Regulation Of Adiponectin Research Articles

Adiponectin Regulates Bone Mass via Opposite Central and Peripheral Mechanisms through FoxO1

The synthesis of adiponectin, an adipokine with ill-defined functions in animals fed a normal diet, is enhanced by the osteoblast-derived hormone osteocalcin. Here we show that adiponectin signals back in osteoblasts to hamper their proliferation and favor their apoptosis, altogether decreasing bone mass and circulating osteocalcin levels. Adiponectin fulfills these functions, independently of its known receptors and signaling pathways, by decreasing FoxO1 activity in a PI3-kinase-dependent manner. Over time, however, these local effects are masked because adiponectin signals in neurons of the locus coeruleus, also through FoxO1, to decrease the sympathetic tone, thereby increasing bone mass and decreasing energy expenditure. This study reveals that adiponectin has the unusual ability to regulate the same function in two opposite manners depending on where it acts and that it opposes, partially, leptin's influence on the sympathetic nervous system. It also proposes that adiponectin regulation of bone mass occurs through a PI3-kinase-FoxO1 pathway.

Circulating microRNA profiling and their association with hypoadiponectinemia

Hypoadiponectinemia is frequently observed in individuals with cardiovascular disease, type 2 diabetes mellitus, obesity, and obesity related cancers among many other metabolic disorders. MicroRNAs appear to play a regulatory role in the expression of adiponectin, but this role remains unclear at this time. Consequently, the aim is to identify microRNAs involved in the regulation and expression of adiponectin. Replication of clinical in vivo observations will be attempted in vitro using the genotyped “body‐on‐a‐chip” BOAC systems. The goal is to have an in vitro model to identify nutritionally induced microRNA profiles. MicroRNA profile assays are performed in pools of 4 groups of donors. Group 1‐BMI >; 40 prior to bariatric surgery, 2‐BMI<30 after bariatric surgery; 3‐patients diagnosed with metabolic syndrome 4‐controls without metabolic syndrome. Circulating microRNAs are isolated from the plasma of patients corresponding to IRB approved clinical trial GHS # 1207–27. The assays are performed with the qiagen human plasma miRNA PCR array (MIHS‐106Z) with internal normalization control C. elegans miR‐39 spike. Circulating microRNA profiles are correlated with circulating levels of total adiponectin and other clinical markers of metabolism. Funding Cornell University Center on the Microenvironment and Metastasis (CMM) outreach pilot grant and Guthrie Foundation Investigator‐Initiated Research Grant.

Postprandial total and HMW adiponectin following a high-fat meal in lean, obese and diabetic men

Recent work suggests that macronutrients are pro-inflammatory and promote oxidative stress. Reports of postprandial regulation of total adiponectin have been mixed, and there is limited information regarding postprandial changes in high molecular weight (HMW) adiponectin. The aim of this study was to assess the effect of a standardised high-fat meal on metabolic variables, adiponectin (total and HMW), and markers of inflammation and oxidative stress in: (i) lean, (ii) obese non-diabetic and (iii) men with type 2 diabetes mellitus (T2DM). Male subjects: lean (n=10), obese (n=10) and T2DM (n=10) were studied for 6 h following both a high-fat meal and water control. Metabolic variables (glucose, insulin, triglycerides), inflammatory markers (interleukin-6 (IL6), tumour necrosis factor (TNF)α, high-sensitivity C-reactive protein (hsCRP), nuclear factor (NF)κB expression in peripheral blood mononuclear cells (p65)), indicators of oxidative stress (oxidised low density lipoprotein (oxLDL), protein carbonyl) and adiponectin (total and HMW) were measured. No significant changes in TNFα, p65, oxLDL or protein carbonyl concentrations were observed. Overall, postprandial IL6 decreased in subjects with T2DM but increased in lean subjects, whereas hsCRP decreased in the lean cohort and increased in obese subjects. There was no overall postprandial change in total or HMW adiponectin in any group. Total adiponectin concentrations changed over time following the water control, and the response was significantly different in lean subjects compared with subjects with T2DM (P=0.04). No consistent significant postprandial inflammation, oxidative stress or regulation of adiponectin was observed in this study. Findings from the water control suggest differential basal regulation of total adiponectin in T2DM compared with lean controls.

Green Tea Polyphenols Reduced Fat Deposits in High Fat-Fed Rats via erk1/2-PPARγ-Adiponectin Pathway

ObjectiveHypoadiponectinemia 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 ResultsMale 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).ConclusionGTPs 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.

Adiponectin concentration is associated with muscle insulin sensitivity, AMPK phosphorylation, and ceramide content in skeletal muscles of men but not women

Adiponectin is an adipokine that regulates metabolism and increases insulin sensitivity. Mechanisms behind this insulin-sensitizing effect have been investigated in rodents, but little is known in humans, especially in skeletal muscle. Women have higher serum concentrations of adiponectin than men and are generally more insulin sensitive in skeletal muscle than men. We show here that large differences exist between men and women with regard to apparent adiponectin regulation of insulin-stimulated glucose uptake in skeletal muscle. Serum adiponectin was significantly associated with leg glucose uptake in healthy, young, lean men, but the association was absent in women. In addition, serum adiponectin was significantly associated with AMP-activated protein kinase (AMPK) phosphorylation in skeletal muscles of men but not in women. Serum adiponectin was also significantly, negatively associated with skeletal muscle ceramide content in men only, and interestingly, ceramide content was negatively associated with adiponectin receptor 1 (AdipoR1) expression in skeletal muscles of men. Women had lower AdipoR1 expression in skeletal muscle and a lower percentage of glycolytic adiponectin-sensitive type 2 muscle fibers than men. These associations suggest that the insulin-sensitizing effect of adiponectin on human male skeletal muscles may be mediated via AdipoR1 to activation of AMPK, leading to lowering of ceramide content. The lower skeletal muscle AdipoR1 protein expression and lower expression of adiponectin-sensitive type 2 muscle fibers in women than in men may explain the apparent lesser sensitivity to adiponectin in women.

Effect of Physical activity on Insulin Resistance, Inflammation and Oxidative Stress in Diabetes Mellitus.

Diabetes Mellitus is a growing health concern projected to affect 366 million people worldwide by around 2030. Multiple approaches to address this health concern are documented; amongst which increased the habitual physical activity has been shown to be beneficial. Various mechanisms demonstrated show improvement of cellular insulin sensitivity. The interplay between insulin sensitivity and insulin resistance plays a key role in development and persistence of the diabetic state, which can be directly linked to the levels of physical activity. Regulation of adiponectin and leptin levels are also linked to physical activity via reduction of central obesity. Inflammatory markers, free radical reduction and up-regulation of physiological antioxidant processes are also observed in subjects with increased physical activity schedules, all of which play a significant role in the pathogenesis of Diabetes Mellitus.

Regulation of adiponectin secretion and expression by insulin and β‐agonists in rat

AbstractThe adipocytokines, including adiponectin, are important factors in the regulation of insulin sensitivity and carbohydrate and lipid metabolism. It is proved that concentrations of adiponectin are decreased in obesity, an insulin resistant state. The current study is to address potential mechanisms regulating adiponectin secretion and expression in vivo. To observe the regulation of adiponectin by fasting‐refeeding and β‐agonists, male Wistar rats were fasted for 18 h and allowed to refeed with/without a β3‐adrenergic receptor agonist infused into refeeding rats. We also investigated the effects of insulin clamp on adiponectin secretion and expression, including euglycemic–hyperinsulinemic clamp and hyperglycemic–hyperinsulinemic clamp. Plasma adiponectin levels were determined by radioimmunoassay. Using real‐time PCR assays, we analyzed the expression of adiponectin genes in rat primary adipocytes. Refeeding of 18‐h fasted rats increased plasma adiponectin concentration (∼2‐fold) and adipose tissue adiponectin expression (∼3‐fold), and these effects were mimicked by hyperinsulinemia in the absence of refeeding and completely blocked by administration of β‐agonists during refeeding. We conclude that (i) adiponectin secretion and expression are acutely regulated in vivo by nutritional status; (ii) in vivo, insulin and β‐agonists act directly at the adipocyte to regulate adiponectin secretion and expression.

Atrial Natriuretic Peptide and Adiponectin Interactions in Man

Reduced circulating natriuretic peptide concentrations are independently associated with insulin resistance and type 2 diabetes, while increased natriuretic peptide levels appear to be protective. Observations in vitro and in heart failure patients suggest that atrial natriuretic peptide (ANP) promotes adiponectin release, an adipokine with insulin sensitizing properties. We tested the hypothesis that ANP acutely raises adiponectin levels in 12 healthy men. We infused ANP intravenously over 135 minutes while collecting venous blood and adipose tissue microdialysates at baseline and at the end of ANP-infusion. We obtained blood samples at identical time-points without ANP infusion in 7 age and BMI matched men. With infusion, venous ANP concentrations increased ∼10 fold. Systemic and adipose tissue glycerol concentrations increased 70% and 80%, respectively (P<0.01). ANP infusion increased total adiponectin 14±5% and high molecular-weight (HMW)-adiponectin 13±5% (P<0.05). Adiponectin did not change in the control group (P<0.05 vs. infusion). ANP-induced changes in HMW adiponectin and adipose tissue lipolysis were directly correlated with each other, possibly suggesting a common mechanism. Our data show that ANP acutely increases systemic total and HMW-adiponectin concentrations in healthy subjects. Our study could have implications for the physiological regulation of adiponectin and for disease states associated with altered natriuretic peptide availability.

Endocannabinoids regulate adipokine production and the immune balance of omental adipose tissue in human obesity

(1) To investigate whether modulation of the cannabinoid type 1 receptor (CB1R) directly regulates the production of adiponectin (ApN) and other adipokines in omental adipose tissue (OAT) of obese subjects, (2) to establish in which cellular fraction of OAT the effects of CB1R blockade take place and (3) to unravel the underlying mechanisms. OAT was obtained from 30 obese subjects (body mass index: 40.6±1.3 kg m(-2)) undergoing abdominal surgery. Primary cultures of explants or of freshly isolated adipocytes or stromal-vascular cells (SVCs) were used. In OAT explants, the CB1R blocker Rimonabant upregulated ApN gene expression. mRNA abundance of omentin that exhibits insulin-sensitizing properties was upregulated as well. Conversely, mRNA levels of two pro-inflammatory cytokines, macrophage inflammatory protein (MIP)-1β and interleukin (IL)-7 were downregulated. We next examined where these effects took place within OAT. CB1R expression was similar in both cellular fractions. In isolated mature adipocytes, blockade of CB1R reproduced the increase of ApN mRNA and the decrease of IL-7 mRNA, while inducing a rise of ApN secretion into the medium. In isolated SVC, gene expression of omentin, which is restricted to this fraction, was augmented, while that of MIP-1β was diminished. Finally, we deciphered the mechanisms leading to ApN regulation by the endocannabinoid system (ES). We first established that ApN regulation was actually mediated by the CB1R: ApN gene expression was upregulated by Rimonabant and downregulated by the CB1R agonist arachidonyl-2-chloroethylamide (ACEA). Upregulation of ApN by Rimonabant was unaltered by inhibiting cAMP production. However, downregulation of ApN by ACEA was fully reversed by an inhibitor of p38 mitogen-activated protein kinase (p38MAPK) and ACEA increased p38MAPK phosphorylation. Blockade of CB1R attenuates the inflammatory state in both cellular fractions of OAT either by increasing ApN and omentin production or by decreasing mRNAs of MIP-1β and IL-7. ApN regulation by the ES partly involves p38MAPK.

Effects of 17β-estradiol on adiponectin regulation of the expression of osteoprotegerin and receptor activator of nuclear factor-κB ligand

Adiponectin may exert a negative effect on bone metabolism by regulating osteoprotegerin (OPG) and receptor activator of nuclear factor-κB ligand (RANKL) expression. However, the action of adiponectin on bone may be influenced by estrogen in women. The present study was undertaken to investigate the effects of 17β-estradiol (E2) on adiponectin-regulated OPG and RANKL expression in human osteoblast. Human osteoblasts were treated with α-MEM containing 10μg/ml adiponectin alone or together with 10−10 to 10−8M E2 for 12–48h. Cells were also treated with α-MEM containing 10μg/ml adiponectin together with 10−8M E2 plus p38 agonist-anisomycin or estrogen receptor (ER) antagonist ICI182780 for 48h. The effects of E2 were also investigated by knockdown of ERs or overexpression of p38 MAPK in osteoblasts. Further, we examined the effects of E2 on adiponectin-dependent osteoclastogenesis by the co-culture systems of osteoblast and CD14+ peripheral blood monocytes (PBMCs). Real-time quantitative PCR (RT-PCR) and ELISA were used to detect OPG/RANKL mRNA and their corresponding protein expression, Western Blot was used to analyze the phosphorylated p38 (p-p38) levels. The results showed that E2 blocked adiponectin-induced p38 phosphorylation, decreased adiponectin-regulated OPG/RANKL mRNA and protein expression in a dose- and time-dependent manner. ICI182780 or knockdown of ERs abolished the effects of E2 on adiponectin-dependent p38 phosphorylation and OPG/RANKL expression. Furthermore, anisomycin or overexpression of p38 also reserved the effects of E2 on adiponectin-dependent p38 phosphorylation and OPG/RANKL expression. E2 inhibited adiponectin-dependent osteoclastogenesis in the co-culture systems of osteoblast and CD14+ PBMCs, whereas anisomycin, ICI182780, knockdown of ERs and overexpression of p38 significantly reversed this response. In conclusions, our findings demonstrated, through blocking the activation of adiponectin-induced p38 MAPK, E2 suppressed the adiponectin-regulated OPG/RANKL expression and then inhibited osteoclastogenesis, which suggested that estrogen would suppress the effect of adiponectin on bone metabolism.

Abstract 207: Differential Regulation of Monocyte/Macrophage Atherogenic Properties by Adiponectin: Role of Macrophage Polarization and Adiponectin Receptors

Adiponectin, an adipocytokine produced by the adipose tissue, exerts metabolic, anti-inflammatory and anti-atherogenic effects to ameliorate diabetes and cardiovascular disease and is a potentially important therapeutic target. However, mechanisms of adiponectin vascular actions and the regulation of macrophage adiponectin receptor expression under inflammatory/atherogenic activation remain unclear. Our studies with human monocytes/macrophages revealed differential adiponectin receptor regulation in subjects with insulin-resistance. Here, we investigated adiponectin regulation of macrophage gene expression under pro- and anti-inflammatory conditions. We addressed the hypothesis that differential activation of macrophages into the classical (M1) or alternative (M2) program alters their adiponectin receptor (AdipoR1 and AdipoR2) expression. The microarray gene expression analyses in human monocytes exposed to TNF-α showed that adiponectin inhibited several inflammatory/atherogenic genes. Our studies revealed that adiponectin itself induces AdipoR1 and AdipoR2 expression in macrophages. We further investigated the effects of macrophage polarization (M1 or M2) on adiponectin receptor expression in bone marrow-derived and peritoneal macrophages. These studies demonstrated that M1 activation (IFN-γ and LPS) significantly reduced AdipoR1 and AdipoR2 expression. In contrast, M2 activation of (IL-4 or IL-10) maintains a significantly higher level of AdipoR1 and AdipoR2. In M2 activation, adiponectin receptor expression was more substantial in IL-10 than IL-4-polarized macrophages. These results provide important evidence that macrophage polarization profoundly alters their adiponectin receptor expression and thus functional responses to adiponectin. Thus, adiponectin-mediated macrophage functions are regulated by adiponectin receptor expression which is modulated by the macrophage polarization which controls their inflammatory and atherogenic properties.

Effect of Endoplasmic Reticulum Stress on Inflammation and Adiponectin Regulation in Human Adipocytes

The endoplasmic reticulum (ER) of adipocytes plays a major role in the assembly and secretion of adipokines. The levels of serum adiponectin, secreted by adipocytes, are decreased in insulin resistance, diabetes, and obesity. The role of ER stress in downregulating adiponectin levels has been demonstrated in mouse models of obesity. Studies examining human adipose tissue have indicated that there is an increase in the ER stress transcript HSPA5 with increased body mass index (BMI). However, it is not established whether ER stress results in changes in adiponectin levels or multimerization in human adipocytes. We examined whether the induction of ER stress using tunicamycin, thapsigargin, or palmitate alters the messenger RNA (mRNA) and protein expression of adiponectin and the mRNA expression of chaperones ERP44 and ERO1 in adult-derived human adipocyte stem (ADHAS) cells. ER stress was measured using key indicators of ER stress-HSPA5, ERN1, CHOP, and GADD34, as well as changes in eIF2α phosphorylation. Because ER stress is suggested to be the proximal cause of inflammation in adipocytes, we further examined the change in inflammatory status by quantitating the change in Iκβ-α protein following the induction of ER stress. Our studies indicate that: (1) ER stress markers were increased to a higher degree using tunicamycin or thapsigargin compared to palmitate; (2) ER stress significantly decreased adiponectin mRNA in response to tunicamycin and thapsigargin, but palmitate did not decrease adiponectin mRNA levels. In all three instances, the induction of ER stress was accompanied by a decrease in adiponectin protein as well as adiponectin multimerization. All three inducers of ER stress increased tumor necrosis factor-α (TNF-α) mRNA and decreased Iκβ-α protein in adipocytes. The data suggest that ER stress modifies adiponectin secretion and induces inflammation in ADHAS cells.

Glucose-Based Peritoneal dialysis solution suppresses adiponectin synthesis through oxidative stress in an experimental model of peritoneal dialysis

Accumulation of visceral fat is one of the major risk factors for the development of cardiovascular disease in peritoneal dialysis (PD) patients. Adiponectin, an adipokine commonly regarded as a negative indicator of metabolic disease, is reported to be downregulated in its gene level in end-stage renal disease patients. Since excessive fat deposit is involved in increased reactive oxygen species (ROS), PD solution (PDS) may contribute to ROS production, resulting in dysregulation of adiponectin. In this study, we tested our hypothesis that oxidative stress induced by PDS may play a role in the regulation of adiponectin. Commercial PDS containing 3.86% glucose (20 - 30 mL) was administered to SD rats for 12 weeks with and without N-acetylcysteine (NAC; 10 mmol/L). ELISA was used to quantify adiponectin in plasma and spent dialysate. For in vitro studies, fully differentiated 3T3-L1 adipocytes and adipocytes isolated from abdominal fat were treated with a high glucose solution, PDS, and H(2)O(2). Adiponectin levels in the conditioned media were measured by ELISA and immunoblot assays. The mRNA levels of adiponectin in mature adipocytes were examined using real-time RT-PCR. The levels of adiponectin in plasma and spent dialysate were significantly downregulated by PDS and this effect was suppressed by NAC. In 3T3-L1 adipocytes, adiponectin secretion was inhibited by 50 mmol/L glucose, PDS diluted 2-fold, and H(2)O(2) (200 μmol/L). In addition, H(2)O(2) downregulated expression of adiponectin mRNA and secretion of adiponectin oligomer complexes. Our data suggest that ROS induced by conventional glucose-based PDS may contribute to pathophysiological changes in abdominal fat and downregulate adiponectin secreted from adipocytes during long-term PD.

Novel multiplex method to assess insulin, leptin and adiponectin regulation of inflammatory cytokines associated with colon cancer

The role of altered levels of insulin, leptin and adiponectin in contributing to the observed increased risk of colon cancer associated with obesity remains to be determined. Elevated insulin and leptin associated with obesity are linked to inflammatory responses. Conversely, adiponectin levels are reduced in obese individuals and this hormone is generally associated with anti-inflammatory responses. Inflammatory cytokines are key components of processes linked with carcinogenesis. Insulin, leptin and adiponectin receptor expression profiles were assessed in human normal, adenomatous polyp and tumour tissue. Insulin, leptin and adiponectin regulation of inflammatory cytokines previously identified as being associated with early events in colon carcinogenesis were further investigated here using a surrogate colon epithelial cell line and a custom designed GeXP assay of the inflammatory cytokines (CCL20, CXCL1, CXCL2, CXCL3, CXCL11, IL1RN, CXCL4, IL8, CCL19, CCL21, CCL23, CCL5, IL10RB and TNFRSF1A). Mean insulin, leptin and adiponectin receptor expression levels were lower in adenomatous polyp samples in comparison with normal and tumour tissue. In contrast to leptin, insulin significantly reduced CCL20 and CXCL11 and increased CXCL3 expression. Full length adiponectin, but not globular adiponectin, induced CCL5, CXCL1, CXCL3 and CCL20 gene expression. GeXP assay permitted measurement of changes in gene expression of cytokines in response to insulin and adiponectin, indicating the potential for insulin and adiponectin regulation of mediators of inflammation associated with early events in colon carcinogenesis.

Leptin, adiponectin and other adipokines in gestational diabetes mellitus and pre‐eclampsia

Proteins secreted from adipocytes - so-called adipokines - influence metabolic and vascular function. Recent data suggest that various adipokines are dysregulated in gestational diabetes mellitus (GDM) and pre-eclampsia (PE) and might be of pathophysiological and prognostic significance in these complications of pregnancy. This review gives an overview on the regulation and pathophysiology of leptin and adiponectin in GDM and PE. Furthermore, data on novel adipokines including resistin, visfatin, retinol-binding protein 4 and vaspin are summarized.

PPARs and Lipid Ligands in Inflammation and Metabolism

Peroxisome proliferator-activated receptors (PPARs) belong to a family of ligand-activated nuclear receptors that includes the estrogen, thyroid hormone, and glucocorticoid receptors1. The PPAR family consists of three subtypes encoded by three separate genes: PPAR-α (NR1C1), PPAR-β/δ (NR1C2), and PPAR-γ (NR1C3). Distinct PPAR subtype tissue distributions2,3 and unique ligand-binding pockets drive separate but often complementary patterns of gene expression in response to PPAR ligands4. PPAR activation occurs upon cognate synthetic or endogenous ligand binding to the ligand-binding domain (LBD). Activated PPARs heterodimerize with retinoid X receptors (RXRs), another class of nuclear receptor, which subsequently bind to the hexameric direct repeat peroxisome proliferator response elements (PPRE)5,6 and recruit co-activator protein complexes to positively regulate expression of target genes (Figure 1A). PPARs also mediate ligand-dependent repression of inflammatory gene expression through the association with co-repressor protein complexes7. Figure 1 PPAR transcriptional regulation and the production of endogenous ligands. A) Endogenous lipid ligand precursors undergo enzymatic conversion to active lipids, leading to their binding to PPAR/RXR heterodimers on target genes and recruitment of co-activator ... Nearly all nuclear receptors share structural similarity consisting of a conserved DNA-binding domain (DBD) and LBD1. The PPAR subtype structural similarities contribute to the partial overlapping function of PPARs across different tissues. In hepatocytes, PPAR-α positively regulates fatty acid β-oxidation, ketogenesis, and gluconeogenesis, while suppressing amino acid catabolism and inflammatory responses8. PPAR-α plays anti-inflammatory roles in smooth muscle cells and vascular endothelial cells9,10. PPAR-β/δ (PPAR-δ) plays roles in lipid metabolism11, fatty acid oxidation and energy dissipation12, anti-inflammation13, and colon cancer14. PPAR-γ is an essential modulator of fat cell differentiation15-17 and lipid storage and plays important anti-inflammatory roles in macrophages18,19 and other tissues such as the colon20. PPAR-γ also contributes to insulin sensitivity21, in part through the regulation of adiponectin, an adipo(cyto)kine that enhances insulin sensitivity22. PPAR-γ is activated by synthetic ligand thiazolidinediones (TZDs)7. TZDs, including rosiglitazone and pioglitazone, are potent insulin sensitizers that have a myriad of potential benefits for patients with cardiovascular disease including improvements in endothelial function, lipid profiles and atherosclerosis23-25. TZDs, however, augment renal sodium reabsorption, leading to fluid retention that can exacerbate heart failure26-28. Recent meta-analyses have raised questions surrounding the safety of TZDs, linking the drugs to the occurrence of myocardial infarction and death29,30. While some studies suggest that the relative risks of rosiglitazone are higher than pioglitazone, the possibility that all TZDs may have adverse risk profiles has not been excluded. The unwanted side effects of TZDs have raised the prospects for the development of newer and safer PPAR ligands, such as the therapeutic usage of natural PPAR ligands. Recent studies have identified physiologically relevant endogenous PPAR ligands linked to the expression of their endogenous synthetic enzymes in specific tissues. Examples include 15-keto-prostaglandin E2 produced by 15-hydroxyprostaglandin dehydrogenase (15-PGDH) in colonic epithelial cells and 15-deoxy-Δ12,14-prostaglandin J2 produced by prostaglandin D2 synthase (PGD2S) in macrophages (Figure 1B). Further study of the effectiveness of natural PPAR ligands or synthetic molecules that mimic the actions of natural ligands is needed to determine their potential as clinical therapeutics. This review will characterize the structural and functional relationships of PPARs, define the regulatory mechanisms that control PPAR activities, and review the candidate natural ligands of PPARs to provide a framework for understanding the roles of PPARs as anti-inflammatory therapeutics.

Circulating adiponectin levels are lower in Latino versus non-Latino white patients at risk for cardiovascular disease, independent of adiposity measures

BackgroundLatinos in the United States have a higher prevalence of type 2 diabetes than non-Latino whites, even after controlling for adiposity. Decreased adiponectin is associated with insulin resistance and predicts T2DM, and therefore may mediate this ethnic difference. We compared total and high-molecular-weight (HMW) adiponectin in Latino versus white individuals, identified factors associated with adiponectin in each ethnic group, and measured the contribution of adiponectin to ethnic differences in insulin resistance.MethodsWe utilized cross-sectional data from subjects in the Latinos Using Cardio Health Actions to reduce Risk study. Participants were Latino (n = 119) and non-Latino white (n = 60) men and women with hypertension and at least one other risk factor for CVD (age 61 ± 10 yrs, 49% with T2DM), seen at an integrated community health and hospital system in Denver, Colorado. Total and HMW adiponectin was measured by RIA and ELISA respectively. Fasting glucose and insulin were used to calculate the homeostasis model insulin resistance index (HOMA-IR). Variables independently associated with adiponectin levels were identified by linear regression analyses. Adiponectin's contribution to ethnic differences in insulin resistance was assessed in multivariate linear regression models of Latino ethnicity, with logHOMA-IR as a dependent variable, adjusting for possible confounders including age, gender, adiposity, and renal function.ResultsMean adiponectin levels were lower in Latino than white patients (beta estimates: -4.5 (-6.4, -2.5), p < 0.001 and -1.6 (-2.7, -0.5), p < 0.005 for total and HMW adiponectin), independent of age, gender, BMI/waist circumference, thiazolidinedione use, diabetes status, and renal function. An expected negative association between adiponectin and waist circumference was seen among women and non-Latino white men, but no relationship between these two variables was observed among Latino men. Ethnic differences in logHOMA-IR were no longer observed after controlling for adiponectin levels.ConclusionsAmong patients with CVD risk, total and HMW adiponectin is lower in Latinos, independent of adiposity and other known regulators of adiponectin. Ethnic differences in adiponectin regulation may exist and future research in this area is warranted. Adiponectin levels accounted for the observed variability in insulin resistance, suggesting a contribution of decreased adiponectin to insulin resistance in Latino populations.

Adiponectin Regulation of Stellate Cell Activation via PPARγ-Dependent and -Independent Mechanisms

In this study, we elucidated the mechanism by which adiponectin modulates hepatic stellate cell activation and fibrogenesis. Adiponectin-overexpressing transgenic mice receiving thioacetamide were resistant to fibrosis, compared with controls. In contrast, adiponectin-null animals developed severe fibrosis. Expression of collagen α1(I) and α-smooth muscle actin (α-SMA) mRNAs were significantly lower in adiponectin-overexpressing mice, compared with controls. In wild-type stellate cells exposed to a lentivirus encoding adiponectin, expression of peroxisome proliferator-activated receptor-γ (PPARγ), SREBP1c, and CEBPα mRNAs was significantly increased (3.2-, 4.1-, and 2.2-fold, respectively; n = 3; P < 0.05, adiponectin virus versus control), consistent with possible activation of an adipogenic transcriptional program. Troglitazone, a PPARγ agonist, strongly suppressed up-regulation of collagen α1(I) and α-SMA mRNA in stellate cells isolated from wild-type mice; however, stellate cells from adiponectin-null animals failed to respond to troglitazone. Furthermore, in isolated stellate cells in which PPARγ was depleted using an adenovirus-Cre-recombinase system and in which adiponectin was also overexpressed, collagen α1(I) and α-SMA were significantly inhibited. We conclude that the PPARγ effect on stellate cell activation and the fibrogenic cascade appears to be adiponectin-dependent; however, the inhibitory effect of adiponectin on stellate cell activation was not dependent on PPARγ, suggesting the presence of PPARγ-dependent as well as independent pathways in stellate cells.

Vasonatrin peptide, a new regulator of adiponectin and interleukin-6 production in adipocytes.

In addition to lipolytic function, ANP plays regulatory roles in the production of various adipokines including adiponectin, leptin, and interleukins. However, the adipose effects of vasonatrin peptide (VNP), a new manmade natriuretic peptide, are largely unknown. The aim of the present study was to identify the roles of VNP on adipokines production, as well as signaling pathways involved. MATERIAL, SUBJECTS, AND METHODS: 3T3-L1 cells were differentiated into adipocytes and exposed to various concentrations of VNP. Quantitative PCR and immunoassays were performed to determine the mRNA and protein levels of adiponectin and interleukin-6 (IL-6), respectively. The involved signaling pathway was identified by radioimmunoassay to detect the levels of intracellular cyclic GMP (cGMP), mimicking experiments using 8-brcGMP (a membrane-permeable cGMP analog). Also, blocking experiments were performed using HS-142-1, an antagonist of particulate guanylyl cyclase-coupled natriuretic peptide receptor (NPR), or KT-5823, the cGMP-dependent protein kinase (PKG) inhibitor. VNP markedly enhanced adiponectin mRNA expression, as well as protein secretion, however, suppressed IL-6 production in mature adipocytes. In addition, VNP significantly increased the intracellular levels of cGMP. The effects of VNP were mimicked by 8-br-cGMP, whereas inhibited by HS-142-1, or KT-5823. Taken together, VNP regulates adiponectin and IL-6 production in adipocytes via guanylyl cyclase-coupled NPR/cGMP/PKG pathway.

Does adiponectin benefit steatotic liver transplantation?

Strategies for improving the viability of steatotic donor livers could increase the number of organs suitable for transplantation. There is evidence that adiponectin, the most abundant adipose-specific adipokine, acts as an anti-obesity and anti-inflammatory hormone. Here we review the signaling pathways of adiponectin and the possible therapies based on adiponectin regulation that have been examined or applied clinically. Recent studies on the role of adiponectin in steatotic livers subjected to ischemia/reperfusion are discussed. The data suggest that further investigations are required to determine whether adiponectin is a potential therapeutic target in liver transplantation.