bluuebunny/crossref_metadata_2025_split huggingface dataset:
Activation of GPR81 Causes Endothelin‐A Receptor‐Dependent Cardiorenal Effects
Authors: Jones Natalie K , Wallenius Kristina , Stewart Kevin , Wiseman John W , Mullins John J , Bailey Matthew A 
Published: June 2021

G protein‐coupled receptor 81 (GPR81) is highly expressed in adipocytes and activation by the endogenous ligand lactate or by the specific agonist AZ’55381 inhibits lipolysis. The receptor is also found in non‐adipose tissue2 but the function here is not well understood; recent studies show that GPR81 activation increases blood pressure1.All animal work was performed in accordance with the UK Home Office Animals (Scientific Procedures) Act of 1986 after ethical review by The University of Edinburgh. Here, we used IV infusion of AZ’5538 in anaesthetised wildtype and GPR81 KO mice to assess the effect of GPR81 activation on blood pressure and renal haemodynamics in vivo. Blood pressure was recorded via a cannula inserted into the carotid artery while renal blood flow was assessed both by a Doppler ultrasound probe placed around the left renal artery or by pulse‐wave Doppler ultrasound in separate experiments. Endothelin‐1 (ET‐1) levels were assessed in plasma samples taken at baseline and post AZ’5538 or vehicle infusion by commercial ELISA.Data are mean±SD. AZ’5538 increased systolic blood pressure by 14.9±6.5mmHg, whereas the 5% mannitol vehicle had no significant effect (0.7±3.1mmHg, n=6). Renal blood flow was decreased compared to vehicle control in both Doppler flow probe and Doppler ultrasound studies (−0.33±0.23mL/min vs vehicle 0.04±0.02ml/min, P=0.027 and −185±25mm/s vs vehicle −0.4±20mm/s, P<0.01, respectively, n=4). The cardiorenal effects of AZ’5538 were absent in GPR81 null mice, confirming on‐target action. Plasma ET‐1 was increased in drug treated animals compared to vehicle (0.44±0.28pg/mL vs 0.12±0.28pg/mL respectively, n=8, P=0.04). Prior infusion of endothelin‐A receptor (ET‐A) inhibitor BQ‐123 prevented the AZ’5538 mediated blood pressure increase in anaesthetised C57 mice (n=4, P=0.04) where as BQ‐788, a specific endothelin‐B receptor antagonist, did not (n=5, P=0.18).These data suggest that GPR81 activation influences cardiorenal haemodynamics in an ET‐A receptor mediated manner by stimulating circulating and tissue levels of the potent vasoconstrictor ET‐1. The sensitivity of the renal circulation to GPR81 activation may become physiologically significant when lactate, the endogenous ligand of GPR81, concentration rises, as can occur in ischemic renal disease.Support or Funding InformationSupported by The British Heart Foundation (FS/15/63/32033) and AstraZeneca (Research Agreement 10028531)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
The Effect of Tempol on Systolic Blood Pressure in Salt‐loaded Hypertensive 129Sv Mice
Authors: Chacko Kevin M. , Liu Lauren P. , Schramm Whitney C. , Malik Zeeshan S. , Alli Abdel A. 
Published: June 2021

The underlying mechanisms of salt‐induced hypertension are not completely understood. The purpose of this study was to determine whether oxidative stress contributes to the increase in exosomal MARCKS and ENaC and the increase in blood pressure of 129Sv mice after salt loading. Adult 129Sv mice were salt loaded to induce hypertension and the antioxidant Tempol was infused by osmotic minipump. Blood pressure was measured by tail cuff before and after Tempol infusion. Metabolic cage studies were performed to obtain 24 hour urine collections for the isolation of urinary exosomes and measurement of electrolytes in the urine. Urinary exosomes and kidneys from these mice were processed for protein biochemistry. Western blot analysis showed MARCKS and ENaC proteins are increased in urinary exosomes isolated from salt‐loaded hypertensive 129Sv mice compared to exosomes isolated from urine of the same mice before salt loading. Urinary sodium increased while potassium in the urine decreased after salt loading the 129Sv mice. Tempol infusion ameliorated the salt‐induced hypertension and decreased MARCKS and ENaC proteins in urinary exosomes of salt‐loaded hypertensive 129Sv mice. Taken together, oxidative stress may play an important role in the salt‐induced hypertension and upregulation of MARCKS and ENaC proteins in the kidneys of these animals.Support or Funding InformationThis project was funded by the U.S. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases (Grant K01 DK099617; to A.A.A.) and the University of Florida College of Medicine.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
In vivo effects of renal Npt2a inhibition
Authors: Thomas Linto , Xue Jianxiang , Rieg Jessica Ann Dominguez , Rieg Timo 
Published: June 2021

Hyperphosphatemia is common in patients with chronic kidney disease and associated with increased mortality. Oral phosphate binders and dietary phosphate restriction are the current management protocols for patients with hyperphosphatemia; however, their effectiveness is insufficient. In the kidney, the sodium‐phosphate cotransporter Npt2a is responsible for bulk uptake of phosphate in the proximal tubule. Recently, an orally bioavailable selective Npt2a inhibitor (Npt2a‐I, PF‐06869206) has been described to reduce phosphate uptake in HEK cells transfected with mouse or rat Npt2a. So far, its physiological in vivo function has not been tested. Based on in vitro IC50 concentrations, we chose to study 30 mg/kg (oral gavage, 1% of body weight) in short‐term (3 hours) metabolic cage experiments in C57BL/6J mice. Compared to vehicle (n=14), bolus administration of Npt2a‐I (n=12) caused significantly higher (~4‐fold) urinary phosphate excretion (104±8 vs 27±6 μmol*min−1, P<0.05). Similarly, urinary phosphate/creatinine ratios were also significantly higher (32±2 vs 8±2 mmol*mmol−1, P<0.05). In addition, Npt2a‐I caused higher urinary excretion of calcium (9±1 vs 3±1 μmol*min−1, P<0.05), sodium (316±37 vs 113±24 μmol*min−1, P<0.05), and chloride (277±31 vs 91±24 μmol*min−1, P<0.05), as well as their respective creatinine ratios (Ca2+: 2.5±0.2 vs 0.8±0.1; Na+: 92±9 vs 31±6; Cl−: 81±8 vs 25±6 mmol*mmol−1; all P<0.05). In contrast, urinary flow rate, urinary potassium excretion, potassium/creatinine ratio, and urinary pH were not significantly different between vehicle and Npt2a‐I. In a different set of mice, we studied the effect of Npt2a‐I on plasma phosphate and calcium. Under baseline conditions, plasma phosphate and calcium levels were not significantly different between the vehicle and Npt2a‐I groups. Oral bolus administration of vehicle did not significantly change plasma phosphate (Δ 0.06±0.08 mmol/L, NS) or calcium (Δ −0.04±0.02 mmol/L, NS) 3 hours after application. In contrast, administration of Npt2a‐I caused a significant decrease in plasma phosphate (Δ −0.5±0.05 mmol/L, P<0.05) without affecting plasma calcium (Δ 0.01±0.03 mmol/L, NS). In summary, our study demonstrates for the first time that in vivo application of a novel Npt2a inhibitor efficiently increases urinary phosphate excretion leading to a decrease in plasma phosphate levels. Thus, inhibiting Npt2a might be a useful treatment strategy for hyperphosphatemia.Support or Funding InformationTR is supported by the National Institute of Diabetes and Digestive and Kidney Diseases (1R01DK110621). JX was supported by an American Heart Association Predoctoral Fellowship (18PRE33990236) and LT by a Postdoctoral Fellowship (19POST34400026).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Role of NHE3 and dietary phosphate in lithium pharmacokinetics
Authors: Valdez Alexandria , Thomas Linto , Xue Jianxiang , Rieg Jessica Ann Dominguez , Rieg Timo 
Published: June 2021

Lithium (Li+) is one of the mainstays for the treatment of bipolar disorder despite its side effects on the endocrine, neurological, and renal systems. Experimentally, Li+ has been used to determine proximal tubule (PT) reabsorption based on the assumption that Li+ and Na+ transport go in parallel in the PT. However, the exact mechanism by which Li+ is reabsorbed remains elusive. The majority of PT Na+ reabsorption is directly or indirectly mediated by the Na+‐H+ exchanger 3 (NHE3). In addition, Na+‐phosphate cotransporters (Npt2a/c) have been implicated in renal Li+ reabsorption. We hypothesized that either NHE3 and/or Npt2a/c are mediating Li+ reabsorption. We studied Li+ pharmacokinetics in: i) tubule‐specific NHE3 knockout mice (NHE3loxloxPax8Cre), and ii) mice challenged with low or high phosphate diets. Intravenous (LiCl 5 mmol/kg, 2 μl/g BW) or oral administration (5 mmol/kg, 1% of BW via oral gavage) of LiCl did not result in differences in Li+ bioavailability (~80% in all groups), half‐life or urinary Li+/creatinine ratios between control and NHE3loxloxPax8Cre mice. After one week of dietary phosphate challenges, Li+ bioavailability was ~30% lower on low vs high dietary phosphate (64±4 vs 93±3%, P<0.05), possibly the consequence of a smaller area under the curve after oral administration (21±1 vs 25±1 mmol × L−1 × h, P<0.05). This was associated with lower urinary Li+/creatinine ratios on low vs high dietary phosphate (15±2 vs 47±7 mmol/mmol, P<0.05). Our data indicate that renal NHE3 does not play a role in Li+ pharmacokinetics; however, dietary phosphate has an indirect effect on Li+ bioavailability and Li+ disposition.Support or Funding InformationTR is supported by the National Institute of Diabetes and Digestive and Kidney Diseases (1R01DK110621). JX was supported by an American Heart Association Predoctoral Fellowship (18PRE33990236) and LT by a Postdoctoral Fellowship (19POST34400026).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Uncoupling Protein 3 Deficiency Prevents Whitening of Brown Fat and Preserves Insulin Sensitivity in High‐Fat Fed Rats
Authors: Lomax Tyler M. , Ashraf Sadia , Wiseman Jessica M. , Edwards Kristin S. , Harmancey Romain 
Published: June 2021

Uncoupling protein 3 (UCP3), a mitochondrial anion carrier promoting fatty acid oxidation in myocytes, is down‐regulated in animal models with obesity, insulin resistance and type 2 diabetes. Although mutations in UCP3 have been linked to obesity in humans, their contribution to increased adiposity and insulin resistance is still unclear. The goal of this study was to investigate the effect of UCP3 loss on the development of high‐fat diet‐induced obesity. UCP3‐deficient rats were generated using CRISPR‐Cas9 genome editing, and male littermates were maintained on a high‐fat diet (HFD) for 14 weeks starting at 8 weeks of age. Compared with wild type control animals, UCP3‐deficient rats experienced a reduction in total body weight gain and body fat percentage. Perirenal fat depots were also lighter and overall contained smaller adipocytes. High‐fat feeding markedly induced whitening of subscapular brown fat depots in wild type rats, which was characterized at the subcellular level by an accumulation of large lipid droplets. Interestingly, whitening of brown fat was reduced in UCP3‐deficient rats. Preservation of brown fat structure in the UCP3 knockout rats was associated with a dramatic change in mitochondrial cristae organization. Although plasma triacylglycerol, free fatty acids, and total cholesterol levels were not different from that of wild type rats, UCP3 deficiency led to a reduction in circulating levels of tumor necrosis factor‐α, improved systemic insulin sensitivity, and improved glucose tolerance. In conclusion, loss of UCP3 unexpectedly reduces fat mass gain and preserves insulin sensitivity under high‐fat feeding in rats. We propose that the improvement of insulin sensitivity is due to decreased fat accumulation in adipose tissue and subsequent reduction of chronic inflammation driven by increased mitochondrial function in brown adipose tissue.Support or Funding InformationThis work was supported by NIH Grants R01HL136438, R00HL112952, P01HL051971, and P20GM104357This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Differential Transcription of CD95 in Abdominal and Lower‐Body Subcutaneous Fat Depot–Implications for Regional Differences in Adipose Tissue Function
Authors: Singh Prachi , Zhang Yuebo , Somers Virend K 
Published: June 2021

BackgroundAbdominal (ABD) and lower‐body (LB) fat depots exert opposing effects on cardiometabolic risk factors. However, molecular mechanisms underlying these differences are not completely understood. Studies suggest an inflammatory role of CD95 in obesity‐associated adipose tissue inflammation and dysfunction. Also, leptin deficiency is associated with increased CD95 expression.ObjectiveTo examine the expression of CD95 in the ABD and LB fat depots and to investigate leptin‐dependent CD95 regulation.MethodsTranscription of CD95 and other adipokines was determined in paired subcutaneous abdominal (ABD) and lower‐body (femoral, LB) fat samples obtained from 29 healthy individuals (10 females, age: 29.4 ± 7.6 years, BMI: 24 ± 4.1 kg/m2). The underlying mechanisms and down‐stream effects of altered CD95 expression were evaluated using differentiated human white preadipocytes (dHWP).ResultsReduced mRNA expression of CD95 was apparent in adipose tissue obtained from LB fat depot [ABD: 4.30 (13.91 – 0.06), LB: 2.49 (10.88 – 0.04), p = 0.01]. mRNA expression of MCP1 [ABD: 0.51 (1.35 – 0.34), LB: 0.51 (1.21 – 0.28), p = 0.51], CCL5 [ABD: 6.60 (43.45 – 1.40), LB: 4.44 (11.28 – 1.27), p = 0.20], TNFα [ABD: 1.10 (6.14 – 0.03), LB: 0.07 (5.84 – 0.03), p = 0.30], and leptin [ABD: 21.86 (31.33 – 14.6), LB: 27.23 (41.69 – 20.35), p = 0.08] was not different between the two fat depots. A positive relationship between CD95 mRNA and other inflammatory cytokines was evident in both ABD (MCP1: ρ = 0.79, p < 0.001; CCL5: ρ = 0.83, p < 0.001; TNFα: ρ = 0.87, p < 0.001) and LB fat depot (MCP1: ρ = 0.87, p < 0.001; CCL5: ρ = 0.78, p < 0.001; TNFα: ρ = 0.83, p < 0.001). Furthermore, leptin‐dependent decreases in CD95 mRNA (p = 0.04) and protein expression (p = 0.03) was seen in dHWP. Also, 24 hour pre‐treatment of dHWP with leptin protected cells from FasL (p = 0.03) induced apoptosis.ConclusionsCompared to ABD adipose tissue, LB fat has reduced transcription of CD95. Additionally, expression of CD95 mRNA was associated with increased expression of inflammatory cytokines in both ABD and LB subcutaneous fat. Moreover, we show that leptin may mediate decreases in CD95 expression thereby protecting adipose tissue from FasL mediated apoptosis. Our studies suggest that the decreased CD95 mRNA expression in LB fat depot may be related to higher localized leptin expression and possibly contribute to depot specific alterations in adipose tissue function and consequent cardiometabolic risk.Support or Funding InformationPrachi Singh is supported by AHA grant‐in‐Aid 17GRNT33660138.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Leptin Signaling Defects in Offspring of Dams Having Received Vertical Sleeve Gastrectomy
Authors: Deer Evangeline M. , Welch Bradley A. , Grayson Bernadette E. 
Published: June 2021

The global incidence of obesity continues to rapidly increase and is a public health concern. Obesity poses substantial risks for hypertension, diabetes mellitus, osteoarthritis, coronary artery disease and hyperlipidemia, collectively known as Metabolic Syndrome (MetS). A long‐term, successful weight loss treatment in morbidly obese individuals is vertical sleeve gastrectomy (VSG), which resects 80% of the stomach creating a tube linking the esophagus to the duodenum. Because most VSG recipients are women of childbearing age, it is important to understand the impact of the surgery on their offspring.Previously, we reported that the adult offspring of VSG dams had increased adiposity and were glucose intolerant in comparison to adult offspring of sham dams after animals were challenged with a high‐saturated fat diet. However, no mechanism for this was identified. Leptin is an adipocyte‐derived hormone that conveys the level of stored nutrition in the form of adiposity to the brain and periphery. Here we test the overall hypothesis that leptin signaling is dysregulated in VSG offspring, thus driving metabolic dysfunction. Female Long Evans rats were made obese on a 40% saturated fat diet for 4 weeks. They then received either Sham or VSG surgery and recovered on chow. Six weeks after surgery, they were mated and gave birth naturally. The offspring were weaned on postnatal day 21 (PND21) on to chow. Food intake studies began to be conducted starting at PND60. Chow was pulled at 4 h prior to lights out. Rats were given either intraperitoneal injections of saline or leptin (1mg/kg, PeproTech, Inc., Rocky Hill, NJ) just prior to lights off. Hoppers were returned and food measured at 30 min, 1, 2, 3, 4 and 24 h following injection. A crossover study was performed 1 week later. Leptin administration reduced food intake at all time points in Sham male and female offspring (p<0.05). However in VSG males and females, leptin did not reduce food intake at any time point measured. We fasted animals for 6 hours and then collected blood to measure leptin. No differences in leptin by surgery were measured, only by sex. We conclude that leptin signaling in VSG offspring PND60 is not functioning appropriately. Further work is being conducted to determine which arm of leptin signaling is dysregulated in VSG offspring (i.e. p/STAT, p/AKT, mTOR, SOCS3 and PTB1). This work will inform us of the long‐term impact of maternal bariatric surgery on the metabolic health of offspring.Support or Funding InformationResearch reported in this publication was supported by the National Institute of General Medical Sciences of the National Institutes of Health under Award Number P20GM104357.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
The Association between Parental Weight Status and Risk of Hypertension in Children Aged 6 to 12 Years: A Cross‐sectional Study in Shanghai, China
Authors: Lu Liping , Chen Cheng , Cai Wei , Wang Jialu , Jiang Ying , Tang Molian , He Ka , Wan Yanping 
Published: June 2021

BackgroundParents may play important roles in the regulation of children's weight status and consequently risk of childhood HTN. However, data relating parental dietary/lifestyle characteristics to risk of HTN in their children is sparse.ObjectiveUsing parental weight status as a marker of their dietary and lifestyle habits, we aimed to examine the association between parental weight status and risk of hypertension (HTN) in their children.MethodsA total of 1,949 children aged 6 to 12 years (1,012 girls) and their parents were enrolled. Information on demographics, anthropometrics, lifestyle, diet, and medical history were obtained from the participants and their parents through self‐administered questionnaires. Multivariable‐adjusted odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) of prevalent HTN in children in relation to parental weight status are presented.ResultsThe HTN prevalence in children was 8.4%, with no significant gender difference (9.0% in boys vs. 7.8% in girls, P=0.36). After adjusting for potential confounders, parental overweight was significantly associated with risk of HTN in children. Compared with children who had both parents being normal weight, the risk of childhood HTN was increased by 94% (OR=1.94; 95% CI: 1.08, 3.50) for children with only father being overweight and 109% (OR=2.09; 95% CI: 1.26, 3.46) for children with both parents being overweight. The observed association was attenuated after further adjustment for children's body mass index.ConclusionsFindings from this cross‐sectional study suggest that parental BMI levels were associated with higher prevalence of HTN in their children through the mediation of children's BMI. Because parental weight status is a marker of the dietary and lifestyle choices in a family, actions focusing on improving health awareness and changing unhealthy habits among parents may exert critical influence on the risk of childhood HTN.Support or Funding InformationThis work was partially supported by a grant from the NIH (R01ES021735).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Effect of early weaning on proliferation and differentiation of intestinal mucosa
Authors: da Costa Aline Vasques , Rattes Isadora Campos , Silva Kethleen Mesquita , Rigonati Cruz Alberto Mendoza , Gama Patricia 
Published: June 2021

Homeostasis of intestinal epithelial tissue is essential for the completion of digestion, absorption and barrier protection mediated by specialized epithelial cells. Growth and regeneration are controlled by stem cell niche located at the base of the crypts. The complete functional and morphological development of the intestine occurs during the weaning period, however, it is still unknown how this niche stem cells and the proliferative population behave in face of alterations in dietetic pattern. By considering that breastfeeding has important roles during the development of intestinal mucosa, we hypothesized that early weaning (EW) might induce changes in proliferation and differentiation processes. In order to determine the influence of EW in mucosal morphology and integrity, we studied the size of crypt–villus axis, cell proliferation, the distribution of goblet cells, and the expression of genes involved in intestinal functions and renewal. Wistar rats were separated into groups: suckling control (S) and early‐weaned (EW) at 15d (Ethical Committee 18/2015; 115/2017). Samples from middle jejunum were collected at 15, 18 and 60d for morphological analyses of cells stained with hematoxylin and eosin (HE); quantification of goblet cell after Periodic Acid‐Schiff (PAS) reaction; determination Ki‐67 proliferative index (PI), and RNA extraction for qPCR. We observed that the villus height was significantly decreased by EW at 18 d, showing an evident atrophy. However, at 60 d we did not detect differences between S and EW groups, suggesting a recovery of villus compartment during growth and ageing periods. The number of goblet cells in the villi was significantly reduced in EW group compared to S animals, without recovery at 60 days. In the crypt compartment, goblet cells were not altered by EW, increasing only as a function of villus growth. The PI (%) decreased in EW pups (18 d), and the effect was maintained in adults (60 d). The target genes for growth and functions were analyzed according to their immediate and late effect, and different responses were detected. Our preliminary findings suggest that EW affects cell proliferation, gene expression and the number of goblet cells immediately after interruption of suckling (18 d), but the effects are sustained to adulthood, indicating the priming of epithelial cells by EW.Support or Funding InformationThis study was financed in parts by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior Brazil (CAPES) – Finance Code 001; FAPESP grant 2018/07782‐8 and fellowship 2018/07409‐5.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.