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Mei-fang Jin - One of the best experts on this subject based on the ideXlab platform.

  • Alterations in the Neurobehavioral Phenotype and ZnT3/CB-D28k Expression in the Cerebral Cortex Following Lithium-Pilocarpine-Induced Status Epilepticus: the Ameliorative Effect of Leptin
    Biological trace element research, 2018
    Co-Authors: Su-hong Chen, Mei-fang Jin
    Abstract:

    Zinc transporter 3 (ZnT3)-dependent “zincergic” vesicular zinc accounts for approximately 20% of the total zinc content of the mammalian telencephalon. Elevated hippocampal ZnT3 expression is acknowledged to be associated with mossy fiber sprouting and cognitive deficits. However, no studies have compared the long-term neurobehavioral phenotype with the expression of ZnT3 in the cerebral cortex following status epilepticus (SE). The aim of this study was to investigate changes in the long-term neurobehavioral phenotype as well as the expression of ZnT3 and calcium homeostasis-related CB-D28k in the cerebral cortex of rats subjected to neonatal SE and to determine the effects of Leptin Treatment immediately after neonatal SE. Fifty Sprague-Dawley rats (postnatal day 6, P6) were randomly assigned to two groups: the pilocarpine hydrochloride-induced status epilepticus group (RS, n = 30) and control group (n = 20). Rats were further divided into the control group without Leptin (Control), control-plus-Leptin Treatment group (Leptin), RS group without Leptin Treatment (RS), and RS-plus-Leptin Treatment group (RS + Leptin). On P6, all rats in the RS group and RS + Leptin group were injected intraperitoneally (i.p.) with lithium chloride (5 mEq/kg). Pilocarpine (320 mg/kg, i.p.) was administered 30 min after the scopolamine methyl chloride (1 mg/kg) injection on P7. From P8 to P14, animals of the Leptin group and RS + Leptin group were given Leptin (4 mg/kg/day, i.p.). The neurological behavioral parameters (negative geotaxis reaction reflex, righting reflex, cliff avoidance reflex, forelimb suspension reflex, and open field test) were observed from P23 to P30. The protein levels of ZnT3 and CB-D28k in the cerebral cortex were detected subsequently by the western blot method. Pilocarpine-treated neonatal rats showed long-term abnormal neurobehavioral parameters. In parallel, there was a significantly downregulated protein level of CB-D28k and upregulated protein level of ZnT3 in the cerebral cortex of the RS group. Leptin Treatment soon after epilepticus for 7 consecutive days counteracted these abnormal changes. Taken together with the results from our previous reports on another neonatal seizure model, which showed a significant positive inter-relationship between ZnT3 and calcium/calmodulin-dependent protein kinase IIα (CaMKIIα), the data here suggest that ZnT3/CB-D28k–associated Zn (2+)/Ca(2+) signaling might be involved in neonatal SE-induced long-term brain damage in the aspects of neurobehavioral impairment. Moreover, consecutive Leptin Treatment is effect at counteracting these hyperexcitability-related changes, suggesting a potential clinical significance.

  • Zinc/CaMK II Associated-Mitophagy Signaling Contributed to Hippocampal Mossy Fiber Sprouting and Cognitive Deficits Following Neonatal Seizures and Its Regulation by Chronic Leptin Treatment
    Frontiers Media S.A., 2018
    Co-Authors: Mei-fang Jin
    Abstract:

    The role of Leptin in the pathogenesis of epilepsy is getting more and more attention in clinical and basic research. Although there are data indicating neuroprotective effects of elevated serum/brain Leptin levels following acute seizures, no study to date has dealt with the impact of chronic Leptin Treatment on long-term brain injury following developmental seizures. The aim of this study was to evaluate whether chronic Leptin Treatment may have neuroprotective effects on cognitive and hippocampal mossy fiber sprouting following flurothyl-induced recurrent neonatal seizures and whether these effects are mediated by the zinc/CaMKII-associated mitophagy signaling pathway. Forty Sprague-Dawley rats (postnatal day 6, P6) were randomly assigned into two groups: neonatal seizure group and control group. At P13, they were further divided into control group, seizure group (RS), control + Leptin (Leptin, i.p., 2 mg/kg/day for 10 days), seizure+Leptin group (RS+Leptin, 2mg/kg/day, i.p., for 10 consecutive days). Morris water maze test was performed during P27-P32. Subsequently, Timm staining and Western blotting were used to detect the mossy fiber sprouting and protein levels in hippocampus. Flurothyl-induced seizures (RS group) significantly down-regulated mitophagy markers PINK, Drp1, PHB, and memory marker CaMK II alpha while up-regulating zinc transporters ZnT3, ZnT4, ZIP7, and autophagy execution molecular cathepsin-E, which were paralleled with hippocampal aberrant mossy fiber sprouting and cognitive dysfunction. However, these changes were restored by chronic Leptin Treatment (RS+Leptin group). The results showed that Leptin had neuroprotective effect on hippocampal pathological damage and cognitive deficits induced by neonatal seizures and suggested that Zinc/CaMK II associated-mitophagy signaling pathway in hippocampus may be a new target of Leptin's neuroprotection, with potential value of translational medicine

  • Leptin Treatment prevents long-term abnormalities in cognition, seizure threshold, hippocampal mossy fiber sprouting and ZnT3/CB-D28k expression in a rat developmental "twist" seizure model.
    Epilepsy research, 2017
    Co-Authors: Su-hong Chen, Mei-fang Jin
    Abstract:

    Abstract The mechanism of linking neonatal seizures with long-term brain damage is unclear, and there is no effective drug to block this long-term pathological process. Recently, the fat-derived hormone Leptin has been appreciated for its neuroprotective function in neurodegenerative processes, although less is known about the effects of Leptin on neonatal seizure-induced brain damage. Here, we developed a “twist” seizure model by coupling pilocarpine-induced neonatal status epilepticus (SE) with later exposure to penicillin to test whether Leptin Treatment immediately after neonatal SE would exert neuroprotective effects on cognition, seizure threshold and hippocampal mossy fiber sprouting, as well if Leptin had any influence on the expression of zinc transporter 3 (ZnT3) and calcium homeostasis-related CB-D28k in the hippocampus. Fifty Sprague-Dawley rats (postnatal day 6, P6) were randomly assigned to four groups: control (n = 10), control with intraperitoneal (i.p.) injection of Leptin (Leptin, n = 10), pilocarpine-induced neonatal SE (RS), and RS i.p. Leptin injection (RS+Leptin). At P6, all the rats in the RS group and RS+Leptin group were injected with lithium chloride i.p. (5 mEq/kg). Pilocarpine (320 mg/kg, i.p.) was administered 30 min after scopolamine methyl chloride (1 mg/kg) injection at P7 to block the peripheral effect of pilocarpine. From P8 to P14, the animals in the Leptin group and RS+Leptin group were given Leptin (4 mg/kg, i.p.). The Morris water maze test was performed during P28-P33. Following routine seizure threshold detection and Timm staining procedures, Western blot analysis was performed for each group. Pilocarpine-induced neonatal SE severely impaired learning and memory abilities, reduced seizure threshold, and induced aberrant hippocampal CA3 mossy fiber sprouting. In parallel, there was a significantly down-regulated protein level of CB-D28k and an up-regulated protein level of ZnT3 in the hippocampus of the RS group. Furthermore, Leptin Treatment soon after neonatal SE for seven consecutive days counteracted these hyperexcitability-related alterations. These novel findings established that Leptin has a neuroprotective role in the model of cholinergic neonatal SE and highlights ZnT3/CB-D28k associated-Zn (2+)/Ca (2+) signaling as a promising therapeutic target.

  • Leptin Treatment prevents long term abnormalities in cognition seizure threshold hippocampal mossy fiber sprouting and znt3 cb d28k expression in a rat developmental twist seizure model
    Epilepsy Research, 2017
    Co-Authors: Su-hong Chen, Mei-fang Jin
    Abstract:

    Abstract The mechanism of linking neonatal seizures with long-term brain damage is unclear, and there is no effective drug to block this long-term pathological process. Recently, the fat-derived hormone Leptin has been appreciated for its neuroprotective function in neurodegenerative processes, although less is known about the effects of Leptin on neonatal seizure-induced brain damage. Here, we developed a “twist” seizure model by coupling pilocarpine-induced neonatal status epilepticus (SE) with later exposure to penicillin to test whether Leptin Treatment immediately after neonatal SE would exert neuroprotective effects on cognition, seizure threshold and hippocampal mossy fiber sprouting, as well if Leptin had any influence on the expression of zinc transporter 3 (ZnT3) and calcium homeostasis-related CB-D28k in the hippocampus. Fifty Sprague-Dawley rats (postnatal day 6, P6) were randomly assigned to four groups: control (n = 10), control with intraperitoneal (i.p.) injection of Leptin (Leptin, n = 10), pilocarpine-induced neonatal SE (RS), and RS i.p. Leptin injection (RS+Leptin). At P6, all the rats in the RS group and RS+Leptin group were injected with lithium chloride i.p. (5 mEq/kg). Pilocarpine (320 mg/kg, i.p.) was administered 30 min after scopolamine methyl chloride (1 mg/kg) injection at P7 to block the peripheral effect of pilocarpine. From P8 to P14, the animals in the Leptin group and RS+Leptin group were given Leptin (4 mg/kg, i.p.). The Morris water maze test was performed during P28-P33. Following routine seizure threshold detection and Timm staining procedures, Western blot analysis was performed for each group. Pilocarpine-induced neonatal SE severely impaired learning and memory abilities, reduced seizure threshold, and induced aberrant hippocampal CA3 mossy fiber sprouting. In parallel, there was a significantly down-regulated protein level of CB-D28k and an up-regulated protein level of ZnT3 in the hippocampus of the RS group. Furthermore, Leptin Treatment soon after neonatal SE for seven consecutive days counteracted these hyperexcitability-related alterations. These novel findings established that Leptin has a neuroprotective role in the model of cholinergic neonatal SE and highlights ZnT3/CB-D28k associated-Zn (2+)/Ca (2+) signaling as a promising therapeutic target.

Su-hong Chen - One of the best experts on this subject based on the ideXlab platform.

  • Alterations in the Neurobehavioral Phenotype and ZnT3/CB-D28k Expression in the Cerebral Cortex Following Lithium-Pilocarpine-Induced Status Epilepticus: the Ameliorative Effect of Leptin
    Biological trace element research, 2018
    Co-Authors: Su-hong Chen, Mei-fang Jin
    Abstract:

    Zinc transporter 3 (ZnT3)-dependent “zincergic” vesicular zinc accounts for approximately 20% of the total zinc content of the mammalian telencephalon. Elevated hippocampal ZnT3 expression is acknowledged to be associated with mossy fiber sprouting and cognitive deficits. However, no studies have compared the long-term neurobehavioral phenotype with the expression of ZnT3 in the cerebral cortex following status epilepticus (SE). The aim of this study was to investigate changes in the long-term neurobehavioral phenotype as well as the expression of ZnT3 and calcium homeostasis-related CB-D28k in the cerebral cortex of rats subjected to neonatal SE and to determine the effects of Leptin Treatment immediately after neonatal SE. Fifty Sprague-Dawley rats (postnatal day 6, P6) were randomly assigned to two groups: the pilocarpine hydrochloride-induced status epilepticus group (RS, n = 30) and control group (n = 20). Rats were further divided into the control group without Leptin (Control), control-plus-Leptin Treatment group (Leptin), RS group without Leptin Treatment (RS), and RS-plus-Leptin Treatment group (RS + Leptin). On P6, all rats in the RS group and RS + Leptin group were injected intraperitoneally (i.p.) with lithium chloride (5 mEq/kg). Pilocarpine (320 mg/kg, i.p.) was administered 30 min after the scopolamine methyl chloride (1 mg/kg) injection on P7. From P8 to P14, animals of the Leptin group and RS + Leptin group were given Leptin (4 mg/kg/day, i.p.). The neurological behavioral parameters (negative geotaxis reaction reflex, righting reflex, cliff avoidance reflex, forelimb suspension reflex, and open field test) were observed from P23 to P30. The protein levels of ZnT3 and CB-D28k in the cerebral cortex were detected subsequently by the western blot method. Pilocarpine-treated neonatal rats showed long-term abnormal neurobehavioral parameters. In parallel, there was a significantly downregulated protein level of CB-D28k and upregulated protein level of ZnT3 in the cerebral cortex of the RS group. Leptin Treatment soon after epilepticus for 7 consecutive days counteracted these abnormal changes. Taken together with the results from our previous reports on another neonatal seizure model, which showed a significant positive inter-relationship between ZnT3 and calcium/calmodulin-dependent protein kinase IIα (CaMKIIα), the data here suggest that ZnT3/CB-D28k–associated Zn (2+)/Ca(2+) signaling might be involved in neonatal SE-induced long-term brain damage in the aspects of neurobehavioral impairment. Moreover, consecutive Leptin Treatment is effect at counteracting these hyperexcitability-related changes, suggesting a potential clinical significance.

  • Leptin Treatment prevents long-term abnormalities in cognition, seizure threshold, hippocampal mossy fiber sprouting and ZnT3/CB-D28k expression in a rat developmental "twist" seizure model.
    Epilepsy research, 2017
    Co-Authors: Su-hong Chen, Mei-fang Jin
    Abstract:

    Abstract The mechanism of linking neonatal seizures with long-term brain damage is unclear, and there is no effective drug to block this long-term pathological process. Recently, the fat-derived hormone Leptin has been appreciated for its neuroprotective function in neurodegenerative processes, although less is known about the effects of Leptin on neonatal seizure-induced brain damage. Here, we developed a “twist” seizure model by coupling pilocarpine-induced neonatal status epilepticus (SE) with later exposure to penicillin to test whether Leptin Treatment immediately after neonatal SE would exert neuroprotective effects on cognition, seizure threshold and hippocampal mossy fiber sprouting, as well if Leptin had any influence on the expression of zinc transporter 3 (ZnT3) and calcium homeostasis-related CB-D28k in the hippocampus. Fifty Sprague-Dawley rats (postnatal day 6, P6) were randomly assigned to four groups: control (n = 10), control with intraperitoneal (i.p.) injection of Leptin (Leptin, n = 10), pilocarpine-induced neonatal SE (RS), and RS i.p. Leptin injection (RS+Leptin). At P6, all the rats in the RS group and RS+Leptin group were injected with lithium chloride i.p. (5 mEq/kg). Pilocarpine (320 mg/kg, i.p.) was administered 30 min after scopolamine methyl chloride (1 mg/kg) injection at P7 to block the peripheral effect of pilocarpine. From P8 to P14, the animals in the Leptin group and RS+Leptin group were given Leptin (4 mg/kg, i.p.). The Morris water maze test was performed during P28-P33. Following routine seizure threshold detection and Timm staining procedures, Western blot analysis was performed for each group. Pilocarpine-induced neonatal SE severely impaired learning and memory abilities, reduced seizure threshold, and induced aberrant hippocampal CA3 mossy fiber sprouting. In parallel, there was a significantly down-regulated protein level of CB-D28k and an up-regulated protein level of ZnT3 in the hippocampus of the RS group. Furthermore, Leptin Treatment soon after neonatal SE for seven consecutive days counteracted these hyperexcitability-related alterations. These novel findings established that Leptin has a neuroprotective role in the model of cholinergic neonatal SE and highlights ZnT3/CB-D28k associated-Zn (2+)/Ca (2+) signaling as a promising therapeutic target.

  • Leptin Treatment prevents long term abnormalities in cognition seizure threshold hippocampal mossy fiber sprouting and znt3 cb d28k expression in a rat developmental twist seizure model
    Epilepsy Research, 2017
    Co-Authors: Su-hong Chen, Mei-fang Jin
    Abstract:

    Abstract The mechanism of linking neonatal seizures with long-term brain damage is unclear, and there is no effective drug to block this long-term pathological process. Recently, the fat-derived hormone Leptin has been appreciated for its neuroprotective function in neurodegenerative processes, although less is known about the effects of Leptin on neonatal seizure-induced brain damage. Here, we developed a “twist” seizure model by coupling pilocarpine-induced neonatal status epilepticus (SE) with later exposure to penicillin to test whether Leptin Treatment immediately after neonatal SE would exert neuroprotective effects on cognition, seizure threshold and hippocampal mossy fiber sprouting, as well if Leptin had any influence on the expression of zinc transporter 3 (ZnT3) and calcium homeostasis-related CB-D28k in the hippocampus. Fifty Sprague-Dawley rats (postnatal day 6, P6) were randomly assigned to four groups: control (n = 10), control with intraperitoneal (i.p.) injection of Leptin (Leptin, n = 10), pilocarpine-induced neonatal SE (RS), and RS i.p. Leptin injection (RS+Leptin). At P6, all the rats in the RS group and RS+Leptin group were injected with lithium chloride i.p. (5 mEq/kg). Pilocarpine (320 mg/kg, i.p.) was administered 30 min after scopolamine methyl chloride (1 mg/kg) injection at P7 to block the peripheral effect of pilocarpine. From P8 to P14, the animals in the Leptin group and RS+Leptin group were given Leptin (4 mg/kg, i.p.). The Morris water maze test was performed during P28-P33. Following routine seizure threshold detection and Timm staining procedures, Western blot analysis was performed for each group. Pilocarpine-induced neonatal SE severely impaired learning and memory abilities, reduced seizure threshold, and induced aberrant hippocampal CA3 mossy fiber sprouting. In parallel, there was a significantly down-regulated protein level of CB-D28k and an up-regulated protein level of ZnT3 in the hippocampus of the RS group. Furthermore, Leptin Treatment soon after neonatal SE for seven consecutive days counteracted these hyperexcitability-related alterations. These novel findings established that Leptin has a neuroprotective role in the model of cholinergic neonatal SE and highlights ZnT3/CB-D28k associated-Zn (2+)/Ca (2+) signaling as a promising therapeutic target.

Magna Cottini Fonseca Passos - One of the best experts on this subject based on the ideXlab platform.

  • Maternal Leptin Treatment during lactation programs the thyroid function of adult rats
    Life sciences, 2007
    Co-Authors: Magna Cottini Fonseca Passos, Patricia Cristina Lisboa, Márcia Clements Lins, F. P. Toste, I. T. Bonomo, Egberto Gaspar De Moura
    Abstract:

    Recently, we showed that both maternal malnutrition during lactation and Leptin Treatment during the neonatal period program thyroid function. In this study we evaluate whether maternal Leptin Treatment during lactation programs thyroid function of the offspring in the adulthood. The dams were divided into 2 groups: Lep-daily sc single injected with 8 microg/100 g of body weight with recombinant rat Leptin during the last 3 days of lactation and control group (C) that received the same volume of saline. The 180 day-old animals received a single i.p. injection of (125)I (2.22x10(4) Bq) and they were killed 2 h after the injection. Triiodothyronine (T3), thyroxine (T4), thyrotropin (TSH) and Leptin concentrations were measured by radioimmunoassay. The milk of Leptin-treated mothers on the last day of Treatment had higher Leptin (p

  • neonatal Leptin Treatment programmes Leptin hypothalamic resistance and intermediary metabolic parameters in adult rats
    British Journal of Nutrition, 2006
    Co-Authors: F. P. Toste, A. T. S. Fagundes, Egberto Gaspar De Moura, Patricia Cristina Lisboa, Elaine De Oliveira, Magna Cottini Fonseca Passos
    Abstract:

    We previously showed that neonatal Leptin Treatment programmes higher body weight and food intake in adult rats. Here we investigate whether Leptin Treatment during lactation affects the anorectic effect of Leptin on adult rats and their hypothalamic Leptin receptors (OB-Rb) and whether those changes could have consequences on intermediary metabolism. When the offspring were born, pups were divided into two groups: the Lep group, injected daily with Leptin (8 microg/100 g body weight, subcutaneously) for the first 10 d of lactation, and the control group, injected daily with saline. After weaning (day 21), body weight and food intake were monitored until the rats were 150 d old. Food intake was higher in the Lep group (approximately 14 %, P<0.05) from day 133 onwards, and body weight was higher (approximately 10 %, P<0.05) from day 69 onwards, compared with the control group. At 150 d of age, the rats were tested for food intake in response to either Leptin (0.5 mg/kg body weight intraperitoneally; groups CL and LepL) or saline (groups CSal and LepSal). The CL group showed a decrease in food intake, but no response was observed in the LepL group, suggesting Leptin resistance. The Lep group demonstrated a decrease in OB-Rb expression (-40 %, P<0.05), hyperLeptinaemia (+78 %, P<0.05), hyperinsulinaemia (+100 %, P<0.02), hypertriacylglycerolaemia (+17 %, P<0.05) and a higher protein content in the body (+16 %, P<0.05) without changes in fat mass and glycaemia. We conclude that neonatal Leptin Treatment programmes both hyperLeptinaemia and hyperinsulinaemia in adulthood, which leads to Leptin resistance by reducing the expression of the hypothalamic Leptin receptor.

  • Neonatal Leptin Treatment programmes Leptin hypothalamic resistance and intermediary metabolic parameters in adult rats.
    The British journal of nutrition, 2006
    Co-Authors: F. P. Toste, A. T. S. Fagundes, Egberto Gaspar De Moura, Patricia Cristina Lisboa, Elaine De Oliveira, Magna Cottini Fonseca Passos
    Abstract:

    We previously showed that neonatal Leptin Treatment programmes higher body weight and food intake in adult rats. Here we investigate whether Leptin Treatment during lactation affects the anorectic effect of Leptin on adult rats and their hypothalamic Leptin receptors (OB-Rb) and whether those changes could have consequences on intermediary metabolism. When the offspring were born, pups were divided into two groups: the Lep group, injected daily with Leptin (8 microg/100 g body weight, subcutaneously) for the first 10 d of lactation, and the control group, injected daily with saline. After weaning (day 21), body weight and food intake were monitored until the rats were 150 d old. Food intake was higher in the Lep group (approximately 14 %, P

  • Effects of maternal Leptin Treatment during lactation on the body weight and Leptin resistance of adult offspring.
    Regulatory peptides, 2005
    Co-Authors: Márcia Clements Lins, Egberto Gaspar De Moura, Patricia Cristina Lisboa, I. T. Bonomo, Magna Cottini Fonseca Passos
    Abstract:

    We investigate whether Leptin Treatment to lactating rats affects food intake, body weight and Leptin serum concentration and its anorectic effect on their adult offspring. Lactating rats were divided into 2 groups: Lep-single injected with recombinant rat Leptin (8 microg/100 g of body weight, daily for the last 3 consecutive days of lactation) and control group (C) that received the same volume of saline. After weaning all pups had free access to the control diet, their body weight and food intake were monitored at each 4 days until 180 days of age, when they were tested for its food intake and response to either Leptin (0.5 mg/kg body wt, ip) or saline vehicle. The offspring of the Leptin-treated dams gained more weight and had higher food intake from day 37 onward (p

  • Leptin Treatment during lactation increases transfer of iodine through the milk.
    The Journal of nutritional biochemistry, 2005
    Co-Authors: Márcia Clements Lins, Magna Cottini Fonseca Passos, Patricia Cristina Lisboa, I. T. Bonomo, Egberto Gaspar De Moura
    Abstract:

    Abstract We have previously shown that protein restriction during lactation is associated with changes in iodine secretion into the milk and that a pup's serum Leptin concentration was increased at the end of lactation. So, here we evaluate whether Leptin Treatment during lactation affects iodine transfer through the milk to the pups. Lactating rats were divided into two groups: the Leptin (Lep) group, single injected with recombinant rat Leptin (8 μg/100g of body weight, daily for 3 consecutive days), and the control (C) group that received the same volume of saline. We studied iodine transfer to the pups through the milk on Days 4, 12 and 21 of lactation. In those days, the dams were separated from their pups for 4 h. Then, the mothers received an injection of 131 I (2.22×10 4 Bq ip) and the pups were allowed to nurse for 2 h. The animals were sacrificed 2 h later. Leptin, total serum T3 and total serum T4 concentrations were higher ( P 131 I on Days 12 (31%) and 21 (128%).

Mark H Vickers - One of the best experts on this subject based on the ideXlab platform.

  • Neonatal Leptin Treatment reverses the bone-suppressive effects of maternal undernutrition in adult rat offspring
    Scientific Reports, 2017
    Co-Authors: Elwyn C. Firth, Greg D. Gamble, Jillian Cornish, Mark H Vickers
    Abstract:

    Alterations in the early life environment, including maternal undernutrition (UN) during pregnancy, can lead to increased risk of metabolic and cardiovascular disorders in offspring. Leptin Treatment of neonates born to UN rats reverses the programmed metabolic phenotype, but the possible benefits of this Treatment on bone tissue have not been defined. We describe for the first time the effects of neonatal Leptin Treatment on bone in adult offspring following maternal UN. Offspring from either UN or ad libitum -fed (AD) rats were treated with either saline or Leptin (2.5 µg/ g.d on postnatal days (D)3–13) and were fed either a chow or high fat (HF) diet from weaning until study completion at D170. Analysis of micro-tomographic data of the left femur showed highly significant effects of UN on cortical and trabecular bone tissue indices, contributing to inferior microstructure and bone strength, almost all of which were reversed by early Leptin life Treatment. The HF fat diet negatively affected trabecular bone tissue, but the effects of only trabecular separation and number were reversed by Leptin Treatment. The negative effects of maternal UN on skeletal health in adult offspring might be prevented or attenuated by various interventions including Leptin. Establishment of a minimal efficacious Leptin dose warrants further study.

  • thrifty metabolic programming in rats is induced by both maternal undernutrition and postnatal Leptin Treatment but masked in the presence of both implications for models of developmental programming
    BMC Genomics, 2014
    Co-Authors: Peter J I Ellis, Mark H Vickers, Peter D Gluckman, Tiffany J Morris, Benjamin M Skinner, Carole A Sargent, Stewart Gilmour, Nabeel A Affara
    Abstract:

    Background Maternal undernutrition leads to an increased risk of metabolic disorders in offspring including obesity and insulin resistance, thought to be due to a programmed thrifty phenotype which is inappropriate for a subsequent richer nutritional environment. In a rat model, both male and female offspring of undernourished mothers are programmed to become obese, however postnatal Leptin Treatment gives discordant results between males and females. Leptin Treatment is able to rescue the adverse programming effects in the female offspring of undernourished mothers, but not in their male offspring. Additionally, in these rats, postnatal Leptin Treatment of offspring from normally-nourished mothers programmes their male offspring to develop obesity in later life, while there is no comparable effect in their female offspring.

  • Thrifty metabolic programming in rats is induced by both maternal undernutrition and postnatal Leptin Treatment, but masked in the presence of both: implications for models of developmental programming
    BMC Genomics, 2014
    Co-Authors: Peter J I Ellis, Mark H Vickers, Peter D Gluckman, Tiffany J Morris, Benjamin M Skinner, Carole A Sargent, Stewart Gilmour, Nabeel A Affara
    Abstract:

    Background Maternal undernutrition leads to an increased risk of metabolic disorders in offspring including obesity and insulin resistance, thought to be due to a programmed thrifty phenotype which is inappropriate for a subsequent richer nutritional environment. In a rat model, both male and female offspring of undernourished mothers are programmed to become obese, however postnatal Leptin Treatment gives discordant results between males and females. Leptin Treatment is able to rescue the adverse programming effects in the female offspring of undernourished mothers, but not in their male offspring. Additionally, in these rats, postnatal Leptin Treatment of offspring from normally-nourished mothers programmes their male offspring to develop obesity in later life, while there is no comparable effect in their female offspring. Results We show by microarray analysis of the female liver transcriptome that both maternal undernutrition and postnatal Leptin Treatment independently induce a similar thrifty transcriptional programme affecting carbohydrate metabolism, amino acid metabolism and oxidative stress genes. Paradoxically, however, the combination of both stimuli restores a more normal transcriptional environment. This demonstrates that “Leptin reversal” is a global phenomenon affecting all genes involved in fetal programming by maternal undernourishment and Leptin Treatment. The thrifty transcriptional programme was associated with pro-inflammatory markers and downregulation of adaptive immune mediators, particularly MHC class I genes, suggesting a deficit in antigen presentation in these offspring. Conclusions We propose a revised model of developmental programming reconciling the male and female observations, in which there are two competing programmes which collectively drive liver transcription. The first element is a thrifty metabolic phenotype induced by early life growth restriction independently of Leptin levels. The second is a homeostatic set point calibrated in response to postnatal Leptin surge, which is able to over-ride the metabolic programme. This “calibration model” for the postnatal Leptin surge, if applicable in humans, may have implications for understanding responses to catch-up growth in infants. Additionally, the identification of an antigen presentation deficit associated with metabolic thriftiness may relate to a previously observed correlation between birth season (a proxy for gestational undernutrition) and infectious disease mortality in rural African communities.

  • the effect of neonatal Leptin Treatment on postnatal weight gain in male rats is dependent on maternal nutritional status during pregnancy
    Endocrinology, 2008
    Co-Authors: Mark H Vickers, A H Coveny, Wayne S Cutfield, Peter D Gluckman, Paul L Hofman, Arieh Gertler, B H Breier, Mark Harris
    Abstract:

    An adverse prenatal environment may induce long-term metabolic consequences, in particular obesity, hyperLeptinemia, insulin resistance, and type 2 diabetes. Although the mechanisms are unclear, this "programming" has generally been considered an irreversible change in developmental trajectory. Adult offspring of rats subjected to undernutrition (UN) during pregnancy develop obesity, hyperinsulinemia, and hyperLeptinemia, especially in the presence of a high-fat diet. Using this model of maternal UN, we have recently shown that neonatal Leptin Treatment in females reverses the postnatal sequelae induced by developmental programming. To examine possible gender-related effects of neonatal Leptin Treatment, the present study investigated the effect of neonatal Leptin Treatment on the metabolic phenotype of adult male offspring. Leptin Treatment (recombinant rat Leptin, 2.5 microg/g.d, sc) from postnatal d 3-13 resulted in a transient slowing of neonatal weight gain, particularly in programmed offspring. Neonatal Leptin Treatment of male offspring from normally nourished mothers caused an increase in diet-induced weight gain and related metabolic sequelae, including hyperinsulinemia and increased total body adiposity compared with saline-treated controls. This occurred without an increase in caloric intake. These effects were specific to offspring of normal pregnancies and were not observed in offspring of mothers after UN during pregnancy. In the latter, neonatal Leptin Treatment conferred protection against the development of the programmed phenotype, particularly in those fed the chow diet postnatally. These data further reinforce the importance of Leptin in determining long-term energy homeostasis, and suggest that Leptin's effects are modulated by gender and both prenatal and postnatal nutritional status.

  • neonatal Leptin Treatment reverses developmental programming
    Endocrinology, 2005
    Co-Authors: Mark H Vickers, Pete D Gluckma, A H Coveny, Paul L Hofma, Wayne S Cutfield, Arieh Gertle, H Eie, Mark Harris
    Abstract:

    An adverse prenatal environment may induce long-term metabolic consequences, in particular obesity and insulin resistance. Although the mechanisms are unclear, this programming has generally been considered an irreversible change in developmental trajectory. Adult offspring of rats subjected to undernutrition during pregnancy develop obesity, hyperinsulinemia, and hyperLeptinemia, especially in the presence of a high-fat diet. Reduced locomotor activity and hyperphagia contribute to the increased fat mass. Using this model of maternal undernutrition, we investigated the effects of neonatal Leptin Treatment on the metabolic phenotype of adult female offspring. Leptin Treatment (rec-rat Leptin, 2.5 μg/g·d, sc) from postnatal d 3–13 resulted in a transient slowing of neonatal weight gain, particularly in programmed offspring, and normalized caloric intake, locomotor activity, body weight, fat mass, and fasting plasma glucose, insulin, and Leptin concentrations in programmed offspring in adult life in contras...

Nabeel A Affara - One of the best experts on this subject based on the ideXlab platform.

  • thrifty metabolic programming in rats is induced by both maternal undernutrition and postnatal Leptin Treatment but masked in the presence of both implications for models of developmental programming
    BMC Genomics, 2014
    Co-Authors: Peter J I Ellis, Mark H Vickers, Peter D Gluckman, Tiffany J Morris, Benjamin M Skinner, Carole A Sargent, Stewart Gilmour, Nabeel A Affara
    Abstract:

    Background Maternal undernutrition leads to an increased risk of metabolic disorders in offspring including obesity and insulin resistance, thought to be due to a programmed thrifty phenotype which is inappropriate for a subsequent richer nutritional environment. In a rat model, both male and female offspring of undernourished mothers are programmed to become obese, however postnatal Leptin Treatment gives discordant results between males and females. Leptin Treatment is able to rescue the adverse programming effects in the female offspring of undernourished mothers, but not in their male offspring. Additionally, in these rats, postnatal Leptin Treatment of offspring from normally-nourished mothers programmes their male offspring to develop obesity in later life, while there is no comparable effect in their female offspring.

  • Thrifty metabolic programming in rats is induced by both maternal undernutrition and postnatal Leptin Treatment, but masked in the presence of both: implications for models of developmental programming
    BMC Genomics, 2014
    Co-Authors: Peter J I Ellis, Mark H Vickers, Peter D Gluckman, Tiffany J Morris, Benjamin M Skinner, Carole A Sargent, Stewart Gilmour, Nabeel A Affara
    Abstract:

    Background Maternal undernutrition leads to an increased risk of metabolic disorders in offspring including obesity and insulin resistance, thought to be due to a programmed thrifty phenotype which is inappropriate for a subsequent richer nutritional environment. In a rat model, both male and female offspring of undernourished mothers are programmed to become obese, however postnatal Leptin Treatment gives discordant results between males and females. Leptin Treatment is able to rescue the adverse programming effects in the female offspring of undernourished mothers, but not in their male offspring. Additionally, in these rats, postnatal Leptin Treatment of offspring from normally-nourished mothers programmes their male offspring to develop obesity in later life, while there is no comparable effect in their female offspring. Results We show by microarray analysis of the female liver transcriptome that both maternal undernutrition and postnatal Leptin Treatment independently induce a similar thrifty transcriptional programme affecting carbohydrate metabolism, amino acid metabolism and oxidative stress genes. Paradoxically, however, the combination of both stimuli restores a more normal transcriptional environment. This demonstrates that “Leptin reversal” is a global phenomenon affecting all genes involved in fetal programming by maternal undernourishment and Leptin Treatment. The thrifty transcriptional programme was associated with pro-inflammatory markers and downregulation of adaptive immune mediators, particularly MHC class I genes, suggesting a deficit in antigen presentation in these offspring. Conclusions We propose a revised model of developmental programming reconciling the male and female observations, in which there are two competing programmes which collectively drive liver transcription. The first element is a thrifty metabolic phenotype induced by early life growth restriction independently of Leptin levels. The second is a homeostatic set point calibrated in response to postnatal Leptin surge, which is able to over-ride the metabolic programme. This “calibration model” for the postnatal Leptin surge, if applicable in humans, may have implications for understanding responses to catch-up growth in infants. Additionally, the identification of an antigen presentation deficit associated with metabolic thriftiness may relate to a previously observed correlation between birth season (a proxy for gestational undernutrition) and infectious disease mortality in rural African communities.