bluuebunny/crossref_metadata_2025_split huggingface dataset:
Chemerin, A Novel Adipokine in the Regulation of Angiogenesis
Authors: Bozaoglu Kiymet , Curran Joanne E. , Stocker Claire J. , Zaibi Mohamed S. , Segal David , Konstantopoulos Nicky , Morrison Shona , Carless Melanie , Dyer Thomas D. , Cole Shelley A. , Goring Harald H. H. , Moses Eric K. , Walder Ken , Cawthorne Michael A. , Blangero John , Jowett Jeremy B. M. 
Published: January 2014

ABSTRACT

Context
Chemerin is a new adipokine associated with obesity and the metabolic syndrome. Gene expression levels of chemerin were elevated in the adipose depots of obese compared with lean animals and was markedly elevated during differentiation of fibroblasts into mature adipocytes.

Objective
To identify factors that affect the regulation and potential function of chemerin using a genetics approach.

Design, setting, patients and intervention
Plasma chemerin levels were measured in subjects from the San Antonio Family Heart Study (SAFHS), a large family-based genetic epidemiological study including 1354 Mexican American individuals. Individuals were randomly sampled without regard to phenotype or disease status.

Main Outcome Measures
A genome wide association analysis using 542,944 SNPs in a subset of 523 of the same subjects was undertaken. The effect of chemerin on angiogenesis was measured using human endothelial cells and interstitial cells in co-culture in a specially formulated medium.

Results
Serum chemerin levels were found to be highly heritable (h2 = 0.25; P = 1.4 x 10−9). The SNP showing strongest evidence of association (rs347344; P = 1.4 x 10−6) was located within the gene encoding EDIL3, which has a known role in angiogenesis. Functional angiogenesis assays in human endothelial cells confirmed that chemerin significantly mediated the formation of blood vessels to a similar extent as VEGF.

Conclusion
Here we demonstrate for the first time that plasma chemerin levels are significantly heritable and identified a novel role for chemerin as a stimulator of angiogenesis.
Periovulatory Expression of Hyaluronan and Proteoglycan Link Protein 1 (Hapln1) in the Rat Ovary: Hormonal Regulation and Potential Function
Authors: Liu Jing , Park Eun-Sil , Curry Thomas E. , Jo Misung 
Published: January 2014

ABSTRACT
Periovulatory follicular matrix plays an important role in cumulus-oocyte complex (COC) expansion, ovulation, and luteal formation. Hyaluronan and proteoglycan link protein 1 (HAPLN1), a component of follicular matrix, was shown to enhance COC expansion in vitro. However, the regulatory mechanisms of periovulatory expression of Hapln1 and its role in periovulatory granulosa cells have not been elucidated. We first determined the periovulatory expression pattern of Hapln1 using pregnant mare serum gonadotropin/human chorionic gonadotropin (hCG)-primed immature rat ovaries. Hapln1 expression was transiently induced both in intact ovaries and granulosa cells at 8 h and 12 h after hCG injection. This in vivo expression of Hapln1 was recapitulated by culturing preovulatory granulosa cells with hCG. The stimulatory effect of hCG was blocked by inhibition of protein kinase A, phosphatidylinositol dependent kinase, p38 MAPK, epidermal growth factor signaling, and prostaglandin synthesis, revealing key mediators involved in LH-induced Hapln1 expression. In addition, knockdown of Runx1 and Runx2 expression by small interfering RNA or inhibition of RUNX activities by dominant-negative RUNX decreased hCG or agonist-induced Hapln1 expression. Chromatin immunoprecipitation assays verified the in vivo binding of RUNX1 and RUNX2 to the Hapln1 promoter in periovulatory granulosa cells. Luciferase reporter assays revealed that mutation of the RUNX binding sites completely obliterated the agonist-induced activity of the Hapln1 promoter. These data conclusively identified RUNX proteins as the crucial transcription regulators for LH-induced Hapln1 expression. Functionally, treatment with HAPLN1 increased the viability of cultured granulosa cells and decreased the number of the cells undergoing apoptosis, whereas knockdown of Hapln1 expression decreased granulosa cells viability. This novel finding indicates that HAPLN1 may promote periovulatory granulosa cell survival, which would facilitate their differentiation into luteal cells.
Cevoglitazar, a Novel Peroxisome Proliferator-Activated Receptor-α/γ Dual Agonist, Potently Reduces Food Intake and Body Weight in Obese Mice and Cynomolgus Monkeys
Authors: Chen Hong , Dardik Beatriz , Qiu Ling , Ren Xianglin , Caplan Shari L. , Burkey Bryan , Boettcher Brian R. , Gromada Jesper 
Published: January 2014

ABSTRACT
Cevoglitazar is a dual agonist for the peroxisome proliferator-activated receptor (PPAR)-α and -γ subtypes. Dual activation of PPARα and -γ is a therapeutic approach in development for the treatment of type 2 diabetes mellitus and diabetic dyslipidemia. In this report, we show that, in addition to improving insulin sensitivity and lipid metabolism like other dual PPAR agonists, cevoglitazar also elicits beneficial effects on energy homeostasis in two animal models of obesity. In leptin-deficient ob/ob mice, administration of cevoglitazar at 0.5, 1, or 2 mg/kg for 18 d led to acute and sustained, dose-dependent reduction of food intake and body weight. Furthermore, plasma levels of glucose and insulin were normalized after 7 d of cevoglitazar treatment at 0.5 mg/kg. Plasma levels of free fatty acids and triglycerides were dose-dependently reduced. In obese and insulin-resistant cynomolgus monkeys, treatment with cevoglitazar at 50 and 500 μg/kg for 4 wk lowered food intake and body weight in a dose-dependent manner. In these animals, cevoglitazar also reduced fasting plasma insulin and, at the highest dose, reduced hemoglobin A1c levels by 0.4%. These preclinical results demonstrate that cevoglitazar holds promise for the treatment of diabetes and obesity-related disorders because of its unique beneficial effect on energy balance in addition to improving glycemic and metabolic control.
Minireview: A Skeleton in Serotonin’s Closet?
Authors: Kawai Masanobu , Rosen Clifford J. 
Published: January 2014

Abstract
The serotonin molecule plays a multifunctional role in mammalian homeostasis serving as a neurotransmitter in the central nervous system, a gut-derived mediator of peristalsis, and a circulating hormone that regulates appetite, cardiovascular function, and hemostasis. Recent evidence from the clinic and the bench highlight an unexpected target for serotonin action, the skeleton. Clinically, two classes of drugs, the second generation antipsychotic drugs (SGAs) and selective serotonin reuptake inhibitors (SSRIs), which modulate central and peripheral serotonin signaling, have been shown to alter bone remodeling although the mechanism is not clear. In contrast, genetically engineered mouse models have demonstrated a bimodal control system whereby gut-derived serotonin under the control of the Wnt/Lrp/β-catenin system acts systemically to suppress bone formation, whereas CNS serotonin activated by leptin modulates sympathetic outflow to the skeleton. In this brief review, we will summarize recent findings linking serotonin to the skeleton and discuss future directions for this new but challenging aspect of this multidimensional molecule.
Inflammation and Obesity Pathogenesis: The Hypothalamus Heats Up
Authors: Thaler Joshua P. , Schwartz Michael W. 
Published: January 2014

Abstract
Obesity induced by high-fat (HF) feeding is associated with low-grade inflammation in peripheral tissues that predisposes to insulin resistance. Recent evidence suggests the occurrence of a similar process in the hypothalamus, which favors weight gain through impairment of leptin and insulin signaling. In addition to its implications for obesity pathogenesis, this hypothesis suggests that centrally targeted antiinflammatory therapies may prove effective in prevention and treatment of this disorder. This article highlights molecular and cellular mechanisms by which hypothalamic inflammation predisposes to diet-induced obesity.
GH Response to Oral Glucose Tolerance Test: A Comparison between Patients with Acromegaly and Other Pituitary Disorders
Authors: Verrua E. , Filopanti M. , Ronchi C. L. , Olgiati L. , Ferrante E. , Giavoli C. , Sala E. , Mantovani G. , Arosio M. , Beck-Peccoz P. , Lania A. G. , Spada A. 
Published: January 2014

Context
The cutoff value of nadir GH after an oral glucose tolerance test (OGTT) used to define disease remission in acromegaly is higher than that observed in healthy subjects. However, it is uncertain whether the impaired GH inhibition might be related to subtle abnormalities of GH secretion or to functional and/or anatomical hypothalamic-pituitary disconnection due to tumor per se or treatments.

Objective
The objective of the study was to evaluate the impact of pituitary disorders other than acromegaly on GH response to OGTT.

Design, Subjects, and Methods
Thirty-three patients (24 females and nine males, aged 50.1 ± 12.3 yr, 13 operated and two irradiated) with various hypothalamic-pituitary disorders (HPDs), 45 healthy subjects (controls), and 42 cured acromegalic patients matched for sex, age. and body mass index were investigated. All subjects were studied for IGF-I levels and GH levels before and during the OGTT.

Results
In HPD patients mean postglucose nadir GH levels were 0.11 ± 0.08 μg/liter without any difference between patients treated with neurosurgery and/or radiotherapy and untreated and between patients with and without pituitary stalk alterations and/or hyperprolactinemia. Mean nadir GH values were similar in HPD patients and controls (0.11 ± 0.08 vs. 0.08 ± 0.08 μg/liter, P = 0.23) and lower than those found in cured acromegalic patients (0.18 ± 0.13 μg/liter, P = 0.02), although there was an overlapping in about half of patients.

Conclusions
Hypothalamic control of glucose-mediated GH suppression is not perturbed in patients with HPD. These data indicate that defective GH suppression to glucose that is found in acromegaly is unlikely to reflect a lack of integrity of hypothalamic function.
Leptin-Independent Programming of Adult Body Weight and Adiposity in Mice
Authors: Cottrell Elizabeth C. , Martin-Gronert Malgorzata S. , Fernandez-Twinn Denise S. , Luan Jian'an , Berends Lindsey M. , Ozanne Susan E. 
Published: January 2014

Abstract
Low birth weight and rapid postnatal weight gain are independent and additive risk factors for the subsequent development of metabolic disease. Despite an abundance of evidence for these associations, mechanistic data are lacking. The hormone leptin has received significant interest as a potential programming factor, because differences in the profile of leptin in early life have been associated with altered susceptibility to obesity. Whether leptin alone is a critical factor for programming obesity has, until now, remained unclear. Using the leptin-deficient ob/ob mouse, we show that low birth weight followed by rapid catch-up growth during lactation (recuperated offspring) leads to a persistent increase in body weight in adult life, both in wild-type and ob/ob animals. Furthermore, recuperated offspring are hyperphagic and epididymal fat pad weights are significantly increased, reflecting greater adiposity. These results show definitively that factors other than leptin are crucial in the programming of energy homeostasis in this model and are powerful enough to alter adiposity in a genetically obese strain.
Effects of Gestation on Enzymes Controlling Aldosterone Synthesis in the Rat Adrenal*
Authors: Brochu Michèle , Lehoux Jean-Guy , Picard Serge 
Published: January 2014

AbstractIn the present study, the effects of gestation on various enzymes implicated in corticosteroid synthesis were evaluated in adrenal zona glomerulosa and zona fasciculata-reticularis of the Sprague-Dawley rat. The activity and expression of cholesterol side-chain cleavage cytochrome P450, 11β-hydroxylase cytochrome P450, and aldosterone synthase cytochrome P450 (P450aldo) were analyzed. Plasma aldosterone levels were increased significantly at 22 days gestation (n = 10) and fell below the nonpregnant levels at 18–36 h postpartum (n = 11). The activity and expression of 11β-hydroxylase cytochrome P450 and cholesterol side-chain cleavage cytochrome P450 were not modified by gestation. P450aldo activity increased at 14 days gestation (n= 4) and returned to the prepregnancy level at 2 weeks postpartum (n = 5). As shown by Northern blot analysis (n = 3), P450aldo messenger RNA increased significantly at 22 days gestation and decreased 18–36 h postpartum. We clearly demonstrated that elevated plasma aldosterone levels during pregnancy are associated with augmented activity and messenger RNA levels of P450aldo in the zona glomerulosa.
Corticotropin-Releasing Hormone Induces Skin Mast Cell Degranulation and Increased Vascular Permeability, A Possible Explanation for Its Proinflammatory Effects*
Authors: Theoharides Theoharis C. , K. Singh Leena , Boucher William , Pang Xinzhu , Letourneau Richard , Webster Elizabeth , Chrousos George 
Published: January 2014

AbstractMast cells are involved in atopic disorders, often exacerbated by stress, and are located perivascularly close to sympathetic and sensory nerve endings. Mast cells are activated by electrical nerve stimulation and millimolar concentrations of neuropeptides, such as substance P (SP). Moreover, acute psychological stress induces CRH-dependent mast cell degranulation. Intradermal administration of rat/human CRH (0.1–10 μm) in the rat induced mast cell degranulation and increased capillary permeability in a dose-dependent fashion. The effect of CRH on Evans blue extravasation was stronger than equimolar concentrations of the mast cell secretagogue compound 48/80 or SP. The free acid analog of CRH, which does not interact with its receptors (CRHR), had no biological activity. Moreover, systemic administration of antalarmin, a nonpeptide CRHR1 antagonist, prevented vascular permeability only by CRH and not by compound 48/80 or SP. CRHR1 was also identified in cultured leukemic human mast cells using RT-PCR. The stimulatory effect of CRH, like that of compound 48/80 on skin vasodilation, could not be elicited in the mast cell deficient W/Wv mice but was present in their +/+ controls, as well as in C57BL/6J mice; histamine could still induce vasodilation in the W/Wv mice. Treatment of rats neonatally with capsaicin had no effect on either Evans blue extravasation or mast cell degranulation, indicating that the effect of exogenous CRH in the skin was not secondary to or dependent on the release of neuropeptides from sensory nerve endings. The effect of CRH on Evans blue extravasation and mast cell degranulation was inhibited by the mast cell stabilizer disodium cromoglycate (cromolyn), but not by the antisecretory molecule somatostatin. To investigate which vasodilatory molecules might be involved in the increase in vascular permeability, the CRH injection site was pretreated with the H1-receptor antagonist diphenhydramine, which largely inhibited the CRH effect, suggesting that histamine was involved in the CRH-induced vasodilation. The possibility that nitric oxide might also be involved was tested using pretreatment with a nitric oxide synthase inhibitor that, however, increased the effect of CRH. These findings indicate that CRH activates skin mast cells at least via a CRHR1-dependent mechanism leading to vasodilation and increased vascular permeability. The present results have implications for the pathophysiology and possible therapy of skin disorders, such as atopic dermatitis, eczema, psoriasis, and urticaria, which are exacerbated or precipitated by stress.
Isolation, Primary Structure, and Effects onα -Melanocyte-Stimulating Hormone Release of Frog Neurotensin**This work was supported by the NSF, INSERM, and the Conseil Régional de Haute-Normandie.
Authors: Desrues Laurence , Tonon Marie-Christine , Leprince Jerome , Vaudry Hubert , Conlon J. Michael 
Published: January 2014

AbstractNeurotensin (NT) was isolated in pure form from the small intestine of the European green frog, Rana ridibunda, and its primary structure was established as pGlu-Ala-His-Ile-Ser-Lys-Ala-Arg-Arg-Pro-Tyr-Ile-Leu. This sequence contains five amino acid substitutions (Leu2→Ala, Tyr3→His, Glu4→Ile, Asn5→Ser, and Pro7→Ala) compared with human NT. A peptide with identical chromatographic properties was identified in an extract of frog brain. Synthetic frog NT produced a concentration-dependent increase in αMSH release from perifused frog pars intermedia cells, with an ED50 of 5 × 10−9m. A maximum response (276.3 ± 45.5% above basal release) was produced by a 10−8-m concentration. Repeated administration of NT to melanotrope cells revealed the occurrence of a rapid and pronounced desensitization mechanism. The data are consistent with a possible role for the peptide as a hypophysiotropic factor in amphibians.
Effects of CP-336,156, a New, Nonsteroidal Estrogen Agonist/Antagonist, on Bone, Serum Cholesterol, Uterus, and Body Composition in Rat Models
Authors: Ke Hua Zhu , Paralkar Vishwas M. , Grasser William A. , Crawford D. Todd , Qi Hong , Simmons Hollis A. , Pirie Christine M. , Chidsey-Frink Kristin L. , Owen Thomas A. , Smock Steven L. , Chen Hong Ka , Jee Webster S. S. , Cameron Kimberly O. , Rosati Robert L. , Brown Thomas A. , Dasilva-Jardine Paul , Thompson David D. 
Published: January 2014

AbstractWe have discovered a new, nonsteroidal, potent estrogen agonist/antagonist, CP-336,156. CP-336,156 binds selectively and with high affinity to the human estrogen receptor-α with a half-inhibition concentration of 1.5 nm, which is similar to that seen with estradiol (4.8 nm). When given orally to immature (3-week-old) female Sprague-Dawley rats for 3 days at doses of 0.1, 1.0, 10, or 100 μg/kg·day, unlike 17α-ethynyl estradiol, CP-336,156 had no effect on uterine wet or dry weight. Similarly, no uterine hypertrophy was observed in aged (17-month-old) female rats treated (po) with CP-336,156 at 10 or 100 μg/kg·day for 28 days. We also found that CP-336,156 decreased total serum cholesterol and fat body mass and had no effect on lean body mass in these aged female rats. In 5-month-old ovariectomized (OVX) Sprague-Dawley female rats, CP-336,156 completely prevented OVX-induced increases in body weight gain, total serum cholesterol, and serum osteocalcin at doses between 10 and 1000 μg/kg·day after 4 weeks. At these doses, CP-336,156 completely prevented OVX-induced bone loss and inhibited the increased bone turnover associated with estrogen deficiency in lumbar vertebrae, proximal tibiae, and distal femora. Similar to estrogen, CP-336,156 induced apoptosis and p53 expression with a concomitant decrease in the number of tartrate-resistant acid phosphatase-positive multinuclear cells in rat bone marrow cell cultures in vitro, suggesting that the induction of apoptosis may be a mechanism for the estrogenic activities of CP-336,156 in bone. In summary, CP-336,156 is a new, orally active, nonsteroidal, potent estrogen agonist/antagonist that has similar effects in bone as estradiol but without the uterine-stimulating effects associated with estradiol in rats.
Phosphate Transport in Pig Proximal Small Intestines during Postnatal Development: Lack of Modulation by Calcitriol*
Authors: Schröder Bernd , Hattenhauer Olaf , Breves Gerhard 
Published: January 2014

AbstractThe role of calcitriol in the intestinal absorption of inorganic phosphate (Pi) during postnatal development was studied in newborn [&lt;1 week postpartum (pp)], suckling (3–4 weeks pp), and weaned (&gt;6 weeks pp) control piglets (con) and piglets suffering from inherited calcitriol deficiency (def). In addition, a number of def piglets were treated with vitamin D3 (def-D3).Regardless of age, plasma calcitriol concentrations in def piglets were unphysiologically low (16–21 pg/ml) and differed significantly from those in respective con animals (60–69 pg/ml) and vitamin D3-treated def piglets (50–56 pg/ml). However, newborn and suckling def piglets had normal Ca (∼3.0 mmol/liter) and Pi (∼2.8 mmol/liter) plasma levels. Def piglets became hypocalcemic (1.9 mmol/liter) and hypophosphatemic (1.9 mmol/liter) between 4–6 weeks pp. Treatment with vitamin D3 significantly increased plasma Ca (3.2 mmol/liter) and Pi (2.7 mmol/liter) levels in weaned def animals.Regardless of calcitriol status, net Pi flux rates (active Pi absorption, as determined with the in vitro Ussing-chamber technique) from the upper small intestines was maximal at birth [170–224 nmol/(cm2·h)] and decreased by approximately 80% during the first week of life before remaining constant [30–50 nmol/(cm2·h)] during the following development. In weaned def piglets, net Pi flux rates were significantly lower by about 80% compared with those in con animals. Treatment of def piglets with vitamin D3 had no effect in newborn and suckling animals but reconstituted net Pi flux rates to normal values at weaning age. Age-dependent and calcitriol-mediated changes in net Pi flux rates were paralleled by respective maximum velocity values of Na+-dependent Pi uptake across the brush border membrane of the enterocytes (newborn piglets, 1.9–2.2 nmol/(mg protein·10 sec); suckling piglets, 0.4–0.6 nmol/(mg protein·10 sec); weaned piglets, 0.7, 0.3, and 0.7 nmol/(mg protein·10 sec) in con, def, and def-D3 animals, respectively). These findings suggest that the apical Pi uptake represents the major rate-limiting step of the overall transepithelial Pi transport. At weaning, Na+/Pi transport across the intestinal brush-border membrane is clearly stimulated by calcitriol, but no significant effects of age or calcitriol on the Km values (0.5–0.7 mmol/liter) were observed.In conclusion, our findings reveal calcitriol-independent mechanisms for active intestinal Pi absorption during the neonatal and suckling periods. The onset of the classical calcitriol-dependent mechanism for active intestinal Pi absorption does not occur until weaning.
Inhibition of Adenylyl Cyclase by Caveolin Peptides*
Authors: Toya Yoshiyuki , Schwencke Carsten , Couet Jacques , Lisanti Michael P. , Ishikawa Yoshihiro 
Published: January 2014

AbstractCaveolae and their principal component caveolin have been implicated in playing a major role in G protein-mediated transmembrane signaling. We examined whether caveolin interacts with adenylyl cyclase, an effector of G protein signaling, using a 20-mer peptide derived from the N-terminus scaffolding domain of caveolin-1. When tissue adenylyl cyclases were examined, cardiac adenylyl cyclase was inhibited more potently than other tissue adenylyl cyclases. The caveolin-1 peptide inhibited type V, as well as type III adenylyl cyclase, overexpressed in insect cells, whereas the same peptide had no effect on type II. The caveolin-3 scaffolding domain peptide similarly inhibited type V adenylyl cyclase. In contrast, peptides derived from the caveolin-2 scaffolding domain and a caveolin-1 nonscaffolding domain had no effect. Kinetic studies showed that the caveolin-1 peptide decreased the maximal rate (Vmax) value of type V without changing the Michaelis constant (Km) value for the substrate ATP. Studies with various truncations and point mutations of this peptide revealed that a minimum of 16 amino acid residues and intact aromatic residues are important for the inhibitory effect. The potency of inhibition was greater when adenylyl cyclase was in stimulated condition vs. basal condition. Thus, caveolin may be another cellular component that regulates adenylyl cyclase catalytic activity. Our results also suggest that the caveolin peptide may be used as an isoform-selective inhibitor of adenylyl cyclase.