bluuebunny/crossref_metadata_2025_split huggingface dataset:
Glp2r is required for postprandial glycemic control (1114.3)
Authors: Shi Xuemei , Wen Shixiang , Chacko Shaji , Chan Lawrence , Guan Xinfu 
Published: June 2021

Glucagon‐like peptide 2 (GLP‐2) is secreted from enteroendocrine L cells and proposed as a key promoter of intestinal metabolic reprogramming and tissue regeneration, contributing to improving glucose homeostasis and insulin sensitivity after RYGB. Through the gut‐brain‐liver axis, GLP‐2 plays crucial roles in the control of food intake and hepatic glucose production. We showed in Cell Metab (2013) that GLP‐2 receptor (Glp2r) in POMC neurons is required for GLP‐2 to promote glucose homeostasis at the postabsorptive status. However, little is known about the physiological relevance of GLP‐2 in the glycemic control at the postprandial status when GLP‐2 is physiologically secreted. In this study, we first developed an innovative stable isotopic tracer approach to quantify non‐steady postprandial glucose kinetics in mice, which were assessed by the appearance rate of ingested glucose (Ra,ingested) after intragastric feeding U‐13C6‐D‐glucose‐enriched elementary diet; and the appearance rate of endogenous glucose (Ra,endogenous) by iv infusion of 6,6‐2H2‐D‐glucose. We then generated mice with Glp2r deletion in the intestinal epithelium by crossing Glp2r‐floxed mice with villin‐Cre mice. Finally, we show that Glp2r global KO mice display glucose intolerance after an oral GTT and postprandial hyperglycemia after the elementary meal as a result of increased hepatic production of endogenous glucose (Ra,endogenous, attributed to the increased rate of gluconeogenesis) and decreased splanchnic sequestration of ingested glucose (Ra,ingested), pointing to a physiological role of GLP‐2 in postprandial glycemic control. Moreover, villin‐Glp2r KO mice display postprandial glucose intolerance, suggesting that the gut epithelium is a key site for GLP‐2 action to promote postprandial glycemic control. We conclude that Glp2r activation is required for postprandial glycemic control and GLP‐2 secretion augmentation may contribute to improving postprandial hyperglycemia in diabetes.Grant Funding Source: Supported by the USDA CRIS 6250‐51000‐055
H1‐antihistamines exacerbate high fat diet‐induced fatty liver disease in wild type but not in apolipoprotein E‐knockout mice (1116.10)
Authors: Vimala Raveendran Vineesh , Kassel Karen , Smith Donald , Cherian Rachel , Reed Gregory , Flynn Colleen , Luyendyk James , Dileepan Kottarappat 
Published: June 2021

Activation of histamine receptor 1 (H1R) reduces adiposity in mice, and chronic use of H1‐antihistamines (H1‐AH) increase weight gain in obese patients. Apolipoprotein E (ApoE) plays a major role in lipid transport. We examined the effects of chronic blockade of H1R by cetirizine or fexofenadine, two therapeutic H1‐AH, on fatty liver disease, adiposity and weight gain in wild‐type (WT) and ApoE‐knockout (ApoE‐/‐) mice. Eight week old male WT or ApoE‐/‐ mice were fed a high fat diet, and concurrently treated with equivalent therapeutic doses of either cetirizine or fexofenadine via drinking water for 3 months. H1‐HA treatments increased weight gain, visceral adiposity, liver weight and macrovesicular hepatosteatosis in WT mice, but not in ApoE‐/‐ mice. These changes were independent of food intake. Serum markers of liver injury tended to increase in H1‐HA‐treated WT mice in association with increased macrovesicular hepatosteatosis. Microvesicular hepatosteatosis and lobular inflammation were not affected by H1‐HA treatments in WT or ApoE‐/‐ mice. Increased hepatic steatosis was not associated with changes in the expression of pro‐lipogenic genes SREBP1c or FAS. H1‐HA treatments significantly reduced hepatic ApoE, but not ApoB100, gene expression, and reduced serum triglycerides and VLDL in WT mice. This effect was not seen in ApoE‐/‐ mice. The results suggest that H1‐HA exacerbate HFD‐induced obesity and hepatic steatosis via a mechanism requiring ApoE.Grant Funding Source: Supported by NIH R01‐HL070101 & 3R01‐HL070101‐04S1, J & E Carey Arthritis Fund & A E Smith Res Fund
Umbelliferone supplementation attenuates alcohol‐induced hepatic steatosis by regulating PPARα‐ and SREBP‐1c pathway in rats (1116.2)
Authors: Sim Mi‐Ok , Lee Hae‐In , Ham Ju Ri , Choi Ra Young , Kim Sung Jin , Seo Kwon‐Il , Kim Myung‐Joo , Lee Mi‐Kyung 
Published: June 2021

Umbelliferone (UF) is a 7‐hydroxycoumarin obtained from plants and edible fruits and roots, which has several biological activities including, antitumor, antioxidant and antiangiogenic activity. This study investigated the effects of UF on alcoholic fatty liver and its underlying mechanism. Rats were fed a Lieber‐DeCarli liquid diet with 36% of calories as alcohol with or without UF (0.05 g/L) for 8 weeks. Normal rats were received isocaloric carbohydrate liquid diet. UF significantly improved alcohol‐induced loss of body weight and hepatic lipid accumulation and droplets as well as dyslipidemia. UF significantly suppressed the lipogenic gene expression (SREBP‐1c, CIDEA, FASN and PPARγ) and stimulated the lipolytic gene expression (PPARα, Acsl1, CPT‐1, ACOX and Acca1a) compared to the alcohol control group, which could lead to inhibit fatty acid synthase activity and stimulate CPT and fatty acid β‐oxidation activities in the liver of chronic alcohol‐fed rats. These results indicated that UF attenuated alcoholic steatosis by down‐regulation of SREBP‐1c‐mediated lipogenesis and up‐regulating of PPARα‐medicated lipolysis. Therefore, UF may provide a promising natural therapeutic strategy against alcoholic fatty liver.Grant Funding Source: Supported by Suncheon Research Center for Natural Medicines
Role of JMJD3 and histone modifications in intermittent hypoxia‐induced neuroinflammation (1120.6)
Authors: Smith Stephanie , Watters Jyoti 
Published: June 2021

Microglial phenotypic plasticity enables them to sense and respond to a variety of stimuli. While much of this plasticity involves transcriptional gene regulation that is highly susceptible to epigenetic modulation, little is known about how post‐translational histone modifications regulate microglial activities. We have shown that intermittent hypoxia (IH), a hallmark of sleep apnea, induces microglial inflammation in vivo, but mechanisms underlying IH‐induced microglial activation are unknown. The Jumonji gene family of histone demethylases are hypoxia‐sensitive, and JMJD3 is known to regulate macrophage inflammatory processes, but nothing is known about its regulation of microglial activities, or its role in IH‐induced neuroinflammation. Thus, using in vivo and in vitro models we tested the hypothesis that JMJD3 is necessary for IH‐induced microglial inflammation. In vivo, JMJD3 mRNA is upregulated in microglia immunomagnetically isolated from the cortex and hippocampus of IH‐treated animals, with a time course that correlates with inflammatory gene induction. To test the requirement of JMJD3 in IH‐induced microglial gene expression, we exposed microglial cell cultures to IH in the presence and absence of the small molecule JMJD3 inhibitor GSK‐J4 (7.5μM). IH increased JMJD3 mRNA levels which correlated with a decrease in histone H3 lysine 27 (H3K27) trimethylation, the enzymatic target of JMJD3 activity. IH‐induced IL‐6, IL‐1β, iNOS, and COX‐2 pro‐inflammatory gene expression was blocked in the presence of GSK‐J4, suggesting a critical role of JMJD3 and H3K27 demethylation in IH‐induced inflammation. This is the first study to investigate a Jumonji demethylase in the context of IH, and the first to link IH‐induced microglial inflammation to JMJD3 activities.Grant Funding Source: Supported by NIH R01 HL111598 and the Graduate Women in Science Ruth Dickie Fellowship
Initial characterization of leptin receptor knockout Dahl salt‐sensitive rats (1121.2)
Authors: McPherson Kasi , White Tiffani , Johnson Ashley , Geurts Aron , Jacob Howard , Garrett Michael , Williams Jan 
Published: June 2021

Obesity‐induced metabolic syndrome (MetS) has grown at an alarming rate within the last decade and has been associated with the development of chronic kidney disease (CKD). In the current study, we created a 16 base pair frame‐shift deletion in exon 11 of the leptin receptor gene within the genetic background of the Dahl SS rat (SSLepr‐/‐ strain) using Zinc‐finger nucleases to study the effect of obesity on the progression of renal injury in SS rats. At 6 weeks of age, body weight was 45% higher in the SSLepr‐/‐ strain compared to SSWT rats and remained markedly elevated throughout the entire study (22 weeks of age). The SSLepr‐/‐ strain exhibited impaired glucose tolerance and increased plasma insulin levels as early as 6 weeks of age suggesting insulin resistance while SSWT rats did not. However, glucose levels remained in the normal range throughout the course of the study. At 22 weeks of age, the SSLepr‐/‐ strain developed severe systolic hypertension compared to the values observed in SSWT rats (242±17 vs. 158±6 mmHg, respectively). After 22 weeks of age, proteinuria increased to 618±36 mg/day in the SSLepr‐/‐ strain while it only increased to 136±28 mg/day in SSWT rats. The SSLepr‐/‐ strain exhibited more glomerular injury and renal fibrosis compared to SSWT rats. Overall, these data indicate that the SSLepr‐/‐ strain may be a useful model to study signaling pathways that play a role in CKD associated with MetS.Grant Funding Source: Supported by P20GM104357
Research community driven development to genetically modify rat models for heart, lung, blood and sleep disorders (1121.3)
Authors: Lazar Jozef , Dwinell Melinda , Geurts Aron , Mattson David , Jacob Howard 
Published: June 2021

Rats have a long history of yielding critical knowledge about the cardiovascular and pulmonary systems, including mechanisms of blood pressure regulation in health and disease and remain a major model system for discovery, validation, defining physiological mechanisms and testing of new compounds to improve human health. As noted in the National Heart, Lung and Blood Institute (NHLBI) Strategic Plan, there is a need for animal models to validate human variants. To address this, we will generate 200 gene modified rat strains in the next 5 years using the most economical gene editing technologies (TALEN, CRISPR/Cas 9 and a few others in development). This resource minimizes the prohibitive cost for individual laboratories to develop a single strain. Strain development is prioritized by our External Advisory Board, in consultation with NHLBI to maximum the utilization of the resources to benefit the NHLBI scientific community. Furthermore, the program will provide not only gene modified animals, but also cryopreservation, and in some cases phenotyping upon a request of investigator. Two competitive application deadlines per year are implemented and can be submitted to: mcwcustomrats@mcw.edu. Additional information is available at: http://rgd.mcw.edu/wg/gerrc. For genes not within the NHLBI portfolio or priority, we can offer economical model development with straight forward licensing and maximum degrees of freedom to work.Grant Funding Source: Supported by NIH NHLBI R24HL114474
Bestrophin‐3 is expressed in the mouse intestine (1122.1)
Authors: Eliasson Emilie , Golubinskaya Veronika , Nilsson Holger 
Published: June 2021

Bestrophins, named after their association with Best’s disease (vitelliform macular dystrophy) are transmembrane proteins that function as calcium‐activated chloride channels (CaCC's), but may also play a role in cell survival. Bestrophins exist in several isoforms. Bestrophin‐3 is a cyclic‐GMP‐regulated CaCC in vascular smooth muscle. Its role in the intestine has not been studied, but another isoform, bestrophin‐2, is present as a chloride or bicarbonate transporter in the goblet cells of the colon. We have here determined the expression of bestrophin‐3 in the intestine of C57BL/6 mice using immunohistochemistry and Western blotting.Bestrophin‐3 was detected in varying proportions in goblet cells all along the intestine, and also in glia‐like cells in the entire myenteric plexus, as well as in stromal cells mainly in the colon submucosa. Staining of cells in the myenteric plexus was also detected in P10 pups.Thus bestrophin‐3 is expressed in several specific locations along the intestine. Its function in these locales remains to be determined.
Acute tetrahydrobiopterin restores endothelial function in patients with COPD (1123.1)
Authors: Harris Ryan , Seigler Nichole , Halasan Karen , Livieratos Speros , Dillard Thomas , Bass Leon 
Published: June 2021

Chronic obstructive pulmonary disease (COPD), although a disease of the lungs, is accompanied by systemic oxidative stress and inflammation, both of which contribute to reductions in nitric oxide (NO) bioavailability. Tetrahydrobiopterin (BH4) is an essential cofactor for eNOS and subsequent NO bioavailability. This study sought to determine if acute ingestion of BH4 improves endothelial function in patients with COPD. 18 patients with COPD and 15 healthy controls participated in this study. The flow‐mediated dilation (FMD) test was performed at baseline in all subjects, and 3 hours following ingestion of either BH4 (5 mg/kg of Kuvan®) dissolved in 4oz of apple juice or placebo only in patients. No differences in sex or race were observed between groups. Age (56±2 vs. 57±2 yrs.), BMI (31.5±1.9 vs. 26.6±1.6 kg/m2), and MAP (93.9±2.8 vs. 88.0±2.7 mm Hg) were all similar (p>0.05) between patients and controls, respectively. FEV1 was significantly lower in patients (56±4 vs. 103±4 %predicted) compared to controls. At baseline, FMD was lower (p=0.046) in patients (4.9±0.5%) compared to controls (6.9±0.9%). Acute BH4 treatment significantly improved FMD (α3.4±0.6%; p<0.001) in patients; however, no change (α‐0.2±0.6%; p=0.703) in FMD was observed following placebo. Findings from this study demonstrate that a single dose of BH4 transiently restores endothelial function in patients with COPD to the values observed in controls. Supported by the American Heart Association (RAH).Grant Funding Source: Supported by AHA 10SDG305006 (RAH)
Inhibition of endoplasmic reticulum function in PVN by thapsigargin increases neuronal excitability and sympathetic nerve activity (1125.4)
Authors: Larson Robert , Gui Le , Chapp Andrew , Huber Michael , Zhu Jianhua , Cheng Zixi , Shan Zhiying , Chen Qing‐Hui 
Published: June 2021

Control of sympathetic outflow by paraventricular nucleus (PVN) is partially mediated through a monosynaptic axon projecting to the rostral ventrolateral medulla (PVN‐RVLM). Here we investigated the role of thapsigargin (TG), the endoplasmic reticulum (ER) Ca2+ ATPase inhibitor, in regulating the excitability of PVN‐RVLM neurons under brain slice preparation. In current‐clamp recordings, graded current injections evoked graded increases in spike frequency. Maximum discharge was evoked by +200 pA injections and averaged 22 ± 2 Hz (n=7) and was significantly greater (P < 0.05) in the presence of TG (0.5 µM) (31 ± 3 Hz, n=9). The effect of ER Ca2+ store depletion in regulating renal SNA (RSNA) and mean arterial pressure (MAP) was assessed by bilateral PVN microinjection of TG in anesthetized rats. PVN injection of TG (0.15, 0.3 0.75 and 1.5 nmol/100nl) increased RSNA and MAP in a dose‐dependent manner. Maximum increases in RSNA and MAP elicited by PVN TG (0.75 nmol/100nl; n=3) were 105 ± 31% and 18 ± 11 mmHg respectively. Pre‐treatment with CyPPA (5 nmol/100 nl), a small conductance, Ca2+ activated K (SK) channel activator (n=3), attenuated the PVN TG evoked sympathoexcitatory and pressor responses (7 ± 7% for RSNA and 4 ± 7 mmHg for MAP). PVN CyPPA did not significantly alter baseline RSNA and MAP. Our data indicate that inhibition of ER function with TG enhances in vitro excitability of PVN‐RVLM neurons and increases in vivo RSNA and MAP. The effect of TG on the excitability of PVN neurons and SNA through ER Ca2+ store depletion may involve reduced SK channel activity.Grant Funding Source: Supported by AHA10SDG2640130
Orexin A in the ventrolateral preoptic area increases feeding and spontaneous physical activity (1126.1)
Authors: Rezaimalek Almira , Teske Jennifer 
Published: June 2021

The brain regulates behaviors influencing energy balance such as arousal, feeding and spontaneous physical activity (SPA), which is all activity excluding formal exercise yet mechanisms are unclear. Orexin A (OXA), an endogenous neuropeptide produced in the lateral hypothalamus (LH), increases arousal, SPA and feeding. Orexin innervates the ventrolateral preoptic area (VLPO). Activation of the VLPO inhibits wakefulness and promotes sleep but whether OXA in VLPO modulates SPA and feeding is unclear. We hypothesized that OXA in VLPO would increase feeding and SPA. To test this, male Sprague‐Dawley rats were implanted with a cannula targeting VLPO. OXA (15, 31, 62, 125 pmol/0.5uL) or artificial cerebrospinal fluid (acsf) was injected in VLPO. SPA was measured for 4.5 hours post‐injection by infrared beam break. In a separate group of rats with VLPO cannula, the feeding response to 125 pmol/0.5uL or acsf was measured 2h post‐injection. OXA dose‐dependently increased distance traveled and speed but not vertical movement for 3h post‐injection. Distance traveled was positively correlated to speed and OXA significantly increased food intake. These data suggest that OXA from the LH acts in the VLPO to modulate behaviors such as feeding and SPA in addition to arousal. Identifying the neural mechanisms underlying feeding and SPA would have profound implications for treating obesity and insomnia.Grant Funding Source: Supported by Department of Veterans Affairs
Regulation of leptin receptor expressing neurons in the brainstem by TRPV1 (1126.11)
Authors: Zsombok Andrea , Jiang Yanyan , Anwar Imran , Rezai‐Zadeh Kavon , Muenzberg‐Gruening Heike 
Published: June 2021

The central nervous system plays a critical role in the regulation of feeding and whole body metabolism via controlling the autonomic output to the visceral organs. Activity of the parasympathetic neurons in the dorsal motor nucleus of the vagus (DMV) determines the vagal tone and thereby modulates the function of the organs. Due to the increased prevalence of eating and metabolic disorders, there is a constant search for new compounds, receptors or modulators to alter the activity of autonomic output and thus influence feeding or metabolism. TRPV1 (transient receptor potential vanilloid type 1) plays a pivotal role in synaptic regulation and here, we tested the hypothesis that TRPV1 regulates the activity of leptin receptor (LepRb) expressing DMV neurons. First, whole‐cell patch‐clamp recordings were performed to determine the effect of TRPV1 activation on LepRb neurons. Capsaicin, a TRPV1 agonist increased the frequency of mEPSCs in 50% of the LepRb neurons. Next, we identified stomach‐projecting LepRb neurons in the DMV using the transsynaptic retrograde viral tracer, PRV‐614. Activation of TRPV1 increased excitatory neurotransmission to stomach‐related LepRb neurons. These data demonstrate that TRPV1 is involved in the regulation of a subpopulation of LepRb DMV neurons via presynaptic mechanism and suggest a potential interaction between TRPV1 and leptin signaling in the DMV.Grant Funding Source: NIH P30GM103337, Tulane Pilot Project
Effects of weight‐reducing chronic vagal nerve stimulation on cardiovascular, autonomic, and respiratory functions (1126.12)
Authors: Stauss Harald , Morgan Donald , Rahmouni Kamal 
Published: June 2021

We assessed potential cardiovascular, autonomic, and respiratory adverse effects of chronic vagal nerve stimulation (VNS). In normotensive rats on standard diet, cervical vagal nerve stimulators were turned on 24 h after surgical implantation or remained off (sham) for the remainder of the study (up to 29 days). After one week of VNS, body weight was reduced by 27% while sham‐treated rats had restored pre‐surgical weight. Chronic VNS caused bradycardia that turned into tachycardia when the stimulators were temporarily turned off. VNS also resulted in hypertension that persisted when the stimulators were turned off. Compared to sham rats, high frequency heart rate variability (parasympathetic cardiac modulation) was markedly increased and low frequency systolic blood pressure variability (sympathetic modulation of vascular tone) was reduced when the stimulators were on, but not when they were off. In rats with chronic VNS a gasping‐like breathing pattern was occasionally noted. Furthermore, respiratory effort assessed by high frequency (respiration‐linked) spectral power of systolic blood pressure, was enhanced in rats with chronic VNS when the stimulators were temporarily turned off. In conclusion, weight‐reducing chronic VNS potentially causes reversible bradycardia, sustained hypertension that cannot be explained by elevated sympathetic modulation of vascular tone, and respiratory distress.Grant Funding Source: Supported by NIH (HL084207 KR), ADA (1‐11‐BS‐127, KR), UI Fraternal Order of Eagles Diabetes Center
Circadian variation in gene expression in the medulla of DOCA/salt hypertensive rats (1126.14)
Authors: Hernandez Morgan , Erdos Benedek , Hayward Linda 
Published: June 2021

Salt intake has been linked to changes in HSD2 expression in the medulla. Hypocretin (HCRT), neuropeptide FF(NPFF), and brain‐derived neurotrophic factor (BDNF) have also been implicated in feeding behavior. Since DOCA/salt treated rats primarily exhibit elevated salt intake during the night, the present study aimed to evaluate circadian related changes in gene expression in the medulla associated with DOCA/salt treatment. Adult 12 wk old Sprague Dawley (SD) and SD DOCA/salt rats (n=3‐5/group) were sacrificed at 9pm (previously identified as peak active period) or 11am (peak inactive period), and the medulla was removed for RT‐PCR analysis of gene expression. In the SDs there was a strong trend (HSD2, NPFF) or a significant (HCRT‐receptor (R1), HCRT‐R2, BDNF) increase in gene expression when transitioning from inactive to active period (100% vs 150‐869%, respectively). Gene expression in the DOCA/salt animals was significantly elevated during the inactive period when compared to SD controls (194‐558%) but DOCA/salt treated rats showed no change in gene expression between the active and inactive period. As a result, gene expression in DOCA/salt rats did not differ significantly from SDs during the active period. These data suggest DOCA/salt treatment may be involved in the interruption of normal circadian rhythms of gene expression, especially with regard to ingestive behavior and salt appetite.Grant Funding Source: Supported by UF‐CVM