normal pregnancies (p<0.001 and p=0.01, respectively); 2) patients with preeclampsia had a lower HMW/Total adiponectin ratio (p<0.001) and higher MMW/Total adiponectin and LMW/Total adiponectin ratios than those with a normal pregnancy (p<0.001 and p=0.009, respectively); 3) the presence of preeclampsia was independently associated with lower maternal serum HMW adiponectin concentrations (p=0.001) and with a low HMW/Total adiponectin ratio (p<0.001) after correction for maternal age, maternal BMI, the difference in BMI between the third and the first trimester, and gestational age at sampling; and 4) overweight/obese pregnant women had a lower median total and HMW adiponectin concentration than normal weight pregnant women among women with normal pregnancies, but not among those with preeclampsia.
1) Preeclampsia is associated with a lower median concentration of the HMW adiponectin isoform, the most active form of this adipokine, and a low HMW/Total adiponectin ratio, a specific marker of adiponectin biologic activity; 2) in contrast to normal pregnancy, preeclampsia is not associated with decreased circulating adiponectin multimers in overweight/obese individuals suggesting altered regulation of this adipokine in preeclampsia; 3) collectively, these findings suggest that preeclampsia is characterized by alterations in adiponectin multimers and their relative distribution implying a role for adiponectin multimers in the mechanism of disease in preeclampsia.
PMCID: PMC3166229  PMID: 19348608
Adipokines; Pregnancy; High-molecular-weight (HMW) adiponectin; Medium-molecular-weight (MMW) adiponectin; Low-molecular-weight (LMW) adiponectin; BMI; overweight; obesity
8.  Adipocytokines: The pied pipers 
Even though there have been major advances in therapy, atherosclerosis and coronary artery disease retain their lead as one of the major causes of morbidity and mortality in the first decade of 21st century. To add to the woes, we have diabetes, obesity and insulin resistance as the other causes. The adipose tissue secretes several bioactive mediators that influence inflammation, insulin resistance, diabetes, atherosclerosis and several other pathologic states besides the regulation of body weight. These mediators are mostly proteins and are termed “adipocytokines”. Adiponectin, resistin, visfatin, retinol binding protein-4 (RBP-4) and leptin are a few such proteins. Adiponectin is a multimeric protein, acting via its identified receptors, AdipoR1 and AdipoR2. It is a potential biomarker for metabolic syndrome and has several antiinflammatory actions. Adiponectin increases insulin sensitivity and ameliorates obesity. Resistin, another protein secreted by the adipose tissue, derived its name due to its involvement in the development of insulin resistance. It plays a role in the pathophysiology of several conditions because of its robust proinflammatory activity mediated through the activation of extracellular signal regulated kinases 1 and 2 (ERK 1/2). In 2007, resistin was reported to have protective effect in ischemia-reperfusion injury and myocyte-apoptosis in the setting of myocardial infarction (MI). RBP-4 is involved in the developmental pathology of type 2 diabetes mellitus and obesity. Visfatin has been described as an inflammatory cytokine. Increased expression of visfatin mRNA has been observed in inflammatory conditions like atherosclerosis and inflammatory bowel disease. Leptin mainly regulates the food intake and energy homeostasis. Leptin resistance has been associated with development of obesity and insulin resistance. Few drugs (thiazolidinediones, rimonabant, statins, etc.) and some lifestyle modifications have been found to improve the levels of adipocytokines. Their role in therapy has a lot in store to be explored upon.
PMCID: PMC3142763  PMID: 21808585
Adipokine; adiponectin; leptin; resistin; retinol binding protein-4; visfatin
9.  Tracing the movement of adiponectin in a parabiosis model of wild-type and adiponectin-knockout mice 
FEBS Open Bio  2014;4:276-282.
•We generated a hetero parabiosis model of wild type and adiponectin knockout (KO) mice.•Adiponectin protein was detected in adipose tissues of the KO parabiotic partner.•High adiponectin levels were found in stromal vascular fraction of the obese KO partner.•Obese parabiotic mice exhibited marked hypoadiponectinemia.
Adiponectin is exclusively synthesized by adipocytes and exhibits anti-diabetic, anti-atherosclerotic and anti-inflammatory properties. Hypoadiponectinemia is associated in obese individuals with insulin resistance and atherosclerosis. However, the mechanisms responsible for hypoadiponectinemia remain unclear. Here, we investigated adiponectin movement using hetero parabiosis model of wild type (WT) and adiponectin-deficient (KO) mice. WT mice were parabiosed with WT mice (WT–WT) or KO mice (WT–KO) and adiponectin levels were measured serially up to 63 days after surgery. In the WT–KO parabiosis model, circulating adiponectin levels of the WT partners decreased rapidly, on the other hand, those of KO partners increased, and then these reached comparable levels each other at day 7. Circulating adiponectin levels decreased further to the detection limit of assay, and remained low up to day 63. However, adiponectin protein was detected in the adipose tissues of not only the WT partner but also WT–KO mice. In the diet-induced obesity model, high adiponectin protein levels were detected in adipose stromal vascular fraction of diet-induced obese KO partner, without changes in its binding proteins. The use of parabiosis experiments shed light on movement of native adiponectin among different tissues such as the state of hypoadiponectinemia in obesity.
PMCID: PMC4048846  PMID: 24918039
APN, adiponectin; KO, adiponectin deficient mice; HF/HS, high fat/high sucrose diet; KO (WT–KO), KO partner of WT–KO; MAF, mature adipocyte fraction; NC, normal chow diet; SVF, stromal vascular fraction; WATmes, mesenteric white adipose tissue; WATsub, subcutaneous white adipose tissue; WT (WT–KO), WT partner of WT–KO; WT (WT–WT), WT partner of WT–WT; WT, wild type mice; WT–KO, parabiosis between WT and KO; WT–WT, parabiosis between WT and WT; Adiponectin; Adipose tissue; Obesity; Parabiosis
10.  Physiological, Pharmacological, and Nutritional Regulation of Circulating Adiponectin Concentrations in Humans 
Adiponectin is an adipocyte hormone that links visceral adiposity with insulin resistance and atherosclerosis. It is unique among adipocyte-derived hormones in that its circulating concentrations are inversely proportional to adiposity, and low adiponectin concentrations predict the development of type 2 diabetes and cardiovascular disease. Consequently, in the decade since its discovery, adiponectin has generated immense interest as a potential therapeutic target for the metabolic syndrome and diabetes.
This review summarizes current research regarding the regulation of circulating adiponectin concentrations by physiological, pharmacological, and nutritional factors, with an emphasis on human studies. In humans, plasma adiponectin concentrations are influenced by age and gender, and are inversely proportional to visceral adiposity. In vitro studies suggest that adiponectin production may be determined primarily by adipocyte size and insulin sensitivity, with larger, insulin-resistant adipocytes producing less adiponectin. While adiponectin concentrations are unchanged after meal ingestion, they are increased by significant weight loss, such as after bariatric surgery. In addition, adiponectin production is inhibited by a number of hormones, including testosterone, prolactin, glucocorticoids and growth hormone, and by inflammation and oxidative stress in adipose tissue. Smoking decreases, while moderate alcohol consumption increases, circulating adiponectin concentrations. Dietary fatty acid composition in rodents influences adiponectin production via ligand-activated nuclear receptors (PPARs); however, current evidence in humans is equivocal. In addition to PPAR agonists (such as thiazolidinediones and fibrates), a number of pharmacological agents (angiotensin receptor type 1 blockers, ACE inhibitors, and cannabinoid receptor antagonists) used in treatment of the metabolic syndrome also increase adiponectin concentrations in humans.
PMCID: PMC3190268  PMID: 18510434
11.  Hypoadiponectinemia in Patients With Paroxysmal Atrial Fibrillation 
Korean Circulation Journal  2012;42(10):668-673.
Background and Objectives
Adiponectin is an adipose tissue-derived hormone that has beneficial effects on cardiac function and has been reported to be associated with lipid metabolism, glucose metabolism, and insulin resistance. Serum levels of adiponectin are reduced in obese individuals compared with non-obese individuals. Obesity is associated with an increased incidence of atrial fibrillation (AF); however, the role of adiponectin in AF is unclear. The aim of this study is to evaluate the relationship between the plasma adiponectin level and AF.
Subjects and Methods
Sixty-one consecutive patients were prospectively enrolled for this study. Subjects were divided into two groups: patients with AF (n=30) and controls (n=31). Laboratory evaluation, including levels of plasma adiponectin, was performed and echocardiographic parameters were measured.
The baseline characteristics were not different between the two groups. The plasma adiponectin level of patients in the AF group was significantly lower than in the control group (14.9±7.2 vs. 19.±8.9 µg/mL, p<0.05). In addition, when we divided the AF patients into paroxysmal and chronic AF, the plasma adiponectin level was significantly lower in patients with paroxysmal AF, compared with the control group. In multiple binary logistic regression analysis to evaluate the independent predictors for AF, adiponectin and left atrial diameter were strong independent predictors of AF.
In this study a lower plasma adiponectin concentration was significantly associated with that of paroxysmal AF. Hypoadiponectinemia can potentially be an important risk factor for AF.
PMCID: PMC3493803  PMID: 23170094
Adiponectin; Atrial fibrillation
12.  Association of chemerin mRNA expression in human epicardial adipose tissue with coronary atherosclerosis 
Growing evidence suggests that epicardial adipose tissue (EAT) may play a key role in the pathogenesis and development of coronary artery disease (CAD) by producing several inflammatory adipokines. Chemerin, a novel adipokine, has been reported to be involved in regulating immune responses and glucolipid metabolism. Given these properties, chemerin may provide an interesting link between obesity, inflammation and atherosclerosis. In this study, we sought to determine the relationship of chemerin expression in EAT and the severity of coronary atherosclerosis in Han Chinese patients.
Serums and adipose tissue biopsies (epicardial and thoracic subcutaneous) were obtained from CAD (n = 37) and NCAD (n = 16) patients undergoing elective cardiac surgery. Gensini score was used to assess the severity of CAD. Serum levels of chemerin, adiponectin and insulin were measured by ELISA. Chemerin protein expression in adipose tissue was detected by immunohistochemistry. The mRNA levels of chemerin, chemR23, adiponectin and TNF-alpha in adipose tissue were detected by RT-PCR.
We found that EAT of CAD group showed significantly higher levels of chemerin and TNF-alpha mRNA, and significantly lower level of adiponectin mRNA than that of NCAD patients. In CAD group, significantly higher levels of chemerin mRNA and protein were observed in EAT than in paired subcutaneous adipose tissue (SAT), whereas such significant difference was not found in NCAD group. Chemerin mRNA expression in EAT was positively correlated with Gensini score (r = 0.365, P < 0.05), moreover, this correlation remained statistically significant (r = 0.357, P < 0.05) after adjusting for age, gender, BMI and waist circumference. Chemerin mRNA expression in EAT was also positively correlated with BMI (r = 0.305, P < 0.05), waist circumference (r = 0.384, P < 0.01), fasting blood glucose (r = 0.334, P < 0.05) and negatively correlated with adiponectin mRNA expression in EAT (r = -0.322, P < 0.05). However, there were no significant differences in the serum levels of chemerin or adiponectin between the two groups. Likewise, neither serum chemerin nor serum adiponectin was associated with Gensini score (P > 0.05).
The expressions of chemerin mRNA and protein are significantly higher in EAT from patients with CAD in Han Chinese patients. Furthermore, the severity of coronary atherosclerosis is positive correlated with the level of chemerin mRNA in EAT rather than its circulating level.
PMCID: PMC3198902  PMID: 21981776
Epicardial adipose tissue; Chemerin; Adipokine; Atherosclerosis
13.  Effects of interventions on adiponectin and adiponectin receptors 
Adiponectin secreted from adipose tissue binds to two distinct adiponectin receptors (AdipoR1 and AdipoR2) identified and exerts its anti-diabetic effects in insulin-sensitive organs including liver, skeletal muscle and adipose tissue as well as amelioration of vascular dysfunction in the various vasculatures. A number of experimental and clinical observations have demonstrated that circulating levels of adiponectin are markedly reduced in obesity, type 2 diabetes, hypertension, and coronary artery disease. Therapeutic interventions which can improve the action of adiponectin including elevation of circulating adiponectin concentration or up-regulation and/or activation of its receptors, could provide better understanding of strategies to ameliorate metabolic disorders and vascular disease. The focus of the present review is to summarize accumulating evidence showing the role of interventions such as pharmacological agents, exercise, and calorie restriction in the expression of adiponectin and adiponectin receptors.
PMCID: PMC4025551  PMID: 24877039
Pharmacological agents; Exercise; Calorie restriction; Adiponectin; Adiponectin receptors
14.  Adiponectin Actions in the Cardiovascular System 
Cardiovascular research  2006;74(1):11-18.
Obesity is strongly associated with the pathogenesis of type 2 diabetes, hypertension, and cardiovascular disease. Levels of the hormone adiponectin are downregulated in obese individuals, and several experimental studies show that adiponectin protects against the development of various obesity-related metabolic and cardiovascular diseases. Adiponectin exhibits favorable effects on atherogenesis, endothelial function, and vascular remodeling by modulation of signaling cascades in cells of the vasculature. More recent findings have shown that adiponectin directly affects signaling in cardiac cells and is beneficial in the setting of pathological cardiac remodeling and acute cardiac injury. Several of these effects of adiponectin have been attributed to the activation of the 5’ AMP-activated protein kinase signaling cascade and other signaling proteins. This review will discuss epidemiological and experimental studies that have elucidated the role of adiponectin in a variety of cardiovascular diseases.
PMCID: PMC1858678  PMID: 17140553
diabetes; epidemiology; heart failure; remodeling; protein kinases
15.  Adiponectin as an anti-inflammatory factor 
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.
PMCID: PMC2755046  PMID: 17343838
adiponectin; anti-inflammatory; cardioprotection; biomarker
16.  Systemic Adiponectin Malfunction as a Risk Factor for Cardiovascular Disease 
Antioxidants & Redox Signaling  2011;15(7):1863-1873.
Adiponectin (Ad) is an abundant protein hormone regulatory of numerous metabolic processes. The 30 kDa protein originates from adipose tissue, with full-length and globular domain circulatory forms. A collagenous domain within Ad leads to spontaneous self-assemblage into various oligomeric isoforms, including trimers, hexamers, and high-molecular-weight multimers. Two membrane-spanning receptors for Ad have been identified, with differing concentration distribution in various body tissues. The major intracellular pathway activated by Ad includes phosphorylation of AMP-activated protein kinase, which is responsible for many of Ad's metabolic regulatory, anti-inflammatory, vascular protective, and anti-ischemic properties. Additionally, several AMP-activated protein kinase-independent mechanisms responsible for Ad's anti-inflammatory and anti-ischemic (resulting in cardioprotective) effects have also been discovered. Since its 1995 discovery, Ad has garnered considerable attention for its role in diabetic and cardiovascular pathology. Clinical observations have demonstrated the association of hypoadiponectinemia in patients with obesity, cardiovascular disease, and insulin resistance. In this review, we elaborate currently known information about Ad malfunction and deficiency pertaining to cardiovascular disease risk (including atherosclerosis, endothelial dysfunction, and cardiac injury), as well as review evidence supporting Ad resistance as a novel risk factor for cardiovascular injury, providing insight about the future of Ad research and the protein's potential therapeutic benefits. Antioxid. Redox Signal. 15, 1863–1873.
PMCID: PMC3159112  PMID: 21091079
17.  Apolipoprotein A-I mimetic peptide L-4F prevents myocardial and coronary dysfunction in diabetic mice 
Journal of cellular biochemistry  2011;112(9):2616-2626.
Diabetes is a major health problem associated with adverse cardiovascular outcomes. The apolipoprotein A-I mimetic peptide L-4F is a putative anti-diabetic drug, has antioxidant and anti-inflammatory proprieties and improves endothelial function. In obese mice L-4F increases adiponectin levels, improving insulin sensitivity and reducing visceral adiposity. We hypothesized that the pleiotropic actions of L-4F can prevent heart and coronary dysfunction in a mouse model of genetically induced Type II diabetes. We treated db/db mice with either L-4F or vehicle for 8 weeks. Trans-thoracic echocardiography was performed; thereafter, isolated hearts were subjected to ischemia/reperfusion (IR). Glucose, insulin, adiponectin, and pro-inflammatory cytokines (IL-1β, TNF-α, MCP-1) were measured in plasma and HO-1, pAMPK, peNOS, iNOS, adiponectin and superoxide in cardiac tissue. In db/db mice L-4F decreased accumulation of subcutaneous and total fat, and increased insulin sensitivity and adiponectin levels while lowering inflammatory cytokines (p<0.05). L-4F normalized in vivo left ventricular (LV) function of db/db mice, increasing (p<0.05) fractional shortening and decreasing (p<0.05) LV dimensions. In I/R experiments, L-4F prevented coronary microvascular resistance from increasing and LV function from deteriorating in the db/db mice. These changes were associated with increased cardiac expression of HO-1, pAMPK, peNOS and adiponectin and decreased levels of superoxide and iNOS (p<0.01). In the present study we showed that L-4F prevented myocardial and coronary functional abnormalities in db/db mice. These effects were associated with stimulation of HO-1 resulting in increased levels of anti-inflammatory, anti-oxidative, and vasodilatatory action through a mechanism involving increased levels of adiponectin, pAMPK and peNOS.
PMCID: PMC3158830  PMID: 21598304
diabetes; inflammation; oxidative stress; insulin sensitivity; adiponectin; heme-oxygenase
18.  High-fat diet and glucocorticoid treatment cause hyperglycemia associated with adiponectin receptor alterations 
Adiponectin is the most abundant plasma protein synthesized for the most part in adipose tissue, and it is an insulin-sensitive hormone, playing a central role in glucose and lipid metabolism. In addition, it increases fatty acid oxidation in the muscle and potentiates insulin inhibition of hepatic gluconeogenesis. Two adiponectin receptors have been identified: AdipoR1 is the major receptor expressed in skeletal muscle, whereas AdipoR2 is mainly expressed in liver. Consumption of high levels of dietary fat is thought to be a major factor in the promotion of obesity and insulin resistance. Excessive levels of cortisol are characterized by the symptoms of abdominal obesity, hypertension, glucose intolerance or diabetes and dyslipidemia; of note, all of these features are shared by the condition of insulin resistance. Although it has been shown that glucocorticoids inhibit adiponectin expression in vitro and in vivo, little is known about the regulation of adiponectin receptors. The link between glucocorticoids and insulin resistance may involve the adiponectin receptors and adrenalectomy might play a role not only in regulate expression and secretion of adiponectin, as well regulate the respective receptors in several tissues.
Feeding of a high-fat diet increased serum glucose levels and decreased adiponectin and adipoR2 mRNA expression in subcutaneous and retroperitoneal adipose tissues, respectively. Moreover, it increased both adipoR1 and adipoR2 mRNA levels in muscle and adipoR2 protein levels in liver. Adrenalectomy combined with the synthetic glucocorticoid dexamethasone treatment resulted in increased glucose and insulin levels, decreased serum adiponectin levels, reduced adiponectin mRNA in epididymal adipose tissue, reduction of adipoR2 mRNA by 7-fold in muscle and reduced adipoR1 and adipoR2 protein levels in muscle. Adrenalectomy alone increased adiponectin mRNA expression 3-fold in subcutaneous adipose tissue and reduced adipoR2 mRNA expression 2-fold in liver.
Hyperglycemia as a result of a high-fat diet is associated with an increase in the expression of the adiponectin receptors in muscle. An excess of glucocorticoids, rather than their absence, increase glucose and insulin and decrease adiponectin levels.
PMCID: PMC3031255  PMID: 21244702
19.  Green Tea Polyphenols Reduced Fat Deposits in High Fat-Fed Rats via erk1/2-PPARγ-Adiponectin Pathway 
PLoS ONE  2013;8(1):e53796.
Hypoadiponectinemia contributes to the development of obesity and related disorders such as diabetes, hyperlipidemia, and cardiovascular diseases. In this study we investigated the effects of green tea polyphenols (GTPs) on adiponectin levels and fat deposits in high fat (HF) fed rats, the mechanism of signaling pathway was explored as well.
Methods and Results
Male Wistar rats were fed with high-fat diet. GTPs (0.8, 1.6, 3.2 g/L) were administered via drinking water. Serum adiponectin and insulin were measured by ELISA, mRNA levels of adiponectin and PPARγ in visceral adipose tissue (VAT) were determined by Real-time PCR, protein levels of PPARγ, phospho (p) - PPARγ, extracellular signal regulated kinase (erk) 1/2 and p-erk1/2 in VAT were determined by western blot. GTPs treatment attenuated the VAT accumulation, hypoadiponectinemia and the decreased mRNA level of adiponectin in VAT induced by HF. Decreased expression and increased phosphorylation of PPARγ (the master regulator of adiponectin), and increased activation of erk1/2 were observed in HF group, and these effects could be alleviated by GTPs treatment. To explore the underlying mechanism, VAT was cultured in DMEM with high glucose to mimic the hyperglycemia condition in vitro. Similar to the results of in vivo study, decreased adiponectin levels, decreased expression and increased phosphorylation of PPARγ, and elevated erk1/2 phosphorylation in cultured VAT were observed. These effects could be ameliorated by co-treatment with GTPs or PD98059 (a selective inhibitor of erk1/2).
GTPs reduced fat deposit, ameliorated hypoadiponectinemia in HF-fed rats, and relieved high glucose-induced adiponectin decrease in VAT in vitro. The signaling pathway analysis indicated that PPARγ regulation mediated via erk1/2 pathway was involved.
PMCID: PMC3546082  PMID: 23342006
20.  Effects of Angiotensin II Type 1 receptor blocker and adiponectin on adipocyte dysfunction in stroke-prone spontaneously hypertensive rats 
Hypoadiponectinemia in lipoatrophy may be related to worsening of hypertension in stroke-prone spontaneously hypertensive rats (SHRSP). One of the beneficial effects of candesartan (Angiotensin II Type 1 receptor blocker) for preventing hypertension may be increasing of adiponectin due to improvement of adipocyte dysfunction. In this study, we determined the effects of candesartan or adiponectin on pathophysiologic features and adipocyte dysfunction in SHRSP.
Candesartan was administered to male SHRSP from 16 to 20 weeks of age (2 mg/kg/day). Adiponectin was cloned and intravenously administered to male SHRSP from 16 to 20 weeks of age. We examined biological parameters, as well as the expression and release of adipokines.
The SHRSP exhibited severe atrophy of visceral fat and progression of severe hypertension. The expression and release of leptin and adiponectin were impaired at 6 and 20 weeks of age. Candesartan suppressed the development of lipoatrophy and reduced the incidence of stroke at 20 weeks of age. Candesartan also enhanced the expression of adiponectin and leptin by inducing the overexpression of peroxisome proliferator activated receptor γ. Circulating level of leptin was significantly higher in candesartan group than in the control group, whereas adiponectin was similar in both groups. Intravenous administration of adiponectin resulted in enhancement of adiponectin expression in adipose tissue, but no remarkable effects were found in pathophysiology in SHRSP.
Our results indicate that candesartan protects against hypertension and adipocyte dysfunction in SHRSP. The induction of leptin expression appeared to be important factor in the inhibition of stroke lesions, whereas adiponectin was not a major regulator of blood pressure in SHRSP with genetic hypertension. Further studies are needed to elucidate the role of the renin–angiotensin system in adipose tissue dysfunction in relation to hypertensive end-organ damage.
PMCID: PMC3750705  PMID: 23876211
Stroke-prone spontaneously hypertensive rats; Adipose tissue; Renin–angiotensin system; Angiotensin II type I receptor blocker; Lipoatrophy; Adipokines
21.  Association between Risk Factors for Vascular Dementia and Adiponectin 
BioMed Research International  2014;2014:261672.
Vascular dementia is caused by various factors, including increased age, diabetes, hypertension, atherosclerosis, and stroke. Adiponectin is an adipokine secreted by adipose tissue. Adiponectin is widely known as a regulating factor related to cardiovascular disease and diabetes. Adiponectin plasma levels decrease with age. Decreased adiponectin increases the risk of cardiovascular disease and diabetes. Adiponectin improves hypertension and atherosclerosis by acting as a vasodilator and antiatherogenic factor. Moreover, adiponectin is involved in cognitive dysfunction via modulation of insulin signal transduction in the brain. Case-control studies demonstrate the association between low adiponectin and increased risk of stroke, hypertension, and diabetes. This review summarizes the recent findings on the association between risk factors for vascular dementia and adiponectin. To emphasize this relationship, we will discuss the importance of research regarding the role of adiponectin in vascular dementia.
PMCID: PMC4016875  PMID: 24860814
22.  Short-Term Overfeeding Increases Circulating Adiponectin Independent of Obesity Status 
PLoS ONE  2013;8(8):e74215.
Adiponectin is an adipose tissue derived hormone which strengthens insulin sensitivity. However, there is little data available regarding the influence of a positive energy challenge (PEC) on circulating adiponectin and the role of obesity status on this response.
The purpose of this study was to investigate how circulating adiponectin will respond to a short-term PEC and whether or not this response will differ among normal-weight(NW), overweight(OW) and obese(OB).
We examined adiponectin among 64 young men (19-29 yr) before and after a 7-day overfeeding (70% above normal energy requirements). The relationship between adiponectin and obesity related phenotypes including; weight, percent body fat (%BF), percent trunk fat (%TF), percent android fat (%AF), body mass index (BMI), total cholesterol, HDLc, LDLc, glucose, insulin, homeostatic model assessment insulin resistance (HOMA-IR) and β-cell function (HOMA-β) were analyzed before and after overfeeding.
Analysis of variance (ANOVA) and partial correlations were used to compute the effect of overfeeding on adiponectin and its association with adiposity measurements, respectively. Circulating Adiponectin levels significantly increased after the 7-day overfeeding in all three adiposity groups. Moreover, adiponectin at baseline was not significantly different among NW, OW and OB subjects defined by either %BF or BMI. Baseline adiponectin was negatively correlated with weight and BMI for the entire cohort and %TF, glucose, insulin and HOMA-IR in OB. However, after controlling for insulin resistance the correlation of adiponectin with weight, BMI and %TF were nullified.
Our study provides evidence that the protective response of adiponectin is preserved during a PEC regardless of adiposity. Baseline adiponectin level is not directly associated with obesity status and weight gain in response to short-term overfeeding. However, the significant increase of adiponectin in response to overfeeding indicates the physiological potential for adiponectin to attenuate insulin resistance during the development of obesity.
PMCID: PMC3758269  PMID: 24023698
23.  Establishment of a concept of visceral fat syndrome and discovery of adiponectin 
Although obesity is a major background of life style-related diseases such as diabetes mellitus, lipid disorder, hypertension and cardiovascular disease, the extent of whole body fat accumulation does not necessarily the determinant for the occurrence of these diseases. We developed the method for body fat analysis using CT scan and established the concept of visceral fat obesity, in other word metabolic syndrome in which intra-abdominal visceral fat accumulation has an important role in the development of diabetes, lipid disorder, hypertension and atherosclerosis. In order to clarify the mechanism that visceral fat accumulation causes metabolic and cardiovascular diseases, we have analyzed gene expression profile in subcutaneous adipose tissue and visceral adipose tissue. From the analysis, we found that adipose tissue, especially visceral adipose tissue expressed abundantly the genes encoding bioactive substances such as cytokines, growth factors and complements. In addition to known bioactive substances, we found a novel collagen-like protein which we named adiponectin. Adiponectin is present in plasma at a very high concentration and is inversely associated with visceral fat accumulation. Adiponectin has anti-diabetic, anti-hypertensive and anti-atherogenic properties and recent studies revealed that this protein has an anti-inflammatory and anti-oncogenic function. Therefore hypoadiponectinemia induced by visceral fat accumulation should become a strong risk factor for metabolic and cardiovascular diseases and also some kinds of cancers.
In this review article, I would like to discuss the mechanism of life style-related diseases by focusing on the dysregulation of adiponectin related to obesity, especially visceral obesity.
PMCID: PMC3417563  PMID: 20154470
visceral fat; metabolic syndrome; adiponectin; hypoadiponectinemia
24.  AMP-Activated Protein Kinase Deficiency Enhances Myocardial Ischemia/Reperfusion Injury but Has Minimal Effect on the Antioxidant/Antinitrative Protection of Adiponectin 
Circulation  2009;119(6):835-844.
Diabetes increases the morbidity/mortality of ischemic heart disease, but the underlying mechanisms are incompletely understood. Deficiency of both AMP-activated protein kinase (AMPK) and adiponectin occurs in diabetes, but whether AMPK is cardioprotective or a central mediator of adiponectin cardioprotection in vivo remains unknown.
Methods and Results
Male adult mice with cardiomyocyte-specific overexpression of a mutant AMPKα2 subunit (AMPK-DN) or wild-type (WT) littermates were subjected to in vivo myocardial ischemia/reperfusion (MI/R) and treated with vehicle or adiponectin. In comparison to WT, AMPK-DN mice subjected to MI/R endured greater cardiac injury (larger infarct size, more apoptosis, and poorer cardiac function) likely as a result of increased oxidative stress in these animals. Treatment of AMPK-DN mice with adiponectin failed to phosphorylate cardiac acetyl-CoA carboxylase as it did in WT mouse heart. However, a significant portion of the cardioprotection of adiponectin against MI/R injury was retained in AMPK-DN mice. Furthermore, treatment of AMPK-DN mice with adiponectin reduced MI/R-induced cardiac oxidative and nitrative stress to the same degree as that seen in WT mice. Finally, treating AMPK-DN cardiomyocytes with adiponectin reduced simulated MI/R-induced oxidative/nitrative stress and decreased cell death (P<0.01).
Collectively, our results demonstrated that AMPK deficiency significantly increases MI/R injury in vivo but has minimal effect on the antioxidative/antinitrative protection of adiponectin.
PMCID: PMC2658653  PMID: 19188503
adipocytokine; apoptosis; diabetes mellitus; myocardial infarction; signal transduction
Journal of perinatal medicine  2009;37(6):623-635.
Several mechanisms of disease have been implicated in the pathophysiology of SGA including an anti-angiogenic state, failure of physiologic transformation of spiral arteries, and an exaggerated intravascular pro-inflammatory response. Adiponectin, an insulin-sensitizing, anti-atherogenic, anti-inflammatory and angiogenic adipokine circulates in oligomeric complexes including low-molecular-weight (LMW) trimers, medium-molecular-weight (MMW) hexamers and high-molecular-weight (HMW) isoforms. Adiponectin plays a role in a wide range of biological activities including those that have been implicated in the pathophysiology SGA. Thus, the aim of this study was to determine if third trimester adiponectin concentrations differed between women with normal weight infants and those with an SGA neonate.
Study design
This cross-sectional study included women with: 1) a normal pregnancy (n=234); and 2) an SGA neonate (n=78). The study population was further stratified by first trimester BMI (normal weight <25 kg/m2 vs. overweight/obese ≥25 kg/m2). Maternal serum adiponectin multimers (total, HMW, MMW and LMW) concentrations were determined by ELISA. Non-parametric statistics were used for analyses.
1) The median maternal serum concentrations of total, HMW and MMW adiponectin were significantly lower in patients with an SGA neonate than in those with normal pregnancies; 2) patients with an SGA neonate had a significantly lower median HMW/total adiponectin ratio and higher median MMW/total adiponectin and LMW/total adiponectin ratios than those with a normal pregnancy; 3) among patients with an SGA neonate, neither maternal serum concentrations of adiponectin multimers, nor their relative distribution differ between normal weight and overweight/obese patients.
1) Pregnancies complicated by an SGA neonate are characterized by a alterations in the maternal serum adiponectin multimers concentrations and their relative abundance; 2) in contrast to normal pregnancies, those complicated by an SGA neonate are not associated with low circulating adiponectin multimers in overweight/obese individuals suggesting altered regulation of this adipokine in the presence of an SGA neonate; 3) collectively, the findings reported herein suggest that maternal adipose tissue may play a role, in the pathogenesis of SGA.
PMCID: PMC3594513  PMID: 19530958
Adipokines; Pregnancy; High-molecular-weight (HMW) adiponectin; Medium-molecular-weight (MMW) adiponectin; Low-molecular-weight (LMW) adiponectin; BMI; overweight; obesity; fetal growth; SGA; pregnancy; Adipose tissue

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