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Adiponectin (APN) is an adipocyte-derived factor that exists at high concentrations in serum and has anti-inflammatory and systemic vascular-protective properties. In this study, we investigated the role of APN in pulmonary vascular homeostasis. We found that APN localizes to the luminal side of blood vessels in lung and acts in vitro to block TNF-[alpha]-induced E-selectin upregulation in pulmonary artery endothelial cells. Targeted deletion of the APN gene in mice leads to a vascular phenotype in lung characterized by E-selectin upregulation and age-dependent increases in perivascular inflammatory cell infiltration and pulmonary arterial pressures. Taken together, these findings demonstrate an important role for APN in lung vascular homeostasis and suggest that APN-deficient states may contribute to the pathogenesis of inflammatory pulmonary vascular disease and to the development of pulmonary hypertension. adipose tissue; inflammation; obesity

Adiponectin is believed to exert hepatoprotective effects and induces CXCL8, a chemokine that functions as a survival factor, in vascular cells. In the current study, it is demonstrated that adiponectin also induces CXCL8 expression in primary human hepatocytes but not in hepatocellular carcinoma cell lines. Knock down of the adiponectin receptor (AdipoR) 1 or AdipoR2 by small-interfering RNA indicates that AdipoR1 is involved in adiponectin-stimulated CXCL8 release. Adiponectin activates nuclear factor (NF)-[kappa]B in primary hepatocytes and pharmacological inhibition of NF-[kappa]B, the p38 mitogen-activated protein kinase, and extracellular signal-regulated kinase (ERK) 1/ERK2 reduces adiponectin-mediated CXCL8 secretion. Furthermore, adiponectin also activates STAT3 involved in interleukin (IL)-6 and leptin-mediated CXCL8 induction in primary hepatocytes. Inhibition of JAK2 by AG-490 does not abolish adiponectin-stimulated CXCL8, indicating that this kinase is not involved. Pretreatment of primary cells with 'STAT3 Inhibitor VI,' however, elevates hepatocytic CXCL8 secretion, demonstrating that STAT3 is a negative regulator of CXCL8 in these cells. In accordance with this assumption, IL-6, a well-characterized activator of STAT3, reduces hepatocytic CXCL8. Therefore, adiponectin-stimulated induction of CXCL8 seems to be tightly controlled in primary human hepatocytes, whereas neither NF-[kappa]B, STAT3, nor CXCL8 are influenced in hepatocytic cell lines. CXCL8 is a survival factor, and its upregulation by adiponectin may contribute to the hepatoprotective effects of this adipokine. adiponectin; hepatocyte; nuclear factor-[kappa]B; adiponectin receptor 1; STAT3; extracellular signal-regulated kinase; mitogen-activated protein kinase

Adiponectin (Ad) is linked to various disease states and mediates antidiabetic and anti-inflammatory effects. While it was originally thought that Ad expression was limited to adipocytes, we demonstrate here that Ad is expressed in mouse skeletal muscles and within differentiated L6 myotubes, as assessed by RT-PCR, Western blot, and immunohistochemical analyses. Serial muscle sections stained for fiber type, lipid content, and Ad revealed that muscle fibers with elevated intramyocellular Ad expression were consistently type IIA and IID fibers with detectably higher intramyocellular lipid (IMCL) content. To determine the effect of Ad on muscle phenotype and function, we used an Ad-null [knockout (KO)] mouse model. Body mass increased significantly in 24-wk-old KO mice [+5.5 [+ or -] 3% relative to wild-type mice (WT)], with no change in muscle mass observed. IMCL content was significantly increased (+75.1 [+ or -] 25%), whereas epididymal fat mass, although elevated, was not different in the KO mice compared with WT (+35.1 [+ or -] 23%; P = 0.16). Fiber-type composition was unaltered, although type IIB fiber area was increased in KO mice (+ 25.5 [+ or -] 6%). In situ muscle stimulation revealed lower peak tetanic forces in KO mice relative to WT (-47.5 [+ or -] 6%), with no change in low-frequency fatigue rates. These data demonstrate that the absence of Ad expression causes contractile dysfunction and phenotypical changes in skeletal muscle. Furthermore, we demonstrate that Ad is expressed in skeletal muscle and that its intramyocellular localization is associated with elevated IMCL, particularly in type IIA/D fibers. Type 2 diabetes; muscle lipids; intramyocellular lipid; obesity; muscle stimulation

In spite of association between high plasma adiponectin and high metabolic and cardiovascular (CV) risk, highest adiponectin increments retain CV and metabolic protective effects in advanced chronic kidney disease (CKD). Passive accumulation can favor CKD-associated hyperadiponectinemia but potential additional regulation by adipose tissue remains undefined. Oxidative stress (OS) is associated with metabolic and CV disease and with CKD [increasing from conservative treatment (CT) to maintenance hemodialysis (MHD)], and OS can reduce adiponectin expression in experimental models. OS (in the form of plasma thiobarbituric acid-reactive substances: TBARS), subcutaneous adipose adiponectin mRNA, and plasma adiponectin were studied in CKD patients (stages 4 and 5) on CT (n = 7) or MHD (n = 11). Compared with CT and controls (C: n = 6) MHD had highest TBARS and lowest adiponectin mRNA (P < 0.05) with lower adipose adiponectin protein (P < 0.05 vs. CT). MHD also had lower plasma adiponectin than CT, although both had higher adiponectin than C (P < 0.05). In renal transplant recipients (RT: CKD stage 3; n = 5) normal TBARS were, in turn, associated with normal adiponectin mRNA (P < 0.05 vs. MHD). In all CKD (n = 23), adiponectin mRNA was associated positively with adiponectin plasma concentration (P < 0.01). In all subjects (n = 29), adiponectin mRNA was related (P < 0.05) negatively with TBARS after adjusting for plasma C-reactive protein (CRP) or CRP and creatinine. Thus altered OS, adiponectin expression, and plasma concentration represent a novel cluster of metabolic and CV risk factors in MHD that are normalized in RT. The data suggest novel roles of 1) MHD-associated OS in modulating adiponectin expression and 2) adipose tissue in contributing to circulating adiponectin in advanced CKD. adipose tissue; hemodialysis doi:10.1152/ajpregu.00745.2006

This study tested the hypothesis that grain and intravenous dextrose challenges would alter plasma concentrations of active ghrelin, adiponectin, leptin, glucose, insulin, and cortisol in Standardbred mares. To deliver 0.5 g of glucose (dextrose solution for the intravenous test)/kg of BW, mares received intravenous dextrose (50% solution) or oral grain administration in 2 trials. In response to the oral grain challenge, plasma glucose and insulin concentrations increased (P < 0.001) by 56 and 802%, respectively. Plasma ghrelin concentration initially decreased (P < 0.001) by 40%, then subsequently increased (P < 0.05) from its nadir by 259%. Plasma leptin concentration decreased (P = 0.002) 17% compared with baseline. There was no change (P = 0.34) in plasma adiponectin concentration in response to oral grain challenge; however, plasma cortisol concentrations decreased (P < 0.001) by 24%. In response to the intravenous dextrose challenge, plasma glucose and insulin concentrations increased (P < 0.001) by 432 and 395%, respectively. Plasma active ghrelin concentration initially decreased (P < 0.001) by 56%, then subsequently increased (P < 0.001) from its nadir by 314%. Plasma leptin concentration also increased (P < 0.001) by 33% compared with baseline. There was no change (P = 0.18) in plasma adiponectin concentration throughout the dextrose challenge. Plasma cortisol concentration increased (P = 0.027) by 20%. Hence, oral grain and intravenous nutrient challenges have the ability to alter variables potentially related to energy metabolism in mates, with acute changes in glucose and insulin possibly modulating changes in ghrelin and leptin. Key words: adiponectin, ghrelin, horse, leptin

Hormones are important bioactive compounds in blood and tissue that vary in concentration in response to stress and certain disease states. Establishing the changes in physiological hormone concentrations over time can lead to more effective diagnoses and perhaps a better understanding of the evolution of stress and disease. To monitor concentration over time, the sampling must be rapid and noninvasive; specimens such as saliva that require little effort to collect are preferred. However, more sensitive assay techniques are needed when compared to blood analysis since free hormone concentration in saliva is only a small fraction of the concentration in circulating blood. In this work, magnetic field-induced structures of paramagnetic particles are used as a solid substrate to demonstrate improved detection limits for a separation-free assay of cortisol. Once formed, the structures are subjected to a rotating magnetic field and this leads to two important features. First is the ability to utilize frequency and phase filtering (lock-in amplification) for the signal generated from surface-bound labeled species. Second is the improved mass transport of the antigen to the surface of the rotating structures. These two unique capabilities result in a quantifiable signal at a relatively low target antigen concentration. This method has been demonstrated with the detection of fluorescein isothiocyanate-labeled cortisol (FITC-cortisol) at a concentration of 300 pM.

Adipokines are predominantly secretory protein hormones from adipose tissue but may also originate in placenta and other organs. Cross-sectionally, we monitored maternal plasma concentration of adiponectin, resistin, and leptin and their mRNA expression in abdominal subcutaneous adipose tissue and placenta from preeclamptic (PE; n = 15) and healthy pregnant (HP; n = 23) women undergoing caesarean section. The study groups were similar in age and BMI, whereas HOMA-IR tended to be higher in the PE group. In fasting plasma samples, the PE group had higher concentrations of adiponectin (18.3 [+ or -] 2.2 vs. 12.2 [+ or -] 1.1 [micro]g/ml, P = 0.011), resistin (5.68 [+ or -] 0.41 vs. 4.65 [+ or -] 0.32 ng/ml, P = 0.028), and leptin (34.4 [+ or -] 3.2 vs. 22.7 [+ or -] 2.1 ng/ml, P = 0.003) compared with the HP group. Adiponectin and leptin concentrations were still different between PE and HP after controlling for BMI and HOMA-IR, whereas resistin concentrations differed only after controlling for BMI but not HOMA-IR. We found similar mean mRNA levels of adiponectin, resistin, and leptin in abdominal subcutaneous adipose tissue in PE and HP women. When data were pooled from PE and HP women, resistin mRNA levels in adipose tissue also correlated with HOMA-IR (r = 0.470, P = 0.012) after controlling for BMI and pregnancy duration. Resistin mRNA levels in placenta were not significantly different between PE and HP, whereas leptin mRNA levels were higher in PE placenta compared with HP. Thus increased plasma concentrations of adiponectin and resistin in preeclampsia may not relate to altered expression levels in adipose tissue and placenta, whereas both plasma and placenta mRNA levels of leptin are increased in preeclampsia. adiponectin; resistin; leptin; pregnancy

The binding of cytokines to their receptors occurs over large surfaces on both the ligand and receptor, as exemplified by the crystal structure of growth hormone (GH) bound to its [...], Random phage display peptide libraries and affinity selective methods were used to isolate small peptides that bind to and activate the receptor for the cytokine erythropoietin (EPO). In a panel of in vitro biological assays, the peptides act as full agonists and they can also stimulate erythropoiesis in mice. These agonists are represented by a 14-amino acid disulfide-bonded, cyclic peptide with the minimum consensus sequence YXCXXGPXTWXCXP, where X represents positions allowing occupation by several amino acids. The amino acid sequences of these peptides are not found in the primary sequence of EPO. The signaling pathways activated by these peptides appear to be identical to those induced by the natural ligand. This discovery may form the basis for the design of small molecule mimetics of EPO.

A study has been conducted to show that transforming growth factor-beta (TGF-beta) mediates cell cycle arrest by inducing the transcription of p21, which is induced by DNA damage through p53. However, analysis of the transcription activity of mutant alleles of p53 showed that induction of p21 by TGF-beta was not mediated by wild-type p53. It also showed that TGF-beta and p53 were induced through different elements in the p21 promoter. These results indicate that TGF-beta can induce p21 through a p53-independent system.