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1.  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.
doi:10.1038/nm1295
PMCID: PMC2828682  PMID: 16155579
2.  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.
doi:10.1016/j.cardiores.2006.10.009
PMCID: PMC1858678  PMID: 17140553
diabetes; epidemiology; heart failure; remodeling; protein kinases
3.  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.
doi:10.1016/j.cca.2007.01.026
PMCID: PMC2755046  PMID: 17343838
adiponectin; anti-inflammatory; cardioprotection; biomarker
4.  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.
doi:10.12965/jer.140104
PMCID: PMC4025551  PMID: 24877039
Pharmacological agents; Exercise; Calorie restriction; Adiponectin; Adiponectin receptors
5.  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.
doi:10.1155/2014/261672
PMCID: PMC4016875  PMID: 24860814
6.  Impact of a Single Intracoronary Administration of Adiponectin on Myocardial Ischemia/Reperfusion Injury in a Pig Model 
Background
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.
Conclusions
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.
doi:10.1161/CIRCINTERVENTIONS.109.872044
PMCID: PMC3668696  PMID: 20332381
adiponectin; myocardial infarction; reperfusion
7.  Physiological, Pharmacological, and Nutritional Regulation of Circulating Adiponectin Concentrations in Humans 
Abstract
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.
doi:10.1089/met.2007.0029
PMCID: PMC3190268  PMID: 18510434
8.  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
9.  Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome 
Journal of Clinical Investigation  2006;116(7):1784-1792.
Adiponectin is an adipokine that is specifically and abundantly expressed in adipose tissue and directly sensitizes the body to insulin. Hypoadiponectinemia, caused by interactions of genetic factors such as SNPs in the Adiponectin gene and environmental factors causing obesity, appears to play an important causal role in insulin resistance, type 2 diabetes, and the metabolic syndrome, which are linked to obesity. The adiponectin receptors, AdipoR1 and AdipoR2, which mediate the antidiabetic metabolic actions of adiponectin, have been cloned and are downregulated in obesity-linked insulin resistance. Upregulation of adiponectin is a partial cause of the insulin-sensitizing and antidiabetic actions of thiazolidinediones. Therefore, adiponectin and adiponectin receptors represent potential versatile therapeutic targets to combat obesity-linked diseases characterized by insulin resistance. This Review describes the pathophysiology of adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome.
doi:10.1172/JCI29126
PMCID: PMC1483172  PMID: 16823476
10.  Role of adiponectin in metabolic and cardiovascular disease 
Under disease conditions including obesity (insulin resistance) and diabetes, dysregulation of adipokines such as tumor necrosis factor (TNF)-α, leptin, resistin, and adiponectin contribute to the development of metabolic and cardiovascular disease. Unlike other adipokines, adiponectin has been shown to be a therapeutic target for metabolic syndrome and cardiovascular disease. Circulating levels of adiponectin are markedly reduced in obese, diabetic, hypertensive, and coronary artery disease patients as well as experimental animal models of insulin resistance and diabetes. Recently, the small molecule adiponectin receptors (AdipoRs) agonist was discovered and suggested that the agonist is a novel therapeutic target for the treatment of type 2 diabetes linked to obesity in an experimental mouse model. This review will focus on signaling pathways involved in adiponectin and its receptors and the role of adiponectin in metabolic and cardiovascular disease including insulin resistance, cardiomyopathy, and cardiovascular dysfunction.
doi:10.12965/jer.140100
PMCID: PMC4025550  PMID: 24877038
Adiponectin receptors; AdipoRON; AMPK; PPARα
11.  Adiponectin Action: A Combination of Endocrine and Autocrine/Paracrine Effects 
The widespread physiological actions of adiponectin have now been well characterized as clinical studies and works in animal models have established strong correlations between circulating adiponectin level and various disease-related outcomes. Thus, conventional thinking attributes many of adiponectin’s beneficial effects to endocrine actions of adipose-derived adiponectin. However, it is now clear that several tissues can themselves produce adiponectin and there is growing evidence that locally produced adiponectin can mediate functionally important autocrine or paracrine effects. In this review article we discuss regulation of adiponectin production, its mechanism of action via receptor isoforms and signaling pathways, and its principal physiological effects (i.e., metabolic and cardiovascular). The role of endocrine actions of adiponectin and changes in local production of adiponectin or its receptors in whole body physiology is discussed.
doi:10.3389/fendo.2011.00062
PMCID: PMC3355882  PMID: 22649379
adiponectin; metabolic syndrome; cardiovascular disease
12.  Hypoadiponectinemia in Type 2 Diabetes: Molecular Mechanisms and Clinical Significance 
SUMMARY
This review focuses upon the regulatory mechanisms of adiponectin (APN) gene expression during physiologic conditions, and both the clinical significance and underlying molecular mechanisms of hypoadiponectinemia during pathologic conditions.APN is a versatile cardiovascular protective factor. It plays an important role in regulating insulin sensitivity and energy homeostasis, with anti-inflammatory and anti-atherosclerotic properties.APN gene expression is down-regulated in both obesity and type 2 diabetes mellitus. Hypoadiponectinemia is an independent risk factor for coronary artery disease in type 2 diabetic patients.Exogenous supplementation of recombinant APN attenuates insulin resistance, improving metabolic disorders. Therefore, APN-targeted pharmaceutical strategies increasing circulating APN levels may be therapeutic against type 2 diabetes.There is great value in elucidating the regulatory mechanisms of APN gene expression during physiologic and pathologic conditions. APN biosynthesis regulation includes transcriptional expression and post-translational modification, oligomerisation, and secretion. Under pathological conditions, including obesity and type 2 diabetes mellitus, hypoxia, oxidative stress, and inflammation suppress APN mRNA levels and its secretion.
doi:10.1111/j.1440-1681.2011.05606.x
PMCID: PMC3225695  PMID: 21916932
Adiponectin; Gene Regulation; Hypoadiponectinemia; Type 2 diabetes
13.  Adiponectin Prevents Diabetic Premature Senescence of Endothelial Progenitor Cells and Promotes Endothelial Repair by Suppressing the p38 MAP Kinase/p16INK4A Signaling Pathway 
Diabetes  2010;59(11):2949-2959.
OBJECTIVE
A reduced number of circulating endothelial progenitor cells (EPCs) are casually associated with the cardiovascular complication of diabetes. Adiponectin exerts multiple protective effects against cardiovascular disease, independent of its insulin-sensitizing activity. The objective of this study was to investigate whether adiponectin plays a role in modulating the bioavailability of circulating EPCs and endothelial repair.
RESEARCH DESIGN AND METHODS
Adiponectin knockout mice were crossed with db+/− mice to produce db/db diabetic mice without adiponectin. Circulating number of EPCs were analyzed by flow cytometry. Reendothelialization was evaluated by staining with Evans blue after wire-induced carotid injury.
RESULTS
In adiponectin knockout mice, the number of circulating EPCs decreased in an age-dependent manner compared with the wild-type controls, and this difference was reversed by the chronic infusion of recombinant adiponectin. In db/db diabetic mice, the lack of adiponectin aggravated the hyperglycemia-induced decrease in circulating EPCs and also diminished the stimulatory effects of the PPARγ agonist rosiglitazone on EPC production and reendothelialization. In EPCs isolated from both human peripheral blood and mouse bone marrow, treatment with adiponectin prevented high glucose–induced premature senescence. At the molecular level, adiponectin decreased high glucose–induced accumulation of intracellular reactive oxygen species and consequently suppressed activation of p38 MAP kinase (MAPK) and expression of the senescence marker p16INK4A.
CONCLUSIONS
Adiponectin prevents EPC senescence by inhibiting the ROS/p38 MAPK/p16INK4A signaling cascade. The protective effects of adiponectin against diabetes vascular complications are attributed in part to its ability to counteract hyperglycemia-mediated decrease in the number of circulating EPCs.
doi:10.2337/db10-0582
PMCID: PMC2963556  PMID: 20802255
14.  Tracing the movement of adiponectin in a parabiosis model of wild-type and adiponectin-knockout mice 
FEBS Open Bio  2014;4:276-282.
Highlights
•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.
doi:10.1016/j.fob.2014.03.002
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
15.  Adiponectin Provides Cardiovascular Protection in Metabolic Syndrome 
Adipose tissue plays a central role in the pathogenesis of metabolic syndrome. Adiponectin (APN) is a bioactive adipocytokine secreted from adipocytes. Low plasma APN levels (hypoadiponectinemia) are observed among obese individuals and in those with related disorders such as diabetes, hypertension, and dyslipidemia. APN ameliorates such disorders. Hypoadiponectinemia is also associated with major cardiovascular diseases including atherosclerosis and cardiac hypertrophy. Accumulating evidence indicates that APN directly interacts with cardiovascular tissue and prevents cardiovascular pathology. Increasing plasma APN or enhancing APN signal transduction may be an ideal strategy to prevent and treat the cardiovascular diseases associated with metabolic syndrome. However, further studies are required to uncover the precise biological actions of APN.
doi:10.4061/2011/313179
PMCID: PMC3034991  PMID: 21318102
16.  Adiponectin promotes endothelial progenitor cell number and function 
FEBS letters  2008;582(11):1607-1612.
Obesity-linked diseases are associated with suppressed endothelial progenitor cell (EPC) function. Adiponectin is an adipose-derived protein that is downregulated in obese and diabetic subjects. Here, we investigated the effects of adiponectin on EPCs. EPC levels did not increase in adiponectin deficient (APN-KO) in response to hindlimb ischemia. Adenovirus-mediated delivery of adiponectin increased EPC levels in both WT and APN-KO mice. Incubation of human peripheral blood mononuclear cells with adiponectin led to an increase of the number of EPCs. Adiponectin induced EPC differentiation into network structures and served as a chemoattractant in EPC migration assays. These data suggest that hypoadiponectinemia may contribute to the depression of EPC levels that are observed in patients with obesity-related cardiovascular disorders.
doi:10.1016/j.febslet.2008.04.006
PMCID: PMC2435501  PMID: 18423403
adiponectin; angiogenesis; endothelial progenitor cells
17.  Ultrastructural Localization of Adiponectin protein in Vasculature of Normal and Atherosclerotic mice 
Scientific Reports  2014;4:4895.
Adiponectin, adipose-specific secretory protein, abundantly circulates in bloodstream and its concentration is around 1000-fold higher than that of other cytokines and hormones. Hypoadiponectinemia is a risk factor for atherosclerosis. There is little or no information on ultrastructural localization of adiponectin in the vasculature. Herein we investigated the localization of vascular adiponectin in the aorta using the immunoelectron microscopic technique. In wild-type (WT) mice, adiponectin was mainly detected on the luminal surface membrane of endothelial cells (ECs) and also found intracellularly in the endocytic vesicles of ECs. In the atherosclerotic lesions of apolipoprotein E-knockout (ApoE-KO) mice, adiponectin was detected in ECs, on the cell surface membrane of synthetic smooth muscle cells, and on the surface of monocytes adherent to ECs. Changes in adiponectin localization within the wall of the aorta may provide novel insight into the pathogenesis of atherosclerosis.
doi:10.1038/srep04895
PMCID: PMC4013939  PMID: 24809933
18.  Linking adiponectin to proteinuria 
The Journal of Clinical Investigation  2008;118(5):1619-1622.
Obesity predisposes toward renal disease independently of diabetes and hypertension. In this issue of the JCI, Sharma and colleagues assessed the role of adiponectin, an adipose-derived hormone, in the pathogenesis of albuminuria (see the related article beginning on page 1645). Obese African Americans had reduced adiponectin levels associated with albuminuria. Adiponectin deficiency in mice induced oxidative stress, fusion of podocyte foot processes in the kidney glomerulus, and urinary albumin excretion. Adiponectin treatment reversed these abnormalities, likely through activation of AMPK. The benefits of adiponectin were observed in diabetic and nondiabetic mice. These findings suggest that adiponectin is a biomarker for kidney disease and may be targeted for prevention and treatment.
doi:10.1172/JCI35655
PMCID: PMC2323198  PMID: 18431507
19.  Clinical review: Adiponectin biology and its role in inflammation and critical illness 
Critical Care  2011;15(2):221.
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.
doi:10.1186/cc10021
PMCID: PMC3219307  PMID: 21586104
20.  Design and development of a peptide-based adiponectin receptor agonist for cancer treatment 
BMC Biotechnology  2011;11:90.
Background
Adiponectin, a fat tissue-derived adipokine, exhibits beneficial effects against insulin resistance, cardiovascular disease, inflammatory conditions, and cancer. Circulating adiponectin levels are decreased in obese individuals, and this feature correlates with increased risk of developing several metabolic, immunological and neoplastic diseases. Thus, pharmacological replacement of adiponectin might prove clinically beneficial, especially for the obese patient population. At present, adiponectin-based therapeutics are not available, partly due to yet unclear structure/function relationships of the cytokine and difficulties in converting the full size adiponectin protein into a viable drug.
Results
We aimed to generate adiponectin-based short peptide that can mimic adiponectin action and be suitable for preclinical and clinical development as a cancer therapeutic. Using a panel of 66 overlapping 10 amino acid-long peptides covering the entire adiponectin globular domain (residues 105-254), we identified the 149-166 region as the adiponectin active site. Three-dimensional modeling of the active site and functional screening of additional 330 peptide analogs covering this region resulted in the development of a lead peptidomimetic, ADP 355 (H-DAsn-Ile-Pro-Nva-Leu-Tyr-DSer-Phe-Ala-DSer-NH2). In several adiponectin receptor-positive cancer cell lines, ADP 355 restricted proliferation in a dose-dependent manner at 100 nM-10 μM concentrations (exceeding the effects of 50 ng/mL globular adiponectin). Furthermore, ADP 355 modulated several key signaling pathways (AMPK, Akt, STAT3, ERK1/2) in an adiponectin-like manner. siRNA knockdown experiments suggested that ADP 355 effects can be transmitted through both adiponectin receptors, with a greater contribution of AdipoR1. In vivo, intraperitoneal administration of 1 mg/kg/day ADP 355 for 28 days suppressed the growth of orthotopic human breast cancer xenografts by ~31%. The peptide displayed excellent stability (at least 30 min) in mouse blood or serum and did not induce gross toxic effects at 5-50 mg/kg bolus doses in normal CBA/J mice.
Conclusions
ADP 355 is a first-in-class adiponectin receptor agonist. Its biological activity, superior stability in biological fluids as well as acceptable toxicity profile indicate that the peptidomimetic represents a true lead compound for pharmaceutical development to replace low adiponectin levels in cancer and other malignancies.
doi:10.1186/1472-6750-11-90
PMCID: PMC3198688  PMID: 21974986
21.  Adiponectin-induced secretion of interleukin-6 (IL-6), monocyte chemotactic protein-1 (MCP-1, CCL2) and interleukin-8 (IL-8, CXCL8) is impaired in monocytes from patients with type I diabetes 
Background
Systemic adiponectin is reduced in patients with cardiovascular disease (CVD) and low adiponectin may contribute to the pathogenesis of atherosclerosis. However, circulating adiponectin is elevated in type 1 diabetes (T1D) patients, who have also a higher incidence to develop CVD. Because monocytes play an important role in atherosclerosis, we analysed the influence of adiponectin on cytokine and chemokine release in monocytes from T1D patients and controls.
Methods
Systemic adiponectin was determined in the plasma and the high-molecular weight (HMW) form of adiponectin was analysed by immunoblot. Monocytes were isolated from T1D patients and controls and the adiponectin-stimulated release of interleukin-6 (IL-6), monocyte chemotactic protein-1 (MCP-1, CCL2) and interleukin-8 (IL-8, CXCL8) was analysed.
Results
Systemic adiponectin was higher in T1D patients. Immunoblot analysis of the plasma indicate abundance of HMW adiponectin in T1D patients and controls. IL-6, CCL2 and CXCL8 secretion in response to adiponectin were found induced in monocytes from controls whereas only IL-6 was upregulated in T1D cells. The induction of IL-6 by adiponectin was abrogated by an inhibitor of the NFκB pathway.
Conclusion
These data indicate that adiponectin-mediated induction of IL-6, CCL2 and CXCL8 is disturbed in monocytes from T1D patients and therefore elevated systemic adiponectin in T1D patients may be less protective when compared to controls.
doi:10.1186/1475-2840-5-17
PMCID: PMC1563998  PMID: 16939660
22.  Emerging role of adipokines as mediators in atherosclerosis 
World Journal of Cardiology  2010;2(11):370-376.
Atherosclerotic cardiovascular disease is a major health problem around the world. Obesity is a primary risk factor for atherosclerosis and is associated with increased morbidity and mortality of cardiovascular diseases. However, the precise molecular pathways underlying this close association remain poorly understood. Adipokines are cytokines, chemokines and hormones secreted by adipose tissue that couple the regulation of lipid accumulation, inflammation, and atherogenesis, and therefore serve to link obesity with cardiovascular disorders. Obesity-related disorders including metabolic syndrome, diabetes, atherosclerosis, hypertension, and coronary artery disease are associated with dysregulated adipokine(s) expression. Recent studies demonstrate the proinflammatory effects as well as atherogenic properties of adipokines. Adipokines also participate in the regulation of endothelial function, which is an early event in atherosclerosis. By contrast, adiponectin, an adipocyte-derived hormone, exerts anti-inflammatory, anti-atherogenic and vascular protective effects. Furthermore, there is an interactive association among adipokines, by which adipokines reciprocally regulate each other’s expression. Understanding this interplay may reveal plausible mechanisms for treating atherosclerosis and coronary heart disease by modulating adipokine(s) expression. In this review, we discuss insights into the role and the therapeutic potential of adipokines as mediators of atherosclerosis.
doi:10.4330/wjc.v2.i11.370
PMCID: PMC3006473  PMID: 21179304
Obesity; Inflammation; Adipokines; Endothelial function; Atherosclerosis
23.  The role of adiponectin in reproduction: from polycystic ovary syndrome to assisted reproduction 
Fertility and sterility  2010;94(6):1949-1957.
Objective
To summarize the effects of the adipokine adiponectin on the reproductive endocrine system, from the hypothalamic-pituitary axis to the gonads and target tissues of the reproductive system.
Design
A Medline computer search was performed to identify relevant articles.
Setting
Research institution.
Intervention(s)
None.
Result(s)
Adiponectin is a hormone secreted by adipose tissue that acts to reduce insulin resistance and atherogenic damage, but it also exerts actions in other tissues. Adiponectin mediates its actions in the periphery mainly via two receptors, AdipoR1 and AdipoR2. Adiponectin receptors are present in many reproductive tissues, including the central nervous system, ovaries, oviduct, endometrium, and testes. Adiponectin influences gonadotropin release, normal pregnancy, and assisted reproduction outcomes.
Conclusion(s)
Adiponectin, a beneficial adipokine, represents a major link between obesity and reproduction. Higher levels of adiponectin are associated with improved menstrual function and better outcomes in assisted reproductive cycles.
doi:10.1016/j.fertnstert.2010.05.010
PMCID: PMC3127205  PMID: 20561616
Adiponectin; hypothalamus; pituitary; gonads; reproduction; polycystic ovary syndrome; PCOS; pregnancy; embryo development; assisted reproduction
24.  Green Tea Polyphenols Reduced Fat Deposits in High Fat-Fed Rats via erk1/2-PPARγ-Adiponectin Pathway 
PLoS ONE  2013;8(1):e53796.
Objective
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).
Conclusion
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.
doi:10.1371/journal.pone.0053796
PMCID: PMC3546082  PMID: 23342006
25.  Association between lifestyle factors and plasma adiponectin levels in Japanese men 
Background
Adiponectin is an adipocyte-specific protein that plays a role in obesity, insulin resistant, lipid metabolism, and anti-inflammation. Hypoadiponectinemia may be associated with a higher risk for type 2 diabetes and cardiovascular disease. Some studies suggest that adiponectin levels are modulated by lifestyle factors, but little is known about the associations between lifestyle factors and plasma adiponectin levels in Japanese people. We therefore investigated the associations between lifestyle factors and plasma adiponectin levels in general Japanese men.
Methods
The subjects were 202 Japanese male workers who participated in an annual health check. They provided details about anthropometrical data, blood collection, their use of prescribed medication, and the clinical history of their families. They also completed a self-administered questionnaire about their lifestyles.
Results
Subjects with plasma adiponectin levels below 4.0 μg/ml had significantly lower levels of HDL cholesterol and higher levels of BMI, SBP, DBP, total cholesterol, FBG, and platelets than did subjects with higher adiponectin levels. In multiple logistic regression after multiple adjustment, a plasma adiponectin level below 4.0 μg/ml was significantly associated with smoking (odds ratio [OR] = 2.08, 95% confidence interval [CI] = 1.01–4.30), a daily diet rich in deep-yellow vegetables (OR = 0.25, 95% CI= 0.07–0.91), frequent eating out (OR = 2.45, 95% CI = 1.19–5.08), and physical exercise two or more times a week (OR = 0.21, 95% CI = 0.06–0.74).
Conclusion
Our findings show that adiponectin levels in general Japanese men are independently related to smoking, dietary factors, and physical exercise. We think that lifestyle habits might independently modulate adiponectin levels and that adiponectin might be the useful biomarker helping people to avoid developing type 2 diabetes and cardiovascular disease by modifying their lifestyles.
doi:10.1186/1476-511X-4-27
PMCID: PMC1291392  PMID: 16262911
adiponectin; smoking; dietary factor; physical exercise; general Japanese men

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