bluuebunny/crossref_metadata_2025_split huggingface dataset:
Astrocyte Specific Insulin Receptor Deletion Contributes to Reproductive and Metabolic Dysregulation in Mice
Authors: Manaserh Iyad H. , Ravi Samyuktha , Hill Jennifer W. 
Published: June 2021

Insulin resistance and obesity are associated with infertility and reduced GnRH release. It has been previously shown that male and female mice lacking insulin signaling in all cell types of the brain during development exhibit subfertility and develop diet‐sensitive obesity, mild insulin resistance and elevated insulin and leptin plasma levels. To determine whether astrocyte insulin sensing plays an important role in the regulation of fertility, we generated mice lacking insulin receptors in astrocytes (GLIRKO mice). GLIRKO males and females showed a delay in balanopreputial separation or vaginal opening and first estrous, respectively. GLIRKO female mice also exhibited longer estrus cycle lengths and irregular estrous cyclicity. In addition, these mice exhibited decrease in pregnancy rate and litter size, and thus decreased fertility. Histological examination of testes and ovaries showed impaired spermatogenesis and ovarian follicle maturation. GLIRKO mice also show hypothalamic hypogonadism, but normal sexual behavior, which confirms that the observed subfertility phenotype is due to HPG axis dysregulation. GLIRKO male mice displayed higher body weight and growth, and significant differences in body composition at 7 months of age. These mice also showed insulin resistance at 2 months and both insulin and glucose intolerance at 7 months of age. Histological analysis showed altered liver morphology with higher fat droplets. GLIRKO mice displayed significant decrease in energy expenditure, and a striking decrease in body temperature during fed state and overnight fasting conditions. However, when fasted mice were exposed to 4C, they were able to mount a robust thermogenic response and rapidly increase body temperature. These observations support the idea that astrocytic population that integrate information about energy stores to regulate body temperature is different from those required to respond to a cold challenge. Overall, our findings suggest that impaired insulin sensing in astrocytes delays the initiation of puberty and affects adult reproductive function. They also suggest that that astrocytic insulin signaling regulate body weight, systematic glucose metabolism and regulate thermogenic responses to nutritional and cold challengesSupport or Funding InformationThis project is supported by NIH R01 HD081792 grant to Dr. Jennifer W. HillThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Non‐invasive, Repeated Measurement of Estrogen Levels within Subjects in Prairie Voles
Authors: Francis Amie , Curtis J. Thomas 
Published: June 2021

Prairie voles are a good model for the studying the formation of social bonds; in particular, the formation of monogamous pair bonds. Previous studies in our lab have shown that successful pair bond formation hinges on pregnancy onset within a short time after mating. Female prairie voles only enter estrous when exposed to a potential mate. A surge in estrogen levels induces behavioral estrous and progressive increases in estrogen are seen throughout the course of pregnancy. Measurements of estrogen are generally taken from blood plasma, but collection methods are highly invasive or require the termination of subjects. To better measure estrogen levels in female prairie voles over a time course, a non‐invasive means of collecting samples is needed.We measured estrogen levels in fecal samples collected from female prairie voles over the course of pairing, mating, and pregnancy. Estrogen was extracted from fecal pellets using an organic solvent and ELISAs were run to measure changes in 17b‐estradiol concentrations. Animals that became pregnant showed progressively increasing levels of fecal estrogen over the course of mating and pregnancy, while animals that did not achieve pregnancy showed distinctly less fecal estrogen over the same time course. Our results suggest that measurement of fecal estrogen provides an alternative to more invasive means of measuring changes in sex hormones across time within subjects.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Calorie Restriction In The Preeclamptic‐like BPH/5 Mouse Reduces Adipose Tissue Gene Expression of Preeclampsia‐Related Inflammatory Genes
Authors: Reijnders Dorien , Olsson Kelsey , Redman Leanne , Sones Jennifer 
Published: June 2021

BackgroundPreeclampsia (PE) is a hypertensive disease of pregnancy that is a leading cause of fetal and maternal morbidity/mortality. Obesity is a risk factor for developing PE, however, the underlying mechanism is unknown. Using the PE‐like BPH/5 mouse model, we previously demonstrated that cyclooxygenase (Cox)‐2 and interleukin (IL)‐15 dysregulation at the maternal‐fetal interface plays a causal role in poor maternal and fetal outcomes. Because BPH/5 mice are obese, we hypothesized that the maternal reproductive white adipose tissue (rWAT) is a source of these pro‐inflammatory molecules, and that reducing rWAT mass by calorie restriction (CR) would decrease the inflammatory uterine milieu in this model.MethodsUsing qRT‐PCR, we measured mRNA expression of Ptgs2 (the gene encoding Cox2), IL‐15 and 18S (housekeeper gene) within the rWAT and implantation sites of non pregnant and pregnant (embryonic day (e) 7.5) ad libitum fed BPH/5 and C57Bl/6J control mice. In addition, we determined Ptgs2 and IL‐15 mRNA expression in BPH/5 rWAT and implantation sites after 7 days CR (pair‐feeding with pregnant C57Bl/6J mice) beginning the day of copulation (e0.5).ResultsPtgs2 expression in non‐pregnant rWAT was comparable between BPH/5 and C57Bl/6J. However, there was a 2‐fold increase in Ptgs2 expression at e7.5 in BPH/5 rWAT versus C57Bl/6J. After CR, Ptgs2 expression in BPH/5 rWAT was significantly lower compared to ad libitum fed BPH/5 mice (p=0.038, n=6). Also in implantation sites, the expression of Ptgs2 was significantly lower in CR as compared to ad libitum fed BPH/5 mice (p=0.046, n=6). IL‐15 expression was 30‐fold higher in BPH/5 rWAT and 8‐fold higher in implantation sites at e7.5 compared to C57Bl/6J control mice (p=0.0015, n=6), but this expression was not significantly affected by CR in either tissue.ConclusionThese data show that 7 days CR in BPH/5 obese mice during early pregnancy reduces the expression of Cox‐2 coding genes in rWAT and at the maternal‐fetal interface, suggesting that WAT‐derived inflammatory mediators might be involved in the development of PE and poor pregnancy outcomes in obese BPH/5 mice. Future studies should investigate the molecular phenotype of WAT in women that are at risk to develop PE, to provide further insight in the mechanisms that make obesity a risk factor and possible interventions to prevent PE.Support or Funding InformationThis study has been funded by the Lousiana Biomedical Collaborative Research Program.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Early life stress reduces in vivo lipolysis efficiency in female mice fed a high fat diet
Authors: Herald Joseph Blake , Leachman Jackeline , Loria Analia S. 
Published: June 2021

Previously, we have shown that female mice exposed to maternal separation and early weaning (MSEW), a model of postnatal neglect, increases fat mass and worsens the cardiometabolic function in response to high fat diet (HF) feeding. We also found that β3 adrenergic receptor mRNA expression, involved in local lipolysis stimulation, was reduced in gonadal white adipose tissue (gWAT). Thus, the aim of this study was to test the hypothesis that female MSEW mice display reduced lipolysis in‐vivo and in‐vitro. MSEW was performed by separating the pups from the mother for periods of 4–8 hr during postnatal days 2–16. Mice were weaned at P17. Control mice remained undisturbed in the home cage all times and weaned at P21. At weaning, mice were placed on a low fat (10% kcal from fat) or high fat (60% kcal from fat) diet for 16 weeks. At week 14, an in‐vivo lipolysis test was performed by injecting with 1mg/kg BW of isoproterenol, IP. Free fatty acids (FFA) were measured in plasma obtained after 15 minutes of the injection. At week 16, an in‐vitro lipolysis test was performed in gWAT. As such, gWAT was removed from female control and MSEW mice, weighed, and washed with ice‐cold PBS. In‐vitro lipolysis was performed in the presence or absence of isoproterenol (10uM, Sigma Aldrich). Free glycerol kit (Sigma Aldrich) was used to measure lipolytic products and results were normalized to tissue weight. In‐vivo, FFAs were reduced in female MSEW mice fed a HF (102±13 uM/ml) when compared with controls (144±24 uM/ml, p=0.066). In‐vitro, we found similar free glycerol levels in control and MSEW mice fed a LF (9.2±0.8 vs. 10.5±1.4 mg/dl/g tissue, respectively). Although HF reduced isoproterenol‐induced free glycerol levels, control and MSEW mice showed not statistically significant differences (4.4±0.6 vs. 3.5±0.6 mg/dl/g tissue, respectively). Taken together, these data indicate that HF reduced lipolysis capacity either in control and MSEW mice. Also, MSEW reduced lipolysis when determined in‐vivo conditions, suggesting that neuroendocrine and autonomic factors may be implicated in the mechanism by which MSEW mice are prone to increase fat mass.Support or Funding InformationThis study was supported by funds from the NIH National Heart, Lung, and Blood Institute to A.S.L (R00 HL111354), start‐up funds from the University of Kentucky to A.S.L, and the pilot project from the University of Kentucky Center of Research in Obesity and Cardiovascular Disease COBRE P20 GM103527‐06 to A.S.L.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
The Efficacy of Electrical Baroreflex Activation Therapy is Independent of Peripheral Chemoreceptor Modulation
Authors: Heusser Karsten , Thöne Arvo , Lipp Axel , Menne Jan , Beige Joachim , Reuter Hannes , Hoffmann Fabian , Halbach Marcel , Eckert Siegfried , Wallbach Manuel , Koziolek Michael , Haarmann Helge , Joyner Michael , Paton Julian F. R. , Diedrich André , Haller Hermann , Jordan Jens , Tank Jens 
Published: June 2021

IntroductionBaroreflex activation through electrical carotid sinus stimulation has been developed for the treatment of patients with arterial hypertension not sufficiently responding to pharmacological therapy. Previous studies suggested that peripheral chemoreflex afferents located in proximity to carotid baroreceptors are tonically active in hypertensive patients and may inhibit baroreflex responses. Therefore, we hypothesized that peripheral chemoreflex activation attenuates the efficacy of electrical carotid sinus stimulation.MethodsWe screened 35 patients with an implanted electrical carotid sinus stimulator. Of those, 11 patients exhibited a consistent acute depressor response and were included in the study (7 men/4 women, age: 67±8 years, BMI: 31.6±5.2 kg/m2, 6±2 antihypertensive drug classes). We assessed responses to electrical baroreflex stimulation during normoxia, isocapnic hypoxia (SpO2: 79.0±1.5%), and hyperoxia (40% end‐tidal O2 fraction) by recording ECG, blood pressure (SBP), ventilation, SpO2, end‐tidal CO2 and O2 fractions, and muscle sympathetic nerve activity (MSNA).ResultsDuring normoxia, baroreflex activation reduced SBP from 164±27 to 151±25 mmHg (means±SD, p<0.001), HR from 64±13 to 61±13 bpm (p=0.002), and MSNA from 42±12 to 36±12 bursts/min (p=0.004). Hypoxia increased SBP 8±12 mmHg (p=0.057), HR 10±6 bpm (p<0.001), MSNA 7±7 bursts/min (p=0.031), and ventilation 10±7 l/min (p=0. 002). However, responses to electrical carotid sinus stimulation did not differ between hypoxic and hyperoxic conditions; SBP: −15±7 vs −14±8 mmHg (p=0.938), HR: −2±3 vs −2±2 bpm (p=0.701), and MSNA: −6±4 vs −4±3 bursts/min (p=0.531).ConclusionThe main finding of our study is that moderate peripheral chemoreflex activation does not attenuate acute responses to electrical baroreflex activation therapy (BAT) in patients with resistant hypertension. These patients provide insight in human baroreflex physiology and baroreflex‐chemoreflex interactions that could not be gained otherwise.Support or Funding InformationFinancial support by Boston Scientific Corporation (St. Paul, MN, U.S.A.)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
mTORC1 in leptin receptor‐containing neurons mediates an obesity‐induced increase in sympathetic tone and blood pressure
Authors: Bell Balyssa , Morgan Donald , Rahmouni Kamal 
Published: June 2021

The adipocyte‐derived hormone leptin acts via the sympathetic nervous system to influence both metabolic homeostasis and blood pressure. Leptin has also been implicated as an important mediator of obesity‐induced elevation in sympathetic nerve activity (SNA) and blood pressure, but the underlying mechanisms remain poorly understood. Here, we investigated the contribution of mechanistic target of rapamycin complex 1 (mTORC1) signaling in leptin receptor (LepRb)‐containing neurons to metabolic, sympathetic and hemodynamic dysregulation associated with obesity. For this, we generated a genetically modified mouse model (LepRbCre/Raptorfl/fl) that lacks a critical subunit of the mTORC1 complex selectively in LepRb expressing cells. Surprisingly, loss of mTORC1 in LepRb‐containing cells had no effect on body weight, fat accumulation, or glucose handling. Furthermore, LepRbCre/Raptorfl/fl mice fed high‐fat or high‐fat/high‐sucrose diet developed obesity to a similar extent as control littermates, indicating that mTORC1 in LepRb expressing cells is dispensable for metabolic homeostasis. On the other hand, while conscious basal renal SNA was significantly elevated in control mice fed high‐fat/high‐sucrose diet relative to control animals on standard diet, this increase in sympathetic tone to the kidneys was attenuated in LepRbCre/Raptorfl/fl mice. Consistent with an impaired cardiovascular autonomic response to diet‐induced obesity in these animals, ganglionic blockade with hexamethonium bromide caused a trend towards a more pronounced decrease in blood pressure in high‐fat/high‐sucrose diet fed control animals as compared to LepRbCre/Raptorfl/fl mice. Interestingly, renal SNA was decreased in response to hexamethonium to a similar extent in all groups, regardless of diet or genotype, indicating an important role for extra‐renal and/or parasympathetic changes in autonomic nerve activity during diet‐induced obesity. High‐fat/high‐sucrose diet treatment also increased blood pressure and decreased cardiac parasympathetic tone in control mice, as determined by radiotelemetry and accompanying spectral analysis, and ICV rapamycin infusion resulted in a trend towards a partial reversal of these effects. Together, these findings indicate that mTORC1 signaling in LepRb‐containing cells is required for obesity‐induced sympathetic nerve activation and hypertension. This signaling pathway may represent an important mechanism for uncoupling obesity from its associated cardiovascular disorders.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Incubation of NTS Neurons in High Glucose Decreases the Sensitivity to a Low Glucose Challenge: Role of KATP Channels
Authors: De Bernardis Murat Cahuê , Leão Ricardo Mauricio 
Published: June 2021

The brainstem nucleus of the tractus solitarius (NTS) is an integrative center for the counterregulatory responses to hypoglycemia, and recent evidences have showed that NTS neurons can directly sense extracellular glucose fluctuations via mechanisms that rely on glucose metabolism. The ATP‐sensitive potassium (KATP) channels play a key role in linking metabolic status and electrical excitability in glucose‐sensing neurons, and KATP channels are expressed in NTS neurons. Therefore, this work aimed to investigate the effect of a low external glucose (0.5 mM) on the membrane properties of NTS neurons of rats, and its interaction with KATP channels, by whole‐cell patch‐clamp. We observed that low glucose induces a voltage‐dependent depolarization in most NTS neurons, i.e., the more negative the resting membrane potential (RMP) of neurons, the higher membrane potential amplitude response. KATP channels are opened at rest in NTS neurons maintained in 5 mM extracellular glucose, and contribute to the hyperpolarized RMP of neurons. Blockage of KATP channels with tolbutamide strongly depolarizes neurons and occludes the effect of low glucose, thus acting as modulators of low‐glucose sensing in NTS neurons. Membrane hyperpolarization after blockage of KATP channels restores the depolarizing effect of low glucose. Additionally, the incubation of NTS neurons in high‐glucose (10 mM) aCSF prior to electrophysiological recordings leads to more depolarized RMP, what contributes to increase the number of neurons unresponsive to a low‐glucose challenge. Again, membrane hyperpolarization restores the depolarization induced by low glucose, however, tolbutamide application did not produced the pronounced membrane depolarization in comparison to NTS neurons incubated in 5 mM glucose aCSF, confirming that KATP channels are closed in a high‐glucose environment. We conclude that (1) low‐glucose sensing in NTS neurons is a voltage‐dependent mechanism; (2) KATP channels influence the RMP of neurons, thus modulating the sensitivity of these neurons to low glucose; (3) incubation of NTS neurons in high‐glucose decrease the number of responsive neurons to low glucose, possibly by depolarization via inhibition of KATP channels following increased amounts of high glucose‐derived ATP levels; (4) this effect could be a permissive mechanism for the decreased brain response to hypoglycemia in individuals that experience recurrent episodes of hypoglycemia, such as insulin‐treated diabetic patients, and; (5) depolarization induced by low glucose might represent a form of homeostatic regulation of the RMP in order to avoid an excessive hyperpolarization by unblocking KATP channels under a hypoglycemia episode.Support or Funding InformationCAPES, CNPq, FAEPA, and FAPESP.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
PLASMA ERYTHROPOIETIN CONCENTRATION DETERMINE THE CAROTID BODY CHEMOSENSITIVITY TO HYPOXIA AND HYPERCAPNIA IN RATS
Authors: LAOUAFA Sofien , TAM Rose , BAIRAM Aida , JOSEPH Vincent , SOLIZ Jorge 
Published: June 2021

We tested the hypothesis that Erythropoietin (Epo) have an impact in the modulation of carotid body (CB) chemoreceptors in response to hypoxia and hypercapnia. To study this subject, we used isolated and perfused ex vivo CB preparations from adult male Sprague Dawley rats. Prior evaluation of the carotid sinus nerve activity (CSNA ‐ throughout a suction glass electrode encircling and sealing the junction of the carotid body and the carotid sinus nerve), preparations were incubated for 1h with (or without) Epo at different concentrations. Then CBs were exposed to hypoxic and hypercapnic conditions. Normoxic baseline activity was not affected by any tested Epo concentration. However, under hypoxia and hypercapnia, Epo doses lower than 0.5U/ml increased the CSNA (by almost 40%), Epo doses higher than 0.5U/ml gradually decreased the CSNA in hypoxic and hypercapnic condition. Complete inhibition of CSNA was reached when preparations were incubated with 2U/ml of Epo concentration. Keeping in mind that nitric oxide (NO) in CB is an inhibitory messenger and that Epo in combination with low oxygen tension increase the endothelial capacity to produce NO, preparations were incubated at the same time with Epo (at the inhibitory concentration of 1 U/ml) and NO inhibitors, 400 μM L‐NAME (Nitric synthase inhibitor) or 100 μM 7NI (specific neuronal Nitric oxide synthase inhibitor). Our results showed that inhibition of NO (with L‐NAME and 7NI) fully restored the hypoxic CSNA. Similar results were found by exposing CB preparations to hypercapnic conditions. Accordingly, to these findings, immunohistochemistry studies showed a dense staining of Epo receptors (EpoR) in the carotid bodies, apparently localized within islets of chemosensitive cells. In summary, our results strongly suggest that the plasma Epo concentration determines the CB chemo‐response to hypoxic and hypercapnic conditions. These novel findings are relevant to better understand respiratory disorders, including those occurring at high altitude.Support or Funding InformationCIHR, Région Rhône Alpes and consulat de France in QuébecThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Angiotensin 1–7 Action in the Lateral Preoptic Area is Involved in Urinary Bladder Regulation in Female Wistar Rats.
Authors: Lamy Gustavo Bertollini , do Vale Barbara , de Almeida Roberto Lopes , de Brito Antonio Bruno , Venancio Daniel Paulino , Sato Monica Akemi 
Published: June 2021

BackgroundChemical lesions of the lateral preoptic area (LPA) enhance water intake induced by subcutaneous injection of hypertonic saline in rats. On the other hand, the LPA section abolishes the increase in intravesical pressure (IP) induced by olfactory tubercle stimulation in dogs. Immunohistochemical labeling has demonstrated the presence of Mas receptors for Angiotensin‐(1–7) in LPA. It is not known whether neurons with Mas receptors in LPA are involved in urinary bladder regulation.AimWe investigated the effects of activation or blockade of Mas receptors for angiotensin‐(1–7) in LPA on intravesical pressure in anesthetized female rats.Materials and methodsFemale Wistar rats (~240 g, N=6) underwent to a stereotaxic surgery for implantation of stainless steel guide cannulas into the LPA under ketamine and xylazin anesthesia. After 7 days, the animals were anesthetized and maintained with 2% isoflurane in 100% O2 and submitted to cannulation of the femoral artery and vein, placement of a miniaturized Doppler flow probe around the left renal artery to measure the renal blood flow and cannulation of the urinary bladder for IP measurements. After baseline IP and cardiovascular parameters recordings for 15 min, angiotensin‐(1–7) (5 nmol/ uL) or saline (1 uL) or A‐779 (Mas receptor antagonist, 50 nmol/uL) was injected into the LPA and the variables were measured for additional 60 min.ResultsUnilateral injection of angiotensin‐(1–7) into LPA evoked a significant increase in IP (187.5±37.2%) compared to saline (−2.1±1.9%). Unilateral injection of A‐779 into LPA decreased the IP (−15.9±2.8%) in comparison to saline (2.0±1.1%). Interestingly, the decrease in IP was enhanced after bilateral injection of A‐779 into LPA (−27.3±3.4%) compared to the unilateral injection of this drug and also in comparison to saline (−2.9±1.6%) bilaterally into LPA. No significant changes in cardiovascular parameters after angiotensin‐(1–7) or saline or A‐779 in APL were observed.ConclusionThe data suggest that LPA is an important part of the circuit that regulates the urinary bladder activity mediated by angiotensin‐(1–7).Support or Funding InformationFinancial support: FAPESP and NEPAS‐FMABCThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.