Endothelin-1 as a neuropeptide: neurotransmitter or neurovascular effects?

Endothelin-1 (ET-1) is an endothelium-derived peptide that also possesses potent mitogenic activity. There is also a suggestion the ET-1 is a neuropeptide, based mainly on its histological identification in both the central and peripheral nervous system in a number of species, including man. A neuropeptide role for ET-1 is supported by studies showing a variety of effects caused following its administration into different regions of the brain and by application to peripheral nerves. In addition there are studies proposing that ET-1 is implicated in a number of neural circuits where its transmitter affects range from a role in pain and temperature control to its action on the hypothalamo-neurosecretory system. While the effect of ET-1 on nerve tissue is beyond doubt, its action on nerve blood flow is often ignored. Here, we review data generated in a number of species and using a variety of experimental models. Studies range from those showing the distribution of ET-1 and its receptors in nerve tissue to those describing numerous neurally-mediated effects of ET-1

Effect of Hypoxia on Metabolic Rate, Core Body Temperature, and C-Fos Expression in the Naked Mole Rat

Recent investigations of hypoxia physiology in the naked mole rat have opened up an interesting line of research into the basic physiological and genomic alterations that accompany hypoxia survival. The extent to which such findings connect the effect of hypoxia to metabolic rate (O2 consumption), core body temperature (Tb), and transcripts encoding the immediate early gene product (such as c-fos) under a constant ambient temperature (Ta) is not well known. We investigated this issue in the current study. Our first sets of experiments measured Tb and metabolic rates during exposure of naked mole rats to hypoxia over a constant Ta. Hypoxia significantly decreased metabolic rates in the naked mole rat. Although core Tb also decreased during hypoxia, the effect of hypoxia in suppressing core Tb was not significant. The second series of experiments revealed that c-fos protein and mRNA expression in the hippocampus neurons (CA1) increased in naked mole rats that were repeatedly exposed to 3% O2 for 60min per day for 5 days when compared to normoxia. Our findings provide evidence for the up-regulation of c-fos and suppression of metabolic rate in hypoxia tolerating naked mole rats under constant ambient temperature. Metabolic suppression and c-fos upregulation constitute part of the physiological complex associated with adaptation to hypoxia

Metabolic Regulatory Clues From the Naked Mole Rat: Toward Brain Regulatory Functions During Stroke

Resistance to tissue hypoxia is a robust fundamental adaptation to low oxygen supply, and represents a novel neuroscience problem with significance to mammalian physiology as well as human health. With the underlying mechanisms strongly conserved in evolution, the ability to resist tissue hypoxia in natural systems has recently emerged as an interesting model in mammalian physiology research to understand mechanisms that can be manipulated for the clinical management of stroke. The extraordinary ability to resist tissue hypoxia by the naked mole rat (NMR) indicates the presence of a unique mechanism that underlies the remarkable healthy life span and exceptional hypoxia resistance. This opens an interesting line of research into understanding the mechanisms employed by the naked mole rat (. Heterocephalus glaber) to protect the brain during hypoxia. In a series of studies, we first examined the presence of neuroprotection in the brain cells of naked mole rats (NMRs) subjected to hypoxic insults, and then characterized the expression of such neuroprotection in a wide range of time intervals. We used oxygen nutrient deprivation (OND), an in vitro model of resistance to tissue hypoxia to determine whether there is evidence of neuronal survival in the hippocampal (CA1) slices of NMRs that are subjected to chronic hypoxia. Hippocampus neurons of NMRs that were kept in hypoxic condition consistently tolerated OND right from the onset time of 5. h. This tolerance was maintained for 24. h. This finding indicates that there is evidence of resistance to tissue hypoxia by CA1 neurons of NMRs. We further examined the effect of hypoxia on metabolic rate in the NMR. Repeated measurement of metabolic rates during exposure of naked mole rats to hypoxia over a constant ambient temperature indicates that hypoxia significantly decreased metabolic rates in the NMR, suggesting that the observed decline in metabolic rate during hypoxia may contribute to the adaptive mechanism used by the NMR to resist tissue hypoxia. This work is aimed to contribute to the understanding of mechanisms of resistance to tissue hypoxia in the NMR as an important life-sustaining process, which can be translated into therapeutic interventions during stroke

The Prevalence and Distribution of Metabolic Syndrome Components in Hispanic Children in Northeast Tennessee: A Pilot Study

Metabolic syndrome (MetS) is a major risk factor for cardiovascular disease yet it has been little studied in Hispanic children of rural areas. This pilot study aimed to estimate the prevalence of MetS and its components (high waist circumference (WC), elevated blood pressure (BP), high triglycerides (TRI), low high-density lipoprotein (HDL), and hyperglycemia) in a sample of Hispanic children aged 2 to 10 years from northeast Tennessee (TN). Between June and October 2015, 46 Hispanic children were recruited during their well-child visit at a community health center in Johnson City, TN. Anthropometric data, blood pressure readings, and a blood sample were collected. Descriptive statistics were used to estimate the prevalence of MetS and its components. Chi-squared test or Fisher’s exact test was used to test differences of proportions. Results showed that 41.3% of Hispanic children (mean age:6.8 years; SD:2.5) were overweight or obese (Body Mass index (BMI) for age and sex ≥85th percentile), 15.2% had a high WC (≥90th percentile for age and sex), 30.4% had elevated BP (systolic or diastolic BP for age, sex and height ≥90th percentile), 13.0% had low HDL (≤5th percentile for age and sex), and 45.6% had high TRI (≥95th percentile for age and sex). Overall, 17 (37%) children were negative for every component of MetS, 17 (37%) were positive for one component, 6 (13%) for two components, 5 (11%) for three components, and 1 (2%) for four components. The prevalence of MetS (≥3 components) was 13%. While the prevalence of MetS did not vary by sex, it tended to be higher (33.3%) in children aged 4 or younger than in 5 to 10 (12.1%) year olds (P=0.05). The prevalence of having 2 or more positivities for MetS was significantly higher among overweight/obese children than in children with lean weight (47.4% vs. 11.1%, P=0.03). Findings provide evidence that Hispanic children are at high risk for MetS. Prevention efforts should begin early and target children with elevated BMI

Glucemia y concentraciones de insulina en sangre de ratas Wistar sometidas a dieta alta en grasa y a tratamiento con péptidos miméticos de leptina

Introducción. La administración de leptina ha demostrado que revierte la resistencia a la insulina y ejerce efectos sobre el metabolismo de la glucosa. Objetivo. Evaluar los cambios en las concentraciones plasmáticas de insulina y glucosa por la administración intraperitoneal de péptidos miméticos de leptina en ratas Wistar alimentadas con dieta alta en grasa. Materiales y métodos. Se definió un grupo de ratas control alimentado con dieta alta en grasa y un grupo control con dieta normal; además, distintos grupos de animales alimentados con dieta alta en grasa y sometidos a la administración de siete diferentes péptidos de leptina, administrados en cuatro concentraciones diferentes y a los cuales se denominó grupos tratamiento. Durante la administración de los péptidos se cuantificó la glucemia y al finalizar las concentraciones de insulina. Resultados. Las concentraciones de insulina en los grupos fueron similares; se observó hiperinsulinemia en los grupos a los cuales se les administró el péptido denominado 83 a dosis de 10 mg/kg y 20 mg/kg de peso corporal. Todos los tratamientos, a excepción del grupo al cual se le administró el péptido denominado con el código 80, redujeron la glucemia; el mayor efecto parece ser el del péptido 116-130 de leptina de ratón y su homólogo humano, aunque sin diferencias estadísticas con los otros tratamientos. Conclusión. Los péptidos no ejercen efectos sobre las concentraciones de insulina pero sí sobre la glucemia; se requieren otras investigaciones para determinar los mecanismos mediante los cuales los péptidos intervienen en el metabolismo de la glucosa, sobre la expresión, secreción, mecanismos de señalización y regulación de la insulina, además, cambios en las concentraciones de insulina teniendo en cuenta el ritmo pulsátil de la hormona

Skeletal phenotype of the leptin receptor-deficient db/db mouse

Leptin, a major hormonal product of the adipocyte, regulates appetite and reproductive function through its hypothalamic receptors. The leptin receptor is present in osteoblasts and chondrocytes, and previously we have shown leptin to be an anabolic bone factor in vitro, stimulating osteoblast proliferation and inhibiting osteoclastogenesis. Leptin increases bone mass and reduces bone fragility when administered peripherally but also can indirectly reduce bone mass when administered into the central nervous system. However, data from animal models deficient in either leptin (ob/ob) or its receptor (db/db) remain contradictory. We compared the bone phenotype of leptin receptor-deficient (db/db) and wild-type mice using micro-computed tomographic (microCT) analysis of the proximal tibias and vertebrae. In the tibia, db/db mice had reduced percent trabecular bone volume (13.0 +/- 1.62% in wild-type versus 6.01 +/- 0.601% in db/db mice, p = .002) and cortical bone volume (411 +/- 21.5 microm(3) versus 316 +/- 3.53 microm(3), p = .0014), trabecular thickness (48.4 +/- 001.07 microm versus 45.1 +/- 0.929 microm, p = .041) and trabecular number (2.68 +/- 0.319 mm(-1) versus 1.34 +/- 0.148 mm(-1), p = .0034). In the fifth lumbar vertebral body, the trabecular thickness and cortical thickness were decreased in the db/db versus wild-type mice (0.053 +/- 0.0011 mm versus 0.047 +/- 0.0013 mm, p = .0002 and 0.062 +/- 0.00054 mm versus 0.056 +/- 0.0009 mm, p = .0001), respectively, whereas the trabecular and cortical percent bone volume and trabecular number did not reach significance. The total (endosteal and periosteal) cortical perimeter (12.2 +/- 0.19 mm versus 13.2 +/- 0.30 mm, p = .01) was increased. The serum osteocalcin levels were reduced in the db/db mice, suggesting that bone formation rates are decreased. The material properties of db/db femurs were determined by three-point bending and nanoindentation, showing decreased bone strength (13.3 +/- 0.280 N versus 7.99 +/- 0.984 N, p = .0074) and material stiffness (28.5 +/- 0.280 GPa versus 25.8 +/- 0.281 GPa, p < .0001). These results demonstrate that bone mass and strength are reduced in the absence of leptin signaling, indicating that leptin acts in vivo as an anabolic bone factor. This concurs with results of in vitro studies and of peripheral leptin administration in vivo and suggests that leptin's direct effects on bone cells are likely to override its actions via the central nervous system.link_to_OA_fulltex